Trial objective: efficacy, safety, and tolerability in early Parkinson's disease

“To evaluate the efficacy, safety, and tolerability of tavapadon in adults with early PD.” (opens the source at this quote in a new tab)
“Can treatment with tavapadon, an oral, once-daily, selective D1/D5 agonist, safely improve motor control for people with early Parkinson disease (<3 years’ disease duration)?” (opens the source at this quote in a new tab)

Objective in the context of the unmet need stated by the investigators

“Therefore, there is a key unmet need for an early PD therapy that improves motor symptoms while reducing the risk of AEs seen with current dopaminergic therapies.” (opens the source at this quote in a new tab)
“The TEMPO-1 trial (Fixed-Dose Trial in Early Parkinson's Disease, NCT04201093) evaluated the efficacy, safety, and tolerability of fixed doses of tavapadon (5 or 15 mg once daily) for treatment of people with early PD.” (opens the source at this quote in a new tab)

Registry statement of purpose

“The purpose of this study is to evaluate the clinical efficacy, safety and pharmacokinetics (PK) of 2 fixed doses of tavapadon and placebo in participants with early PD.” (opens the source at this quote in a new tab)

Sponsor description of the trial objective

“The TEMPO-1 trial evaluated the efficacy, safety and tolerability of two fixed doses (5 mg and 15 mg, once daily) of tavapadon as a monotherapy in adults with early Parkinson's disease.” (opens the source at this quote in a new tab)

Summary: sites, countries, and study period

The primary publication reports that TEMPO-1 was conducted at 102 sites across 12 countries from December 2019 to June 2024, with data analysis completed from July 2024 to May 2025. The registry record for NCT04201093 lists 77 locations in 12 countries (the United States, Bulgaria, Spain, France, Germany, Italy, Israel, Ukraine, Australia, Czechia, Poland, and Canada), 27 of them in the United States. The registry gives an actual study start date of December 13, 2019 and actual primary completion and study completion dates of June 28, 2024. The protocol identifier is CVL-751-PD-001 and the EudraCT number is 2019-002949-38. The protocol names Cerevel Therapeutics as sponsor; the registry now lists AbbVie.

Number of sites, countries, and trial period

“TEMPO-1 was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted at 102 sites across 12 countries between December 2019 and June 2024.” (opens the source at this quote in a new tab)
“Data analysis was completed from July 2024 to May 2025.” (opens the source at this quote in a new tab)

Registry dates and location count

Field	Quoted record
Study start (actual)	“2019-12-13”
Primary completion (actual)	“2024-06-28”
Study completion (actual)	“2024-06-28”
Enrollment (actual)	“529”
Locations	“This study has 77 locations”
Other study identifiers	“CVL-751-PD-001”

Phase 3, double-blind, placebo-controlled, parallel-group design

“TEMPO-1 (NCT04201093) was a prospective, phase 3, multicenter, double-blind, placebo-controlled, parallel-group, 27-week randomized clinical trial conducted at 102 sites across 12 countries (see the trial protocol in Supplement 1 for more details). The trial ran from December 2019 to June 2024, and participation lasted approximately 34 weeks (4-week maximum screening period, 27-week treatment period, 4-week safety follow-up period; eFigure 1 in Supplement 3).” (opens the source at this quote in a new tab)
“Independent ethics committees approved the protocol prior to study initiation; the trial was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonization Good Clinical Practice guidelines, and Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.” (opens the source at this quote in a new tab)

Randomization, stratification, and blinding

“Participants were randomized 1:1:1 to receive 1 of 2 doses of tavapadon (5 or 15 mg once daily) or placebo using a computer-generated randomization scheme, stratified by concomitant use of MAO-B inhibitors. Participants received the study drug corresponding to their sequentially assigned randomization number. Tablets and packaging were identical in appearance.” (opens the source at this quote in a new tab)

Protocol overall design and trial periods

“This is prospective, Phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group, 27-week trial to evaluate the efficacy, safety, tolerability, and PK of 2 fixed doses of tavapadon (5 mg QD and 15 mg QD) in male and female subjects aged 40 to 80 years who have a diagnosis of PD (consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic criteria); a modified Hoehn and Yahr stage of 1, 1.5, or 2; an MDS-UPDRS Part II score ≥2 and a Part III score ≥10; and are not receiving antiparkinsonian medication other than MAO-B inhibitors. The trial will include a Screening Period (maximum of 4 weeks), a 27-week Treatment Period, and a 4-week Safety Follow-up Period (Figure 1). Each subject will participate in the trial for up to approximately 35 weeks.” (opens the source at this quote in a new tab)

Scientific rationale for the placebo-controlled design

“The randomized, double-blind, placebo-controlled, parallel-group trial design is widely accepted as one that minimizes the risk of bias and that is appropriate for evaluating the effects of a trial treatment in indications in which use of a placebo is ethical (US FDA, 2001).” (opens the source at this quote in a new tab)

Registered design

Field	Quoted record
Official title	“A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, 27-Week Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses of Tavapadon in Early Parkinson's Disease (TEMPO-1 TRIAL)”
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Primary purpose	“Treatment”

Option to enter the open-label extension

“Subjects who complete through Week 27 of the trial may have the opportunity to enter an open-label extension trial (Protocol CVL-751-PD-004).” (opens the source at this quote in a new tab)

Design as described in the prescribing information

“The efficacy of JUVMO for the treatment of PD in adults not on concomitant levodopa was established in two 27-week randomized, multicenter, double-blind, placebo-controlled studies, Study 1 (NCT04201093) and Study 2 (NCT04223193).” (opens the prescribing information at this quote)
“Patients that completed the 27-week treatment period had the option to receive JUVMO in a 58-week open-label treatment period.” (opens the prescribing information at this quote)

Age, diagnosis, disease stage, and prior treatment

“Eligible participants included adults aged 40 to 80 years with a diagnosis of PD consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic criteria; a modified Hoehn and Yahr score of 1, 1.5, or 2; disease duration of 3 years or less; and naive to or previously had less than 3 months of treatment with levodopa or DAs.” (opens the source at this quote in a new tab)
“Exclusion criteria included history of essential tremor, atypical or secondary parkinsonian syndromes, any clinically significant medical or psychiatric condition per investigator discretion, cognitive impairment, or abnormal laboratory values during screening.” (opens the source at this quote in a new tab)

Permitted and prohibited Parkinson's disease medications as published

“Prior and concurrent use of monoamine oxidase type B (MAO-B) inhibitors was permitted if initiated less than 90 days before the baseline visit (dosage needed to remain stable for the duration of the trial); all other PD medications were prohibited for the duration of the trial.” (opens the source at this quote in a new tab)

Key inclusion criteria as registered

“Participants with disease duration (from time of diagnosis) of less than (<) 3 years and disease progression in the 3 years before signing the ICF” (opens the source at this quote in a new tab)
“Participants with an MDS-UPDRS Part II score >=2 and Part III score >=10 at the Screening Visit and at the Baseline Visit” (opens the source at this quote in a new tab)
“Participants with early PD who, in the opinion of the investigator, require pharmacologic intervention for disease management” (opens the source at this quote in a new tab)
“Participants who are treatment naïve or have a history of prior incidental treatment with dopaminergic agents (including Levodopa [L-Dopa] and dopamine receptor agonist medications) for <3 months in total but not within 2 months of the Baseline Visit. Prior and concurrent use of monoamine oxidase B (MAO-B) inhibitors is permitted if use was initiated >90 days before the Baseline Visit and the dosage will remain stable for the duration of the trial (i.e, no change in the MAO-B inhibitor dose is permitted during the trial)” (opens the source at this quote in a new tab)

Key exclusion criteria: neuropsychiatric history

“Participants with a history or current diagnosis of a clinically significant impulse control disorder (Disruptive, Impulse Control, and Conduct Disorder per DSM-5).” (opens the source at this quote in a new tab)
“Participants with a history of psychosis or hallucinations within the previous 12 months.” (opens the source at this quote in a new tab)
“Participants with a Montreal Cognitive Assessment (MoCA) score <26” (opens the source at this quote in a new tab)
“Participants with a history of nonresponse or insufficient response to L-Dopa at therapeutic dosages.” (opens the source at this quote in a new tab)

Key exclusion criteria: cardiovascular, renal, and drug interaction criteria

“Participants with clinically significant orthostatic hypotension (eg, syncope)” (opens the source at this quote in a new tab)
“Participants with a 12-lead ECG demonstrating a QTcF interval >450 msec” (opens the source at this quote in a new tab)
“Participants who are currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors (except for topical administration).” (opens the source at this quote in a new tab)
“Participants with moderate or severe renal impairment (creatinine clearance as estimated by Cockcroft-Gault formula <30 mL/min or on dialysis)” (opens the source at this quote in a new tab)

Enrollment criteria summarized in the prescribing information

“diagnosis consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic criteria;” (opens the prescribing information at this quote)
“modified Hoehn and Yahr stage of 1, 1.5, or 2;” (opens the prescribing information at this quote)
“not receiving medications to treat Parkinson’s disease (e.g., levodopa) other than concomitant stable dose of an MAO-B inhibitor.” (opens the prescribing information at this quote)

Fixed-dose titration schedule

“For participants treated with tavapadon, the dose was titrated to the target dose using a fixed titration scheme (see eTable 1 in Supplement 3); participants were withdrawn from the study if they could not achieve the target dose. Both tavapadon groups were titrated to the 5-mg dose by approximately week 6; the 15-mg group achieved the target dose by approximately week 10.” (opens the source at this quote in a new tab)

Protocol treatment period, blinding by tablet count, and dosing days

“The dose of tavapadon will be titrated to either 5 mg QD or 15 mg QD and then maintained for the duration of the 27-week Treatment Period.” (opens the source at this quote in a new tab)
“Subjects will take 3 tablets of investigational medicinal product (IMP), either all tavapadon tablets, all placebo tablets, or a combination of tavapadon and placebo tablets, throughout the trial to maintain the trial blind.” (opens the source at this quote in a new tab)
“Subjects who are randomized to the tavapadon 5 mg QD treatment group will receive this dose from Day 41 until Day 189 (end of Week 27). The dose of tavapadon will continue to be titrated for subjects who are randomized to the tavapadon 15 mg QD treatment group; these subjects will receive 10 mg QD of tavapadon from Day 57 through Day 72 and then 15 mg QD of tavapadon from Day 73 until Day 189 (end of Week 27).” (opens the source at this quote in a new tab)

Registered treatment arms

Arm	Quoted record
Tavapadon 5 mg	“Participants will receive tavapadon tablet titrated up to 5 milligram (mg) once daily (QD) orally for 27 weeks.”
Tavapadon 15 mg	“Participants will receive tavapadon tablet titrated up to 15 milligram (mg) QD orally for 27 weeks.”
Placebo	“Participants will receive placebo matching to tavapadon tablet QD orally for 27 weeks.”

Titration as described in the prescribing information

“In each study, the dose of JUVMO was gradually titrated from 0.25 mg once daily to the target dose, which was then maintained for the remainder of the 27-week treatment period.” (opens the prescribing information at this quote)
“Patients were titrated based on their randomized arm to either 5 mg or 15 mg dose based on the recommended titration schedule” (opens the prescribing information at this quote)

Protocol justification for the 5 mg to 15 mg dose range

“Of the 26 subjects who were randomized to tavapadon and who reached the 6-week maintenance dosing phase, 73% required doses of 5 to 15 mg QD to achieve optimized motor control based on clinical judgement.” (opens the source at this quote in a new tab)
“These data suggest that doses <5 mg QD are unlikely to deliver clinically meaningful benefit over placebo in motor symptom control to most patients with PD.” (opens the source at this quote in a new tab)
“The safety and pharmacokinetic data from this Phase 1 trial suggest that doses >15 mg QD are unlikely to have an optimal risk/benefit profile for patients with PD.” (opens the source at this quote in a new tab)

Primary and key secondary endpoints

“The primary end point was the change from baseline to week 26 (primary efficacy time point) in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II (motor aspects of experiences of daily living) and part III (motor evaluation) combined score. Key secondary end points were the change from baseline to week 26 in the MDS-UPDRS part II score and the percentage of participants who had a Patient Global Impression of Change (PGIC) score of “much improved” or “very much improved” at week 26 (PGIC responders).” (opens the source at this quote in a new tab)

Other secondary, exploratory, and safety endpoints

“Other secondary efficacy end points, assessed at several predefined time points (see eTable 2 in Supplement 3), included change from baseline in the following elements: MDS-UPDRS parts II and III combined score and MDS-UPDRS part II score (other time points beyond week 26), MDS-UPDRS parts I, II, and III combined and individual scores, and Clinician Global Impression–Severity of Illness (CGI-S), CGI-Improvement (CGI-I), and PGIC scores. Other end points included changes from baseline in scores on the 39-item Parkinson Disease Questionnaire, Schwab and England activities of daily living scale, and EuroQol 5-dimension 5-level index and visual analog scale (VAS).” (opens the source at this quote in a new tab)
“Safety end points included AEs, clinical laboratory values, vital signs, electrocardiograms, and scores on the Columbia–Suicide Severity Rating Scale,12 Epworth Sleepiness Scale (ESS),13 and Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease Rating Scale (QUIP-RS).14” (opens the source at this quote in a new tab)

Registered primary outcome measure and score ranges

“The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) rating tool was used to follow longitudinal course of Parkinson's Disease. It was made up of 4 parts: Part 1: Non-motor aspects of experiences of daily living (13 items. Score range: 0-52); Part 2: Motor aspects of experiences of daily living (13 items. Score range: 0-52); Part 3: Motor examination (18 items. Score range: 0-132); Part 4: Motor complications (6 items. Score range: 0-24. Part 4 was not collected in this trial). Each item has 0-4 rating on scale from 0 (normal) to 4 (severe). Higher values represent a worse outcome. A negative change from baseline represents an improvement in motor function. Parts 2 and 3 combined is the sum of Part 2 score and Part 3 score at each assessment time for each participant. The combined score assesses 31 items with score range: 0-184.” (opens the source at this quote in a new tab)

Protocol rationale for the primary and key secondary endpoints

“The MDS-UPDRS is a comprehensive assessment that is designed to monitor the burden and extent of PD across the longitudinal disease course and provides a clinical endpoint in therapy trials (Goetz et al, 2008). The primary endpoint, the change from baseline to endpoint in the MDS-UPDRS Parts II (motor aspects of experiences of daily living) and III (motor examination) combined score represents a clinically applicable outcome measure (Makkos et al, 2018).” (opens the source at this quote in a new tab)
“The key secondary efficacy endpoint of the percentage of responders at endpoint, defined as a score of “much improved” or “very much improved” on the Patient Global Impression of Change (PGIC), is an accepted measure of treatment response and is widely used in clinical trials as a patient-reported measurement of treatment success.” (opens the source at this quote in a new tab)

Validation of the MDS-UPDRS

“The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications.” (opens the source at this quote in a new tab)
“Several questions from Part I and all questions from Part II have been designed to be amenable to a patient/caregiver questionnaire format and therefore can be completed without the investigator’s input.” (opens the source at this quote in a new tab)
“The full MDS-UPDRS contains questions/evaluations (Table 1), divided across Part I (13), Part II (13), Part III (33 scores based on 18 items, several with right, left or other body distribution scores), and Part IV (6).” (opens the source at this quote in a new tab)
“the five-point range for each item was retained, and clinical anchors of normal (0), slight (1), mild (2), moderate (3), and severe (4) were added to provide a consistency across items. Importantly, the MDS-UPDRS places greater emphasis on distinguishing relatively mild impairments and disabilities, drawing distinctions between slight and mild, whereas former distinctions between severe and marked are now collapsed into the severe rating (4). This decision was anchored in the realities that clinical trials are focusing increasingly on early disease, and functional differences between severe and marked impairments from the original scale may not be clinically relevant.” (opens the source at this quote in a new tab)
“The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96).” (opens the source at this quote in a new tab)
“Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.” (opens the source at this quote in a new tab)
“A total of 877 native English-speaking PD patients were examined with the UPDRS and MDS-UPDRS (560 men and 317 women).” (opens the source at this quote in a new tab)
“The mean age of the cohort was 68.2 years (SD: 10.8; range: 31–98), and the mean PD duration was 8.3 years (SD: 6.7; range: 0–40 years).” (opens the source at this quote in a new tab)
“Mean scores (SD) for each part were: Part I: 11.5 (7.0); Part II: 16.0 (10.0); Part III: 36.8 (18.4); Part IV: 4.0 (4.2).” (opens the source at this quote in a new tab)
“The next steps in the MDS-UPDRS program include the non-English translations, testing the MDS-UDPRS for responsivity to change over time, and analysis of questions with DIF.” (opens the source at this quote in a new tab)
“Thus, it is important that temporal stability, sensitivity to change, and interrater reliability be established in the MDS-UPDRS.” (opens the source at this quote in a new tab)

Internal consistency, agreement with the original scale, and score distribution of each MDS-UPDRS part

MDS-UPDRS part	Items	Cronbach's alpha	Correlation with the corresponding UPDRS part (r)	Mean score (SD)	Lowest possible score, % of participants	Highest possible score, % of participants
Part I	“13”	“0.79”	“0.76”	“11.5 (7.0)”	“0.1%”	“0.8%”
Part II	“13”	“0.90”	“0.92”	“16.0 (10.0)”	“0.1%”	“0.7%”
Part III	“33”	“0.93”	“0.96”	“36.8 (18.4)”	“0.1%”	“0.2%”
Part IV	“6”	“0.79”	“0.89”	“4.0 (4.2)”	“36.7%”	“0.1%”

“The MDS-UPDRS showed strong concurrent validity based on high correlations between the two scales (total score r = 0.96), as well as between the individual parts of the two scales:” (opens the source at this quote in a new tab)
“These analyses confirmed that each part assesses a different aspect of PD, with most parts, except Parts I and II, having relatively low correlations (Parts I and II, r = 0.67; Parts I and III, r = 0.43; Parts I and IV, r = 0.39; Parts II and IV, r = 0.44; Parts III and IV, r = 0.22).” (opens the source at this quote in a new tab)

Factor structure of combined parts and the scale developers' reporting recommendation

“Exploratory testing of the combined four parts of the MDS-UPDRS did not identify a single factor structure that could be confirmed (CFI = 0.74).” (opens the source at this quote in a new tab)
“A factor structure combining Parts II and III was explored, but could not be confirmed.” (opens the source at this quote in a new tab)
“As anticipated, Parts II and III that covered patient perceptions of motor function and the objective examination were more highly correlated (r = 0.66).” (opens the source at this quote in a new tab)
“These combined results preclude using a total MDS-UPDRS score or scores based on combinations of parts.” (opens the source at this quote in a new tab)
“In this light, we recommend that each of the parts (I–IV) should be reported separately and not collapsed into a single ‘‘Total MDS-UPDRS’’ summary score.” (opens the source at this quote in a new tab)

Minimal clinically important difference for the Parts II and III combined score

“Briefly, 501 patients fulfilling the UK Brain Bank criteria for Parkinson’s disease (PD) underwent 1,312 sequential examinations” (opens the source at this quote in a new tab)
“Because of the presence of a major neurocognitive disorder, the data of 49 patients were excluded; therefore, the data of 452 patients with 1,113 sequenced examinations were analyzed.” (opens the source at this quote in a new tab)
“Because a correlation coefficient higher than 0.3 between the anchor and the outcome measure is required for detecting MCID,” (opens the source at this quote in a new tab)
“the PGI-I was chosen as an anchor score for the further analyses (Supplementary Data).” (opens the source at this quote in a new tab)
“Because we could build significant ordinal regression models between the evaluated composite scores and the PGI-I (Nagelkerke pseudo-R-square values: 0.316, 0.411, and 0.343 for MDS-UPDRS II+III, MDS-UPDRS I+II+III, and a total score of MDS-UPDRS, respectively; P < 0.05 in all instances), we considered them as clinically applicable outcome measures.” (opens the source at this quote in a new tab)
“The mean change in the composite scores among patients reporting no change on PGI-I (score 4) was negligible, with the effect size varying between 0.02 and 0.05.” (opens the source at this quote in a new tab)
“Based on the ordinal regression modeling, the MDS-UPDRS II+III, MDS-UPDRS I+II+III, and the total score of MDS-UPDRS are clinically applicable outcome measures. Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change.” (opens the source at this quote in a new tab)
“this variable can simultaneously measure the severity of PD (objective motor examination) and the disability associated with it (motor experiences of daily living reported by patients).” (opens the source at this quote in a new tab)
“Consequently, the inventors of the scale unambiguously declared that each part of the MDS-UPDRS should be interpreted individually and the development of composite or total scores is not advised.” (opens the source at this quote in a new tab)
“Although our data support the concept of the usage of various composite scores, we also have to mention that the MCID thresholds for the individual MDS-UPDRS Parts have generally better discriminative abilities than those of the composite scores. Therefore, the analysis of the changes in the individual subscales is advised cardinally unless the clinical situation or the study aims require the utilization of the composite scores.” (opens the source at this quote in a new tab)
“Although we tried to minimize its effects, another issue might be the existence of a possible sampling bias on the correlation between the utilized anchors (PGI-I and CGI-I) and the scores based on PRO and CRO parts.” (opens the source at this quote in a new tab)

Change in composite scores by patient-rated global impression, receiver operating characteristic cutoffs, and thresholds by disease severity

Score and patient-rated global impression of improvement	Paired visits	Mean change	SD	95% CI lower limit	95% CI upper limit	Effect size (Cohen's d)
Parts II+III, a little better	“237”	“−4.9”	“8.3”	“−8.1”	“−2.3”	“0.19”
Parts II+III, the same	“414”	“0.4”	“7.9”	“−0.7”	“1.5”	“0.02”
Parts II+III, a little worse	“208”	“4.2”	“9.2”	“2.2”	“6.4”	“0.22”
Parts I+II+III, a little better	“237”	“−6.7”	“17.5”	“−9.4”	“−3.9”	“0.23”
Parts I+II+III, the same	“414”	“−1.2”	“13.2”	“−4.8”	“−1.6”	“0.04”
Parts I+II+III, a little worse	“208”	“5.2”	“16.4”	“0.7”	“6.7”	“0.19”
Total score, a little better	“237”	“−7.1”	“18.7”	“−10.0”	“−4.2”	“0.25”
Total score, the same	“414”	“−1.7”	“15.2”	“−3.4”	“0.2”	“0.05”
Total score, a little worse	“208”	“6.3”	“17.8”	“3.2”	“8.7”	“0.22”

Score and patient-rated global impression of improvement	Optimal cutoff	Sensitivity	Specificity	Positive likelihood ratio	Negative likelihood ratio
Parts II+III, a little better	“−4.5”	“0.525”	“0.627”	“1.625”	“0.715”
Parts II+III, the same	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable
Parts II+III, a little worse	“4.5”	“0.507”	“0.621”	“1.227”	“0.798”
Parts I+II+III, a little better	“−6.5”	“0.590”	“0.545”	“1.385”	“0.785”
Parts I+II+III, the same	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable
Parts I+II+III, a little worse	“5.5”	“0.502”	“0.671”	“1.379”	“0.884”
Total score, a little better	“−7.5”	“0.528”	“0.642”	“1.499”	“0.726”
Total score, the same	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable
Total score, a little worse	“6.5”	“0.502”	“0.698”	“1.463”	“0.799”

Score and patient-rated global impression of improvement	Mild (Hoehn and Yahr stage 1 and 2)	Moderate (Hoehn and Yahr stage 3)	Severe (Hoehn and Yahr stage 4 and 5)	Overall (Hoehn and Yahr stage 1 to 5)
Parts II+III, a little better	“−4.3”	“−4.7”	“−5.2”	“−4.9”
Parts II+III, the same	“0.3”	“0.4”	“0.6”	“0.4”
Parts II+III, a little worse	“3.9”	“4.1”	“4.7”	“4.2”
Parts I+II+III, a little better	“−5.9”	“−6.4”	“−7.2”	“−6.7”
Parts I+II+III, the same	“−0.8”	“−1.2”	“−1.3”	“−1.2”
Parts I+II+III, a little worse	“3.7”	“4.1”	“4.9”	“4.2”
Total score, a little better	“−6.1”	“−6.9”	“−7.9”	“−7.1”
Total score, the same	“−1.1”	“−1.6”	“−1.9”	“−1.7”
Total score, a little worse	“5.3”	“6.5”	“7.1”	“6.3”

Minimal clinically important difference for Part III

“In this study 306 patients fulfilling the UK Brain Bank criteria for PD were enrolled between 2012 and May, 2015.” (opens the source at this quote in a new tab)
“After recording medication levels and changes, the nurse practitioners assessed the MDS-UPDRS and HYS at each visit along with a modified Clinical Global Impression-Improvement (CGI-I) scale at all follow-up visits.” (opens the source at this quote in a new tab)
“Assessments of MDS-UPDRS ME were scheduled on the same part of the day to ensure “true” ON condition.” (opens the source at this quote in a new tab)
“Therefore, 728 paired follow-up visits of 260 patients were utilized for the analyses.” (opens the source at this quote in a new tab)
“The Spearman correlation coefficient assessing the correlation between the CGI-I and the change in MDS-UPDRS ME was 0.706 (p < 0.001).” (opens the source at this quote in a new tab)
“The mean change in MDS-UPDRS ME for CGI-I scores of 4 (no change, n = 270 paired visits) was 0.38 (effect size d = 0.02) and varied slightly by PD severity (mild = 0.29; moderate = 0.38; severe = 0.65).” (opens the source at this quote in a new tab)
“The mean MDS-UPDRS ME change for CGI-I scores of 3 (minimal clinically pertinent improvement, n = 138 paired visits) was −3.25 with the effect size of 0.23 and varied slightly across PD severity, being highest in HYS 4&5 patients (mild = −3.67; moderate = −2.94; severe = −2.91).” (opens the source at this quote in a new tab)
“was +4.63 with the effect size of 0.27 and varied slightly across PD severity being highest in HYS 1&2 patients (mild = 4.86; moderate = 4.80; severe = 3.93).” (opens the source at this quote in a new tab)
“When number of return visits was included as a covariate, the MDS-UPDRS ME change scores for no change, minimal improvement and minimal decline did not appreciably change (0.39, −3.29 and 4.67 respectively).” (opens the source at this quote in a new tab)
“Based on the ROC analysis, the best cut-off values discriminating no change from minimal clinical improvement and no change from minimal clinical worsening were −3.5 and +4.5, respectively (Table 3).” (opens the source at this quote in a new tab)
“The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening.” (opens the source at this quote in a new tab)
“Because both anchor-based analyses gave similar results, we considered 3.25 points improvement and 4.63 points worsening as the most appropriate MICD values for MDS-UPDRS.” (opens the source at this quote in a new tab)
“Based on these data, we can conclude that our MCID estimates for MDS-UPDRS are mostly in the range of previously published estimates for UPDRS and MDS-UPDRS.” (opens the source at this quote in a new tab)

Baseline characteristics of the Part III threshold derivation cohort

Characteristic	Mean or count	SD or percentage
Age, mean (SD)	“64.4”	“9.2”
Disease duration, mean (SD)	“9.2”	“6.1”
Male, No. (%)	“161”	“61.9%”
Female, No. (%)	“99”	“38.1%”
Mild (Hoehn and Yahr stage 1 and 2), No. (%)	“155”	“59.6%”
Moderate (Hoehn and Yahr stage 3), No. (%)	“70”	“26.9%”
Severe (Hoehn and Yahr stage 4 and 5), No. (%)	“35”	“13.5%”
MDS-UPDRS Part I, mean (SD)	“15.5”	“7.1”
MDS-UPDRS Part II, mean (SD)	“17.0”	“8.6”
MDS-UPDRS Part III, mean (SD)	“40.7”	“14.8”
MDS-UPDRS Part IV, mean (SD)	“5.6”	“3.8”
Levodopa equivalent dosage at baseline, mean (SD)	“787.5”	“579.7”

Change in Part III score by clinician-rated global impression, and receiver operating characteristic cutoffs

Clinician-rated global impression of improvement	Paired visits	Mean change	95% CI lower limit	95% CI upper limit	Effect size (Cohen's d)
3, minimal clinically pertinent improvement	“138”	“−3.25”	“−4.32”	“−2.17”	“0.23”
4, no change	“270”	“0.38”	“−0.24”	“0.99”	“0.02”
5, minimal clinically pertinent worsening	“108”	“4.63”	“3.52”	“5.73”	“0.27”

Clinician-rated global impression of improvement	Optimal cutoff	Sensitivity	Specificity	Positive likelihood ratio	Negative likelihood ratio	Area under the curve
3, minimal clinically pertinent improvement	“−3.5”	“0.94”	“0.70”	“3.08”	“0.09”	“0.81”
4, no change	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable
5, minimal clinically pertinent worsening	“4.5”	“0.78”	“0.95”	“15.00”	“0.23”	“0.90”

Severity group counts that differ between the results text and table 1

“The final dataset included all severity ranges (HYS 1&2 Mild = 110, HYS 3 Moderate = 85 and HYS 4&5 Severe = 65).” (opens the source at this quote in a new tab)

Table 1 characteristic	Count	Percentage
Severity of PD, mild (Hoehn and Yahr stage 1 and 2)	“155”	“59.6%”
Severity of PD, moderate (Hoehn and Yahr stage 3)	“70”	“26.9%”
Severity of PD, severe (Hoehn and Yahr stage 4 and 5)	“35”	“13.5%”
Neurocognitive disorder, normal	“110”	“42.3%”
Neurocognitive disorder, mild	“85”	“32.7%”
Neurocognitive disorder, major	“65”	“25.0%”

Minimal clinically important differences for Parts I and II

“Nine hundred eighty-five paired investigations of 365 patients were reviewed, implementing three different techniques simultaneously.” (opens the source at this quote in a new tab)
“During each office visit, patients were asked to express how their perceived difficulties changed, assessed by the Patient-rated Global Impression of Improvement scale (PGI-I).” (opens the source at this quote in a new tab)
“Because of the presence of a major neurocognitive disorder, the data of 40 patients were excluded.” (opens the source at this quote in a new tab)
“In considering the 985 paired investigations, the data of 656 pairs were utilized for MCID calculations (Table 1).” (opens the source at this quote in a new tab)
“Any improvement greater than 2.64 points or any worsening more than 2.45 points on MDS-UPDRS Part I represent a minimal, yet clinically meaningful change.” (opens the source at this quote in a new tab)
“In reference to Part II, the smallest changes considered clinically relevant were 3.05 and 2.51 points for improvement and deterioration, respectively.” (opens the source at this quote in a new tab)
“The mean change in Part II for PGI-I scores of 4 (the same) was 0.25 (effect size: d = 0.03) and varied slightly by PD severity (mild = 0.16; moderate = 0.41; severe = 0.58).” (opens the source at this quote in a new tab)
“The mean Part II change for PGI-I scores of 3 (minimal improvement) was –3.05 with the effect size of 0.26 and varied slightly across PD severity (mild = –3.18; moderate = –2.46; severe = –2.90).” (opens the source at this quote in a new tab)
“The mean change for PGI-I scores of 5 (minimal decline) was + 2.51 with the effect size of 0.17 and varied slightly across PD severity (mild = 2.38; moderate = 2.98; severe = 2.89).” (opens the source at this quote in a new tab)
“Given that our MICD estimates varied only slightly across PD severity, they can be utilized in clinical practice for judging overall changes.” (opens the source at this quote in a new tab)

Change in Parts I and II scores by patient-rated global impression, and receiver operating characteristic cutoffs

Score and patient-rated global impression of improvement	Paired visits	Mean change	SD	95% CI lower limit	95% CI upper limit	Effect size (Cohen's d)
Part I, a little better	“177”	“−2.64”	“5.32”	“−3.43”	“−1.84”	“0.23”
Part I, the same	“309”	“0.23”	“5.54”	“−0.39”	“0.85”	“0.04”
Part I, a little worse	“170”	“2.45”	“6.18”	“1.41”	“3.29”	“0.19”
Part II, a little better	“177”	“−3.05”	“5.81”	“−3.91”	“−2.19”	“0.26”
Part II, the same	“309”	“0.25”	“6.35”	“−0.46”	“0.96”	“0.03”
Part II, a little worse	“170”	“2.51”	“7.20”	“1.42”	“3.60”	“0.17”
Parts I and II, a little better	“177”	“−5.73”	“9.29”	“−7.11”	“−4.35”	“0.25”
Parts I and II, the same	“309”	“0.49”	“10.38”	“−0.68”	“1.65”	“0.04”
Parts I and II, a little worse	“170”	“4.70”	“11.86”	“2.90”	“6.50”	“0.19”

Score and patient-rated global impression of improvement	Optimal cutoff	Sensitivity	Specificity	Positive likelihood ratio	Negative likelihood ratio
Part I, a little better	“−2.5”	“0.574”	“0.619”	“1.506”	“0.689”
Part I, the same	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable
Part I, a little worse	“2.5”	“0.568”	“0.531”	“1.211”	“0.814”
Part II, a little better	“−2.5”	“0.514”	“0.646”	“1.453”	“0.752”
Part II, the same	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable
Part II, a little worse	“2.5”	“0.512”	“0.601”	“1.159”	“0.874”
Parts I and II, a little better	“−5.5”	“0.642”	“0.694”	“1.774”	“0.605”
Parts I and II, the same	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable
Parts I and II, a little worse	“4.5”	“0.667”	“0.632”	“1.270”	“0.843”

Investigators' interpretation of the observed change against the threshold

“Once-daily dosing with tavapadon, 5 mg or 15 mg, led to reductions from baseline of MDS-UPDRS parts II and III combined scores at week 26 (−9.7 and −10.2 points with 5-mg and 15-mg doses of tavapadon, respectively) that were approximately twice as large as the minimum clinically important difference (>4.9-point improvement) in MDS-UPDRS parts II and III combined scores seen in other studies.” (opens the source at this quote in a new tab)

Endpoint on which the prescribing information bases efficacy

“Efficacy was determined based on the change from baseline in the MDS-UPDRS Part II score at Week 26. The MDS-UPDRS Part II contains 13 questions related to activities of daily living, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. A reduction in the score represents improvement, and a beneficial change from baseline appears as a negative number.” (opens the prescribing information at this quote)

Planned sample size and power

“A sample size of 174 participants per group was determined to provide at least 90% power to detect a 4-point treatment difference in the primary outcome measure (2-sided significance level of 0.05; assumed SD of 9 points; 27% dropout rate).” (opens the source at this quote in a new tab)

Planned randomization total in the protocol

“A total of 522 subjects are planned to be randomized in a 1:1:1 ratio to the tavapadon 5mg QD, tavapadon 15 mg QD, or placebo QD treatment group.” (opens the source at this quote in a new tab)
“In the event of higher than anticipated early terminations due to COVID-19 or other reasons, Cerevel may extend enrollment in order to maintain the planned statistical power.” (opens the source at this quote in a new tab)

Participants screened, randomized, and analyzed

“Of 751 screened individuals, 529 were randomized to 5 mg of tavapadon (n = 177), 15 mg of tavapadon (n = 177), or placebo (n = 175); all 529 participants met criteria for the safety population, and 520 met criteria for the mITT population (Figure 1).” (opens the source at this quote in a new tab)

Participants analyzed at week 26 in the registry results

Analysis	Placebo	Tavapadon 5 mg	Tavapadon 15 mg
Primary endpoint, participants analyzed at week 26	“148”	“132”	“116”

Efficacy and safety populations

“Efficacy analyses were performed using a modified intent-to-treat (mITT) population (ie, randomized participants who received ≥1 dose of study treatment and had baseline and ≥1 postbaseline MDS-UPDRS assessment).” (opens the source at this quote in a new tab)
“The safety population included all participants who received 1 or more doses of the study drug.” (opens the source at this quote in a new tab)

Hierarchical testing and mixed model for repeated measures

“Primary and key secondary end points were assessed for each of the 2 tavapadon dose groups vs placebo using a hierarchical testing procedure, with comparisons between the 15-mg tavapadon group vs placebo on the primary end point followed by comparison between the 5-mg tavapadon group vs placebo on the primary end point; analysis of key secondary end points followed the same hierarchical test order for MDS-UPDRS part II scores, followed by the PGIC response rate. A mixed model for repeated measures (MMRM) approach was used for analyses of MDS-UPDRS parts II and III combined scores and MDS-UPDRS part II scores, including fixed effects of treatment, visits, interaction between treatment and visit, and concomitant use of MAO-B inhibitors, with baseline scores included as a covariate and participant as a random effect.” (opens the source at this quote in a new tab)
“The proportion of PGIC responders from each postbaseline visit (repeated measures) was analyzed using a generalized linear mixed model with logit link, with the same model specifications as the MMRM previously described.” (opens the source at this quote in a new tab)

Protocol definitions of analysis populations

Population	Description	Analysis
ITT	“All randomized subjects”	“Demographic and Baseline Characteristics”
FAS	“All randomized subjects who receive at least 1 dose of IMP. This will be the safety analysis set.”	“Safety analysis”
mITT	“All randomized subjects who receive at least 1 dose of IMP and have both a baseline and at least 1 postbaseline MDS-UPDRS assessment”	“Primary analysis set for efficacy”
Endpoint completers	“All subjects in the mITT population who have an MDS-UPDRS assessment at baseline and endpoint”	“Sensitivity analysis for efficacy”

Handling of missing data in the primary analysis

“The missing values, including missing due to missed visits or early termination due to COVID-19 control measures, are assumed to be missing at random (MAR) in the main MMRM analysis. Sensitivity analyses will be performed to assess the impact of deviation from MAR assumptions on the analysis results.” (opens the source at this quote in a new tab)

Discontinuation by treatment group

“In total, 129 participants (24.4%) discontinued the trial: 43 (24.3%), 59 (33.3%), and 27 (15.4%) in the tavapadon, 5 mg, tavapadon, 15 mg, and placebo groups, respectively. The most common reasons for discontinuation were AEs and withdrawal by the participant (Figure 1).” (opens the source at this quote in a new tab)

Registry participant flow

Milestone or reason	Placebo	Tavapadon 5 mg	Tavapadon 15 mg
Started	“175”	“177”	“177”
Completed	“148”	“134”	“118”
Not completed	“27”	“43”	“59”
Adverse event	“6”	“29”	“35”
Death	“2”	“1”	“0”
Lack of efficacy	“5”	“1”	“2”
Site terminated by sponsor	“5”	“3”	“1”
Withdrawal by subject	“7”	“8”	“15”

Discontinuation due to adverse events and its timing

“AEs led to treatment discontinuation in 7 participants (4.0%) in the placebo group and 64 participants (18.1%) in the tavapadon groups; the risk of discontinuation decreased after the titration phase.” (opens the source at this quote in a new tab)

Demographic and disease characteristics of the randomized population

“Mean (SD) age was 63.7 (9.6) years, and 187 participants (35.3%) were female.” (opens the source at this quote in a new tab)
“Demographics and baseline disease characteristics were similar across groups and expected for a population with early PD (Table 1). The mean (SD) duration since diagnosis was 0.73 (0.80) years, mean (SD) baseline MDS-UPDRS parts II and III combined score was 31.8 (10.8), and 137 participants (25.9%) had concomitant use of MAO-B inhibitors.” (opens the source at this quote in a new tab)

Baseline characteristics by treatment group

Characteristic	Placebo (n = 175)	Tavapadon 5 mg (n = 177)	Tavapadon 15 mg (n = 177)	Overall (N = 529)
Age, mean (SD), y	“63.5 (9.6)”	“63.7 (9.8)”	“63.8 (9.4)”	“63.7 (9.6)”
Age ≥65 y, No. (%)	“89 (50.9)”	“92 (52.0)”	“94 (53.1)”	“275 (52.0)”
Age ≥75 y, No. (%)	“22 (12.6)”	“27 (15.3)”	“22 (12.4)”	“71 (13.4)”
Female, No. (%)	“63 (36.0)”	“66 (37.3)”	“58 (32.8)”	“187 (35.3)”
Male, No. (%)	“112 (64.0)”	“111 (62.7)”	“119 (67.2)”	“342 (64.7)”
Black, No. (%)	“3 (1.7)”	“0”	“2 (1.1)”	“5 (0.9)”
White, No. (%)	“168 (96.0)”	“174 (98.3)”	“172 (97.2)”	“514 (97.2)”
Years since initial diagnosis, mean (SD)	“0.69 (0.77)”	“0.75 (0.84)”	“0.76 (0.80)”	“0.73 (0.80)”
Modified Hoehn and Yahr stage 1, No. (%)	“23 (13.1)”	“33 (18.6)”	“36 (20.3)”	“92 (17.4)”
Modified Hoehn and Yahr stage 1.5, No. (%)	“23 (13.1)”	“29 (16.4)”	“14 (7.9)”	“66 (12.5)”
Modified Hoehn and Yahr stage 2, No. (%)	“129 (73.7)”	“115 (65.0)”	“127 (71.8)”	“371 (70.1)”
MDS-UPDRS Part I, mean (SD)	“5.2 (3.3)”	“5.1 (3.8)”	“4.8 (3.8)”	“5.0 (3.7)”
MDS-UPDRS Part II, mean (SD)	“7.4 (3.8)”	“7.1 (4.0)”	“7.7 (4.2)”	“7.4 (4.0)”
MDS-UPDRS Part III, mean (SD)	“24.7 (8.1)”	“24.1 (8.6)”	“24.3 (9.1)”	“24.4 (8.6)”
MDS-UPDRS Parts II + III, mean (SD)	“32.0 (10.0)”	“31.3 (10.9)”	“32.1 (11.6)”	“31.8 (10.8)”
CGI-S score, mean (SD)	“3.0 (0.7)”	“3.0 (0.6)”	“3.1 (0.7)”	“3.0 (0.7)”
MAO-B inhibitor use, No. (%)	“42 (24.0)”	“47 (26.6)”	“48 (27.1)”	“137 (25.9)”

Baseline demographics in the prescribing information

“Patients had a mean age of 63.7 years (range: 40 to 80 years), 65% were male, 97% were White, and 6% were Hispanic. The mean duration of PD at baseline was 0.8 years (range: 0 to 3 years). The mean MDS-UPDRS Part II score at baseline was 7.4 and was similar across treatment groups.” (opens the prescribing information at this quote)

Primary endpoint: MDS-UPDRS Parts II and III combined score at week 26

“The change from baseline to week 26 in the MDS-UPDRS parts II and III combined score was significantly improved in both the 5-mg tavapadon group (least-squares mean [LSM] decrease of 9.7 points vs increase of 1.8 points with placebo; LSM treatment difference, −11.5; 95% CI, −13.8 to −9.2; P < .001; d = 1.14) and 15-mg tavapadon group (LSM decrease of 10.2 points vs increase of 1.8 points with placebo; LSM treatment difference, −12.1; 95% CI, −14.4 to −9.8; P < .001; d = 1.20). Improvements in MDS-UPDRS parts II and III combined scores in tavapadon-treated vs placebo-treated participants were observed as early as week 5 and continued through the end of treatment (Figure 2A).” (opens the source at this quote in a new tab)

Key secondary endpoints: MDS-UPDRS Part II and PGIC responders

“Treatment with tavapadon significantly improved MDS-UPDRS part II scores from baseline to week 26 compared with placebo (LSM decrease of 1.6 points with 5-mg tavapadon vs increase of 0.9 points with placebo; LSM treatment difference, −2.5; 95% CI, −3.3 to −1.7; P < .001; d = 0.68; LSM decrease of 1.7 points with 15-mg tavapadon vs increase of 0.9 points with placebo; LSM treatment difference, −2.6; 95% CI, −3.4 to −1.7; P < .001; d = 0.70).” (opens the source at this quote in a new tab)
“Compared with placebo, the proportion of PGIC responders at week 26 was higher with 5-mg tavapadon (45.5% vs 12.2%; odds ratio, 6.15; 95% CI, 3.34-11.32; P < .001) and 15-mg tavapadon (44.4% vs 12.2%; odds ratio, 5.97; 95% CI, 3.22-11.06; P < .001).” (opens the source at this quote in a new tab)
“Any improvement on the PGIC at week 26 was observed in 73.5%, 72.6%, and 31.3% of the 5-mg tavapadon, 15-mg tavapadon, and placebo groups, respectively.” (opens the source at this quote in a new tab)

Registry results for the primary and key secondary endpoints

Outcome at week 26	Placebo	Tavapadon 5 mg	Tavapadon 15 mg
MDS-UPDRS Parts II and III, LSM change (SE)	“1.8 (0.82)”	“-9.7 (0.86)”	“-10.2 (0.88)”
MDS-UPDRS Part II, LSM change (SE)	“0.9 (0.30)”	“-1.6 (0.31)”	“-1.7 (0.32)”
PGIC much or very much improved, participants analyzed	“147”	“132”	“117”
PGIC much or very much improved, count (%)	“18”( “12.2%”)	“60”( “45.5%”)	“52”( “44.4%”)

Secondary efficacy outcomes at week 26

Outcome	Placebo, week 26 (n = 174)	Tavapadon 5 mg, week 26 (n = 174)	Tavapadon 5 mg, treatment difference	Tavapadon 5 mg, P value	Tavapadon 15 mg, week 26 (n = 172)	Tavapadon 15 mg, treatment difference	Tavapadon 15 mg, P value
MDS-UPDRS Part I, LSM change (95% CI)	“0.5 (0.0 to 1.0)”	“0.2 (−0.3 to 0.8)”	“−0.3 (−1.0 to 0.5)”	“.48”	“0.4 (−0.2 to 1.0)”	“−0.1 (−0.9 to 0.6)”	“.77”
MDS-UPDRS Part III, LSM change (95% CI)	“0.9 (−0.4 to 2.1)”	“−8.1 (−9.4 to −6.9)”	“−9.0 (−10.8 to −7.3)”	“<.001”	“−8.5 (−9.9 to −7.2)”	“−9.4 (−11.2 to −7.6)”	“<.001”
MDS-UPDRS Parts I + II + III, LSM change (95% CI)	“2.3 (0.5 to 4.2)”	“−9.4 (−11.4 to −7.4)”	“−11.7 (−14.4 to −9.1)”	“<.001”	“−9.7 (−11.7 to −7.7)”	“−12.0 (−14.7 to −9.3)”	“<.001”
CGI-I mean score, LSM (95% CI)	“3.9 (3.8 to 4.1)”	“2.8 (2.7 to 3.0)”	“−1.1 (−1.4 to −0.9)”	“<.001”	“3.0 (2.8 to 3.1)”	“−1.0 (−1.2 to −0.7)”	“<.001”
CGI-I minimally improved or better, %	“31.76”	“74.24”	Not applicable	Not applicable	“68.38”	Not applicable	Not applicable
PGIC mean score, LSM (95% CI)	“4.0 (3.8 to 4.2)”	“2.8 (2.6 to 3.0)”	“−1.2 (−1.4 to −0.9)”	“<.001”	“2.8 (2.6 to 3.0)”	“−1.2 (−1.5 to −0.9)”	“<.001”

Change in MDS-UPDRS Part II in the prescribing information

MDS-UPDRS Part II	Juvmo 5 mg (N = 174)	Juvmo 15 mg (N = 172)	Placebo (N = 174)
Baseline (SD)	“7.1 (4.00)”	“7.7 (4.26)”	“7.4 (3.83)”
LS mean change (SE) from baseline to week 26	“-1.6 (0.31)”	“-1.7 (0.32)”	“0.9 (0.30)”
LSMD vs placebo (95% CI)	“-2.5 (-3.3, -1.7)”	“-2.6 (-3.4, -1.7)”	Not applicable
p-value	“<0.0001”	“<0.0001”	Not applicable

Onset of effect, dose comparison, and subgroup consistency

“Nominal improvements in MDS-UPDRS parts II and III combined scores and MDS-UPDRS part II individual scores were observed as early as week 5, before the end of the titration period (tavapadon dose, 3 mg), with continued separation from the placebo group through approximately week 11. Improvements vs placebo were sustained through the end of study.” (opens the source at this quote in a new tab)
“In addition to the consistent efficacy outcomes in the overall tavapadon group, subgroup analyses of participants treated with both 5-mg and 15-mg doses of tavapadon demonstrated motor improvement across predefined subgroups, although greatest consistency in improvements was seen in the 15-mg group, which suggests a higher dose of tavapadon may be necessary for specific populations.” (opens the source at this quote in a new tab)

Topline results announced by the sponsor

“The trial met its primary endpoint – patients treated with tavapadon in both dose groups experienced a statistically significant reduction (improvement) from baseline compared to placebo (placebo: +1.8; 5 mg: -9.7; 15 mg: -10.2; p-value <0.0001 each dose versus placebo) in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III combined score at week 26.” (opens the source at this quote in a new tab)

Pooled effect estimate for early-stage monotherapy

“In early-stage monotherapy, tavapadon improved the combined MDS-UPDRS Parts II and III score by 10.55 points versus placebo (95% CI − 13.11 to − 7.99; two trials).” (opens the source at this quote in a new tab)
“With the two TEMPO-1 dose arms combined into a single active group (n = 248) using the arm-level least-squares means and standard errors reported in the trial results posting, that trial yielded a mean difference of − 11.73 points (95% CI − 13.74 to − 9.72) against its full placebo arm (n = 148).” (opens the source at this quote in a new tab)
“Between-study heterogeneity was moderate but not statistically significant (I² = 59.4%, τ² = 2.05, Q(1) = 2.46, p = 0.117), and with two trials the I² estimate is imprecise. A fixed-effect model gave a closely similar estimate of − 10.75 (95% CI − 12.34 to − 9.16).” (opens the source at this quote in a new tab)

Health-related quality of life and activities of daily living outcomes at week 26

Outcome	Placebo, week 26 (n = 174)	Tavapadon 5 mg, week 26 (n = 174)	Tavapadon 5 mg, treatment difference	Tavapadon 5 mg, P value	Tavapadon 15 mg, week 26 (n = 172)	Tavapadon 15 mg, treatment difference	Tavapadon 15 mg, P value
PDQ-39, LSM change (95% CI)	“0.09 (−1.18 to 1.36)”	“−0.92 (−2.25 to −0.42)”	“−1.00 (−2.78 to 0.77)”	“.27”	“0.22 (−1.18 to 1.62)”	“0.13 (−1.70 to 1.96)”	“.89”
Schwab and England ADL, LSM change (95% CI)	“−0.8 (−1.9 to 0.4)”	“1.6 (0.4 to 2.7)”	“2.3 (0.7 to 3.9)”	“.004”	“1.5 (0.3 to 2.7)”	“2.2 (0.6 to 3.8)”	“.006”
EQ-5D-5L index, LSM change (95% CI)	“−0.0223 (−0.0379 to −0.0068)”	“0.0157 (−0.0007 to −0.0320)”	“0.038 (0.0162 to 0.0598)”	“.001”	“0.0058 (−0.0113 to 0.0228)”	“0.0281 (0.0057 to 0.0506)”	“.01”
EQ-5D-5L VAS, LSM change (95% CI)	“−2.5 (−4.6 to −0.5)”	“−0.6 (−2.8 to 1.5)”	“1.9 (−1.0 to 4.8)”	“.20”	“−1.7 (−4.0 to 0.5)”	“0.8 (−2.2 to 3.8)”	“.60”
PGIC minimally improved or better, %	“31.3”	“73.5”	Not applicable	Not applicable	“72.6”	Not applicable	Not applicable

Investigators' interpretation of patient global impression results

“Finally, the proportion of PGIC responders was significantly higher in the tavapadon groups compared with the placebo group at week 26, suggesting that treatment benefits were meaningful to patients.” (opens the source at this quote in a new tab)
“Similarly, a significantly greater proportion of PGIC responders in the tavapadon groups relative to placebo was first observed at week 5; the proportion of responders in the tavapadon groups reached a plateau at week 14 in the 5-mg group and week 18 in the 15-mg group.” (opens the source at this quote in a new tab)

Summary of adverse events in the safety analysis set

Safety outcome, No. (%)	Placebo (n = 175)	Tavapadon 5 mg (n = 177)	Tavapadon 15 mg (n = 177)	All tavapadon (n = 354)
Any AE	“100 (57.1)”	“142 (80.2)”	“139 (78.5)”	“281 (79.4)”
Mild	“55 (31.4)”	“73 (41.2)”	“54 (30.5)”	“127 (35.9)”
Moderate	“34 (19.4)”	“62 (35.0)”	“68 (38.4)”	“130 (36.7)”
Severe	“11 (6.3)”	“7 (4.0)”	“17 (9.6)”	“24 (6.8)”
AE related to study drug	“34 (19.4)”	“90 (50.8)”	“99 (55.9)”	“189 (53.4)”
Serious AEs	“11 (6.3)”	“4 (2.3)”	“10 (5.6)”	“14 (4.0)”
AE leading to discontinuation	“7 (4.0)”	“29 (16.4)”	“35 (19.8)”	“64 (18.1)”
Discontinuation due to nausea	“0”	“11 (6.2)”	“9 (5.1)”	“20 (5.6)”
Discontinuation due to dizziness	“1 (0.6)”	“6 (3.4)”	“3 (1.7)”	“9 (2.5)”
Discontinuation due to headache	“0”	“2 (1.1)”	“6 (3.4)”	“8 (2.3)”
Death	“2 (1.1)”	“1 (0.6)”	“0”	“1 (0.3)”
Nausea	“3 (1.7)”	“42 (23.7)”	“48 (27.1)”	“90 (25.4)”
Headache	“9 (5.1)”	“22 (12.4)”	“37 (20.9)”	“59 (16.7)”
Dizziness	“8 (4.6)”	“24 (13.6)”	“21 (11.9)”	“45 (12.7)”
Dysgeusia	“0”	“14 (7.9)”	“14 (7.9)”	“28 (7.9)”
Fatigue	“6 (3.4)”	“10 (5.6)”	“16 (9.0)”	“26 (7.3)”
Vomiting	“1 (0.6)”	“12 (6.8)”	“9 (5.1)”	“21 (5.9)”
Dry mouth	“0”	“11 (6.2)”	“9 (5.1)”	“20 (5.6)”
Anxiety	“5 (2.9)”	“10 (5.6)”	“9 (5.1)”	“19 (5.4)”
Orthostatic hypotension (safety topic of interest)	“2 (1.1)”	“15 (8.5)”	“8 (4.5)”	“23 (6.5)”
Hypotension (safety topic of interest)	“4 (2.3)”	“7 (4.0)”	“9 (5.1)”	“16 (4.5)”
Hallucination (safety topic of interest)	“0”	“0”	“11 (6.2)”	“11 (3.1)”
Somnolence (safety topic of interest)	“6 (3.4)”	“6 (3.4)”	“5 (2.8)”	“11 (3.1)”
Impulse control disorders (safety topic of interest)	“0”	“2 (1.1)”	“1 (0.6)”	“3 (0.8)”

Overall adverse events, discontinuations, serious adverse events, and deaths

“In the safety population, 100 participants (57.1%) in the placebo group and 281 participants (79.4%) in the tavapadon groups experienced 1 or more AEs (Table 3); rates of AEs were similar in the 5-mg and 15-mg tavapadon groups. AEs led to treatment discontinuation in 7 participants (4.0%) in the placebo group and 64 participants (18.1%) in the tavapadon groups; the risk of discontinuation decreased after the titration phase. Most AEs were nonserious and mild to moderate in severity. Rates of serious AEs were low overall, with lower rates in the tavapadon groups compared to the placebo group. Two deaths occurred in the placebo group due to COVID-19 infection, and 1 death occurred in the 5-mg tavapadon group due to an unknown cause; no deaths were considered by the investigator to be related to the study drug.” (opens the source at this quote in a new tab)

Adverse events by study phase

“The most common AEs observed more frequently in the tavapadon vs placebo groups were nausea, headache, and dizziness (Table 3). Common AEs (>5% incidence) occurred less frequently during the maintenance phase relative to titration, except for dysgeusia in the 15-mg tavapadon group, which was higher during the maintenance phase (see eTable 3 in Supplement 3, which reports select AEs by study phase).” (opens the source at this quote in a new tab)

Somnolence and Epworth Sleepiness Scale

“Incidence of somnolence was similar across tavapadon and placebo groups (Table 3). Mean changes from baseline to week 27 in ESS scores were comparable between placebo and tavapadon groups (LSM change from baseline: placebo, −0.4; 5-mg tavapadon, −0.7; LSM treatment difference, −0.2; 95% CI, −0.9 to 0.4; P = .44; 15-mg tavapadon, −0.4; LSM treatment difference, 0.0; 95% CI, −0.6 to 0.7; P = .91).” (opens the source at this quote in a new tab)

Impulse control disorders and QUIP-RS scores

“Overall, 3 tavapadon-treated participants experienced AEs suggestive of ICDs (Table 3). All events occurred during the maintenance phase and were nonserious and mild or moderate in severity; 1 event led to treatment discontinuation and 1 event was unresolved at the end of the study.” (opens the source at this quote in a new tab)
“Changes from baseline to week 26 in total QUIP-RS scores were comparable between groups (LSM: placebo, −2.1; 5-mg tavapadon, −2.2; 15-mg tavapadon, −2.4; LSM treatment difference for 5-mg tavapadon, −0.1; 95% CI, −1.4 to 1.1; P = .85; treatment difference for 15-mg tavapadon, −0.3; 95% CI, −1.6 to 1.0; P = .64), resulting in mean (SD) total QUIP-RS scores of 2.9 (7.23) in the placebo group and 2.7 (6.82) in the overall tavapadon group.” (opens the source at this quote in a new tab)

Hallucinations and peripheral edema

“Hallucination AEs were reported in 11 participants in the 15-mg tavapadon group. All events were mild or moderate in severity and nonserious, except for 1 serious event that led to treatment discontinuation.” (opens the source at this quote in a new tab)
“Peripheral edema was uncommon in the tavapadon groups (overall, 5 participants [1.4%]; 5-mg tavapadon, 4 [2.3%]; 15-mg tavapadon, 1 [0.6%]) and incident at similar rates during the titration (0.8%) and maintenance (0.7%) phases. Peripheral edema was not reported in the placebo group.” (opens the source at this quote in a new tab)

Blood pressure, laboratory, and cardiovascular findings

“Mean systolic and diastolic blood pressure (BP) decreased during titration in tavapadon-treated participants, with a mean (SD) decrease of −6.7 (7.31) mm Hg in supine diastolic BP in the overall tavapadon group vs a mean (SD) increase of 0.1 (7.45) mm Hg in the placebo group at week 27. The mean (SD) decrease in supine systolic BP at week 27 was −12.0 (13.17) mm Hg in the overall tavapadon group and −1.7 (12.25) mm Hg in the placebo group.” (opens the source at this quote in a new tab)
“No clinically significant safety trends were observed based on clinical laboratory findings, vital signs, and cardiovascular assessments.” (opens the source at this quote in a new tab)

Suicidal ideation and behavior on the C-SSRS

C-SSRS outcome at week 27, count (%)	Placebo (n = 175)	Tavapadon 5 mg (n = 177)	Tavapadon 15 mg (n = 177)
Participants with any suicidal ideation	“3”( “1.7%”)	“3”( “1.7%”)	“3”( “1.7%”)
Participants with any suicidal behavior	“0”( “0.0%”)	“0”( “0.0%”)	“0”( “0.0%”)

Pooled Study 1 and Study 2 safety findings in the prescribing information

“In Study 1 and Study 2 in patients with PD who were not taking levodopa [see Clinical Studies (14.1)], orthostatic hypotension was reported in 5% of patients treated with JUVMO compared to 1% of patients who received placebo. Hypotension was reported in 4% of patients treated with JUVMO tablets compared to 1% on placebo.” (opens the prescribing information at this quote)
“In Study 1 and Study 2, impulse control disorders were reported in 1% of patients treated with JUVMO compared to no patients on placebo.” (opens the prescribing information at this quote)
“In Study 1 and Study 2, hallucination was reported in 3% of patients treated with JUVMO compared to no patients on placebo.” (opens the prescribing information at this quote)
“In Study 1 and Study 2, among patients 65 years of age and older, hallucination was reported in 4% of patients treated with JUVMO compared to no patients on placebo.” (opens the prescribing information at this quote)
“In Study 1 and Study 2, 0.6% of patients with PD treated with JUVMO reported dyskinesia compared with no patients on placebo.” (opens the prescribing information at this quote)

Summary: limitations of TEMPO-1

TEMPO-1 compared each fixed dose with placebo over 27 weeks, with the primary endpoint at week 26; it included no active comparator and was not designed to compare the 5 mg and 15 mg doses with each other. The fixed titration scheme withdrew participants who could not reach their target dose, and the investigators state that this requirement may have confounded discontinuation rates during titration: 59 of 177 participants (33.3%) in the 15 mg group and 43 of 177 (24.3%) in the 5 mg group discontinued, compared with 27 of 175 (15.4%) with placebo, and adverse events led to discontinuation in 35 (19.8%), 29 (16.4%), and 7 (4.0%), respectively. The registry results report week-26 primary endpoint data for 148 placebo, 132 tavapadon 5 mg, and 116 tavapadon 15 mg participants, and the statistical analysis plan assumes that missing values are missing at random in the primary mixed model. Of the 529 participants, 514 (97.2%) were White, which the investigators state may limit generalizability. The prescribing information bases efficacy on the change in MDS-UPDRS Part II, the first key secondary endpoint, where the placebo-adjusted differences were -2.5 and -2.6 points. The publication states that MAO-B inhibitors were permitted if initiated less than 90 days before baseline, while the registry states more than 90 days. The trial was funded by AbbVie, which coordinated the study design, analysis, and approval of the publication, and a pooled analysis of the tavapadon trials notes that no trial used an active comparator or exceeded 27 weeks.

Strengths and limitations stated by the investigators

“The strength of this study was its rigorous, multicenter, double-blind, randomized, adequately powered design. Limitations include the fixed-dose design and rigid titration schedule, which precludes determination of optimal dosing, and the relatively short 6-month follow-up duration. Most participants (514 of 529 [97.2%]) were White, which may impact generalizability.” (opens the source at this quote in a new tab)

Titration requirement and discontinuation rates

“This may be due in part to the fixed titration schedule and protocol requirement that participants who could not tolerate a titration step were to be withdrawn from the trial, which may have confounded discontinuation rates during titration.” (opens the source at this quote in a new tab)

Limits on dose comparison and cross-trial comparison

“This study was designed to compare outcomes following treatment with tavapadon vs placebo, not to compare 5-mg vs 15-mg doses of tavapadon.” (opens the source at this quote in a new tab)
“However, this should be interpreted with caution, as some AEs observed more frequently with participants randomized to 15-mg tavapadon occurred prior to reaching the target dose, and the overall AE incidence was comparable between the tavapadon groups.” (opens the source at this quote in a new tab)
“Although the trial design precludes head-to-head comparisons, the low rate of these AEs in this study potentially supports the approach of selective D1/D5 agonism relative to on-market dopamine agonists, which primarily target D2/D3 receptors.” (opens the source at this quote in a new tab)

Need for longer-term data

“Mean QUIP-RS scores after 26 weeks of treatment (2.7 in the overall tavapadon group) were well below the threshold when impulsive or compulsive behaviors become concerning (≥10 points), although longer-term evaluation is needed to confirm these findings.” (opens the source at this quote in a new tab)
“Further studies are needed to support the long-term safety and efficacy of tavapadon in this population.” (opens the source at this quote in a new tab)

Sponsor funding and role

“Funding for this study was provided by AbbVie. Cerevel Therapeutics is now a part of AbbVie.” (opens the source at this quote in a new tab)
“Study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication were coordinated by the sponsor.” (opens the source at this quote in a new tab)

Absence of active-comparator and longer-duration trials

“Its proposed neuropsychiatric advantage over D2/D3 agonists remains untested: no trial used an active comparator or exceeded 27 weeks.” (opens the source at this quote in a new tab)

Attrition and certainty of evidence appraised in a meta-analysis

“attrition in the monotherapy trials was substantial and differential: efficacy analysis sets comprised 132 of 177 and 116 of 177 participants in the TEMPO-1 tavapadon arms against 148 of 175 receiving placebo” (opens the source at this quote in a new tab)
“Although the primary analyses used mixed models for repeated measures, which are valid under a missing-at-random assumption, dropout driven predominantly by adverse events in the active arms may not satisfy that assumption and could bias the treatment effect away from the null.” (opens the source at this quote in a new tab)
“Certainty was moderate for three outcomes: the primary outcome of combined MDS-UPDRS Parts II and III in early-stage monotherapy, good ON-time without troublesome dyskinesia in the adjunctive setting, and dizziness. Each was rated down by a single level for risk of bias, arising from the registry-only reporting of TEMPO-2 and B7601003, the early termination of B7601003, and substantial differential attrition in the monotherapy trials.” (opens the source at this quote in a new tab)

Trial objective: safety, tolerability, and efficacy of flexible-dose tavapadon

“Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson’s disease motor symptoms. We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson’s disease.” (opens the source at this quote in a new tab)
“The aim of the phase 3 TEMPO-2 trial was to evaluate the safety, tolerability, and efficacy of flexible-dose tavapadon in people with early-stage Parkinson’s disease.” (opens the source at this quote in a new tab)

Objective in the context of the unmet need stated by the investigators

“A key unmet need for Parkinson’s disease is the availability of treatment modalities that provide a balance of dopamine signalling to improve motor symptoms while reducing the risk of specific adverse events associated with current D2/D3 receptor-targeting dopamine agonists.” (opens the source at this quote in a new tab)
“By selectively targeting D1/D5 receptors, tavapadon might improve motor symptoms with minimal risk of the adverse events associated with current dopaminergic therapy.” (opens the source at this quote in a new tab)

Registry statement of purpose

“The purpose of this study is to assess the efficacy, safety, tolerability and pharmacokinetics (PK) of flexible doses of tavapadon in participants with Parkinson's Disease.” (opens the source at this quote in a new tab)

Sponsor description of the trial objective

“The TEMPO-2 trial evaluated the efficacy, safety and tolerability of a flexible-dose (5 mg to 15 mg, once daily) treatment with tavapadon as a monotherapy in adults with early Parkinson's disease.” (opens the source at this quote in a new tab)

Summary: sites, countries, and study period

The primary publication reports that TEMPO-2 was conducted at 75 clinical sites, in hospital or academic and community settings, across 13 countries, and that participants were screened and randomized between January 6, 2020 and February 22, 2024. The registry record for NCT04223193 lists 53 locations in 13 countries (the United States, Italy, Poland, Germany, France, Hungary, South Korea, Thailand, Ukraine, Spain, Taiwan, Australia, and Serbia), 18 of them in the United States. The registry gives an actual study start date of January 6, 2020 and actual primary completion and study completion dates of October 1, 2024. The protocol identifier is CVL-751-PD-002 and the EudraCT number is 2019-002950-22. The protocol names Cerevel Therapeutics as sponsor; the registry now lists AbbVie.

Number of sites, countries, and enrollment period

“TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled, parallel-group, 27-week trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries (Australia, France, Germany, Hungary, Italy, Poland, Serbia, South Korea, Spain, Taiwan, Thailand, Ukraine, and the USA; see appendix pp 7–352 for the protocol).” (opens the source at this quote in a new tab)
“Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5–15 mg (n=151) or placebo (n=153).” (opens the source at this quote in a new tab)

Registry dates and location count

Field	Quoted record
Study start (actual)	“2020-01-06”
Primary completion (actual)	“2024-10-01”
Study completion (actual)	“2024-10-01”
Enrollment (actual)	“304”
Locations	“This study has 53 locations”
Other study identifiers	“CVL-751-PD-002”

Phase 3, randomized, double-blind, placebo-controlled design

“TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries.” (opens the source at this quote in a new tab)
“Participants were randomly assigned 1:1 to flexible-dose tavapadon (5–15 mg) or placebo orally once daily for 27 weeks.” (opens the source at this quote in a new tab)
“The trial comprised a 4-week screening period, a 27-week treatment period, a 10-day safety or withdrawal assessment period (to assess potential withdrawal symptoms after discontinuation of the study drug), and a 20-day safety follow-up period (figure 1).” (opens the source at this quote in a new tab)
“This trial was conducted in accordance with the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines, the International Council for Harmonization Guideline for Good Clinical Practice, and all applicable laws and regulations.” (opens the source at this quote in a new tab)

Randomization, stratification, and blinding

“Participants were centrally randomly assigned in a 1:1 ratio to receive flexible-dose tavapadon (5–15 mg once daily) or placebo at the baseline visit via an interactive voice response system or interactive web response” (opens the source at this quote in a new tab)
“system, or both, by use of a computer-generated randomisation scheme stratified by concurrent use of MAO-B inhibitors.” (opens the source at this quote in a new tab)
“Participants were sequentially assigned to the next available randomisation number within the appropriate randomisation stratum and were assigned to groups on the basis of that randomisation number. Treatment assignments were masked to investigators, other trial personnel, participants, and all sponsor personnel involved in the conduct of the trial. Furthermore, tavapadon and placebo tablets were identical in both appearance and blister card packaging.” (opens the source at this quote in a new tab)

Protocol overall design and trial periods

“This is prospective, Phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group, 27-week trial to evaluate the efficacy, safety, tolerability, and PK of flexible doses (5 to 15 mg QD) of tavapadon in male and female subjects aged 40 to 80 years who have a diagnosis of PD (consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic criteria); a modified Hoehn and Yahr stage of 1, 1.5, or 2; an MDS-UPDRS Part II score ≥2 and a Part III score ≥10; and are not receiving antiparkinsonian medication other than MAO-B inhibitors. The trial will include a Screening Period (maximum of 4 weeks), a 27-week Treatment Period, a 10-day Safety/Withdrawal Assessment Period to assess potential withdrawal symptoms after discontinuation of the investigational medicinal product (IMP), and a 20-day Safety Follow-up Period (Figure 1). Each subject will participate in the trial for up to approximately 35 weeks.” (opens the source at this quote in a new tab)

Randomization ratio and stratification

“Subjects who continue to meet the eligibility criteria at the Baseline Visit will be randomized in a 1:1 ratio to 2 treatment groups:” (opens the source at this quote in a new tab)
“Randomization will be stratified by concurrent use of allowed PD medications (MAO-B inhibitors) during the Treatment Period.” (opens the source at this quote in a new tab)

Registered design

Field	Quoted record
Official title	“A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Flexible-Dose, 27-Week Trial to Evaluate the Efficacy, Safety, and Tolerability of Tavapadon in Early Parkinson's Disease (TEMPO-2 Trial)”
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Primary purpose	“Treatment”

Sponsor description of the design

“TEMPO-2 was a Phase 3 double-blind, randomized, placebo-controlled, parallel-group, 27-week trial to evaluate the efficacy, safety and tolerability of flexible doses of tavapadon (5-15 mg QD) as a monotherapy in early Parkinson's disease.” (opens the source at this quote in a new tab)

Option to enter the open-label extension

“Subjects who complete through Week 27 of the trial may have the opportunity to enter an open-label extension trial (Protocol CVL-751-PD-004).” (opens the source at this quote in a new tab)

Age, diagnosis, disease stage, and prior treatment

“Adults aged 40–80 years with early-stage Parkinson’s disease (<3 years’ disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible.” (opens the source at this quote in a new tab)
“Eligible participants included adults aged 40–80 years with a diagnosis of Parkinson’s disease consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic criteria; a Modified Hoehn & Yahr Scale (mH&Y) score of 1, 1·5, or 2; a disease duration of less than 3 years; and those who were treatment naive or had a total of less than 3 months of treatment with dopaminergic agents including levodopa and dopamine receptor agonist medications (but not within 2 months of the baseline visit).” (opens the source at this quote in a new tab)

Permitted Parkinson's disease medications as published

“Previous and concurrent use of monoamine oxidase-B (MAO-B) inhibitors was permitted if initiated more than 90 days before the baseline visit (dose needed to remain stable for the duration of the trial). Medications that were prohibited before the trial are listed in the appendix (pp 43–45).” (opens the source at this quote in a new tab)

Key inclusion criteria as registered

“Participants with a diagnosis of PD that is consistent with the UK Parkinson's Disease Society Brain Bank diagnostic criteria.” (opens the source at this quote in a new tab)
“Participants with modified Hoehn and Yahr stage 1, 1.5, or 2.” (opens the source at this quote in a new tab)
“Participants with an MDS-UPDRS Part II score >=2 and Part III score >=10 at the Screening Visit and at the Baseline Visit.” (opens the source at this quote in a new tab)
“Participants who are treatment naive or have a history of prior incidental treatment with dopaminergic agents (including L-Dopa and dopamine receptor agonist medications) for <3 months in total but not within 2 months of the Baseline Visit. Prior and concurrent use of MAO-B inhibitors is permitted if use was initiated >90 days before the Baseline Visit and the dosage will remain stable for the duration of the trial (ie, no change in the MAO-B inhibitor dose is permitted during the trial).” (opens the source at this quote in a new tab)

Key exclusion criteria: neuropsychiatric history

“Participants with a history or current diagnosis of a clinically significant impulse control disorder (Disruptive, Impulse Control, and Conduct Disorder per DSM-5).” (opens the source at this quote in a new tab)
“Participants with a history of psychosis or hallucinations within the previous 12 months.” (opens the source at this quote in a new tab)
“Participants with a Montreal Cognitive Assessment (MoCA) score <26.” (opens the source at this quote in a new tab)

Key exclusion criteria: cardiovascular, renal, and drug interaction criteria

“Participants with clinically significant orthostatic hypotension (eg, syncope).” (opens the source at this quote in a new tab)
“Participants who are currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors (except for topical administration).” (opens the source at this quote in a new tab)
“Participants with moderate or severe renal impairment (creatinine clearance as estimated by Cockcroft-Gault formula <30 mL/min or on dialysis).” (opens the source at this quote in a new tab)

Flexible-dose titration, dose adjustment, and maintenance as published

“titrated over 6 weeks to a 5-mg once-daily dose, and with masked dose adjustment up to 15 mg once daily (the maximum tolerated dose) by week 14 by use of a fixed titration scheme (appendix p 2). No dose adjustments were permitted through the first eight titration steps (ie, up to 5 mg) and participants who were unable to tolerate this dose were discontinued from the trial.” (opens the source at this quote in a new tab)
“During the dose adjustment phase, dose reductions (eg, from 15 mg to 10 mg once daily) were allowed on the basis of tolerability. Participants who required a dose reduction during this phase could be rechallenged one time with the higher dose (at the discretion of the investigator) to address symptomatic needs. Dose reductions and rechallenges were only permitted during the dose adjustment phase. Participants then received the highest tolerated dose that was reached during the dose adjustment phase for the duration of the maintenance phase; no adjustments were allowed during this period and participants who were unable to tolerate the maintenance dose were discontinued from the trial.” (opens the source at this quote in a new tab)

Maintenance dose counts that differ between the figure 3 legend and the discussion

“Participants received the highest tolerated dose level that was achieved during the dose adjustment phase (5 mg, 18 [12%] participants; 10 mg, 13 [9%] participants; 15 mg, 94 [62%] participants).” (opens the source at this quote in a new tab)
“Notably, 110 (73%) of 151 participants who received tavapadon reached maintenance dosing (appendix p 4).” (opens the source at this quote in a new tab)

Blinding by tablet count and timing of clinic assessments

“All participants received three tablets daily during the treatment period, either all tavapadon tablets, all placebo tablets, or a combination of tavapadon and placebo tablets. Tavapadon was supplied in three dose strengths (0·25 mg, 1 mg, and 5 mg); tablets were packaged in this manner to allow dose adjustments to be made without unblinding the trial.” (opens the source at this quote in a new tab)
“Assessments were conducted in the clinic at the end of weeks 2, 5, 8, 11, 14, 18, 22, 26, 27, and 28–29. During the treatment period, the in-clinic assessments occurred approximately 2–6 h after participants took their daily dose of study drug (at home).” (opens the source at this quote in a new tab)

Flexible-dose titration and dose adjustment

“The dose of tavapadon will be gradually titrated to 15 mg QD in all subjects over the first 14 weeks of the trial during the Dose Titration and Dose Adjustment Phases unless prevented by intolerance. A reduction in dose (from 15 mg QD to 10 mg QD or from 10 mg QD to 5 mg QD) will be allowed based on individual subject tolerability.” (opens the source at this quote in a new tab)
“Subjects who cannot achieve or tolerate the Step 8 dose (5 mg QD) will be discontinued from the trial.” (opens the source at this quote in a new tab)
“Subjects will receive the highest tolerated dose level that is achieved during the Dose Adjustment Phase for the duration of the subsequent 13-week Maintenance Phase. Adjustments in the dose of tavapadon will not be allowed during the Maintenance Phase. Subjects who cannot tolerate their maintenance dose will be discontinued from the trial.” (opens the source at this quote in a new tab)

Protocol dosing schedule

Trial days	Titration step	Blinded treatment assignment
Days 1 to 4 (blinded dose titration phase)	“Step 1”	“0.25 mg tavapadon or placebo QD”
Days 5 to 8	“Step 2”	“0.5 mg tavapadon or placebo QD”
Days 9 to 12	“Step 3”	“0.75 mg tavapadon or placebo QD”
Days 13 to 16	“Step 4”	“1 mg tavapadon or placebo QD”
Days 17 to 20	“Step 5”	“1.5 mg tavapadon or placebo QD”
Days 21 to 24	“Step 6”	“2.25 mg tavapadon or placebo QD”
Days 25 to 40	“Step 7”	“3 mg tavapadon or placebo QD”
Days 41 to 56	“Step 8”	“5 mg tavapadon or placebo QD”
Days 57 to 72 (blinded dose adjustment phase)	“Step 9”	“10 mg tavapadon or placebo QD”
Days 73 to 104	“Step 10”	“15 mg tavapadon or placebo QD”
Days 105 to 189 (blinded maintenance phase)	“Step 11”	“Maximum tolerated tavapadon dose (5-15 mg) or placebo QD”

Registered treatment arms

Arm	Quoted record
Tavapadon	“Participants will receive tavapadon tablet titrated up to 15 milligram (mg) once daily (QD) orally for 27 weeks.”
Placebo	“Participants will receive placebo matching to tavapadon tablet QD orally for 27 weeks.”

Titration as described in the prescribing information

“Patients in the JUVMO arm were titrated to receive 5 mg to 15 mg according to the recommended titration schedule unless limited by tolerability” (opens the prescribing information at this quote)

Protocol justification for the 5 mg to 15 mg dose range

“Taken together, these findings suggest that an optimal dose range of tavapadon for the treatment of PD may reasonably be between 5 and 15 mg QD for the individual patient, based on symptomatic needs and tolerability thresholds.” (opens the source at this quote in a new tab)

Primary and key secondary endpoints

“The primary endpoint was change from baseline to week 26 in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II (motor aspects of experiences of daily living) and Part III (motor evaluation) combined score. The post-baseline MDS-UPDRS assessments were conducted in the clinic at the end of weeks 5, 8, 11, 14, 18, 22, 26, 27, and 28–29. Key secondary endpoints were change from baseline to week 26 in the MDS-UPDRS Part II score and the proportion of participants with a Patient Global Impression of Change (PGIC) score of “much improved” or “very much improved” at week 26.” (opens the source at this quote in a new tab)

Other secondary, exploratory, and safety endpoints

“Other secondary efficacy endpoints were assessed at several pre-defined time points from baseline to the end of the study (week 27) and included change from baseline in the MDS-UPDRS Parts II and III combined score at additional timepoints beyond the primary efficacy endpoint; changes from baseline in MDS-UPDRS Parts I, II, and III combined and individual scores; and change from baseline in the Clinician Global Impression–Severity of Illness (CGI-S), Clinician Global Impression–Improvement (CGI-I), and PGIC scores. Other endpoints included change from baseline in scores on the 39-Item Parkinson’s Disease Questionnaire (PDQ-39), Schwab and England Activities of Daily Living (ADL) scale, and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) index and visual analogue scale (VAS). The post-baseline assessments for CGI-S, CGI-I, PGIC, and ADL were conducted at weeks 5, 8, 11, 14, 18, 22, 26, and 27. PDQ-39 and EQ-5D-5L were assessed at weeks 26 and 27; EQ-5D-5L was also assessed at week 14.” (opens the source at this quote in a new tab)
“Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms. Scores on the Columbia–Suicide Severity Rating Scale (C-SSRS), Epworth Sleepiness Scale (ESS), and the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS) were assessed at each visit (weeks 2, 5, 8, 11, 14, 18, 22, 26, and 27; C-SSRS was also assessed at week 29). The Study Medication Withdrawal Questionnaire (SMWQ) was administered during the withdrawal assessment period (weeks 27–29).” (opens the source at this quote in a new tab)

Registered primary outcome measure and score ranges

“The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) rating tool was used to follow longitudinal course of Parkinson's Disease. It was made up of 4 parts: Part 1: Non-motor aspects of experiences of daily living (13 items. Score range: 0-52); Part 2: Motor aspects of experiences of daily living (13 items. Score range: 0-52); Part 3: Motor examination (18 items. Score range: 0-132); Part 4: Motor complications (6 items. Score range: 0-24. Part 4 was not collected in this trial). Each item has 0-4 rating on scale from 0 (normal) to 4 (severe). Higher values represent a worse outcome. A negative change from baseline represents an improvement in motor function. Parts 2 and 3 combined is the sum of Part 2 score and Part 3 score at each assessment time for each participant. The combined score assesses 31 items with score range: 0-184.” (opens the source at this quote in a new tab)

Key secondary endpoints

“Key secondary endpoints included change from baseline in the MDS-UPDRS Parts II score and percentage of responders with "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC).” (opens the source at this quote in a new tab)

Protocol rationale for the primary endpoint and the safety scales

“The MDS-UPDRS is a comprehensive assessment that is designed to monitor the burden and extent of PD across the longitudinal disease course and provides a clinical endpoint in therapy trials (Goetz et al, 2008). The primary endpoint, the change from baseline to endpoint in the MDS-UPDRS Parts II (motor aspects of experiences of daily living) and III (motor examination) combined score represents a clinically applicable outcome measure (Makkos et al, 2018).” (opens the source at this quote in a new tab)
“The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS) is a global screening instrument that assesses impulsive control disorders (ICDs) and related disorders (punding, hobbyism, and dopamine dysregulation syndrome) in patients with PD (Weintraub et al, 2012), and the Epworth Sleepiness Scale (ESS) is a scale that is intended to measure daytime sleepiness (Johns, 1991).” (opens the source at this quote in a new tab)

Clinically meaningful thresholds cited in the protocol

“The magnitude of the placebo-adjusted treatment difference in improvement from baseline in the MDS-UPDRS Part III score met the threshold for a clinically meaningful change (>3-point decrease from baseline; Horváth et al, 2015), as did the magnitude of the placebo-adjusted treatment difference in improvement from baseline in the MDS-UPDRS Parts II and III combined score (>4.9-point decrease from baseline; Makkos et al, 2018).” (opens the source at this quote in a new tab)

Validation of the MDS-UPDRS

“The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96).” (opens the source at this quote in a new tab)
“The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.” (opens the source at this quote in a new tab)
“A factor structure combining Parts II and III was explored, but could not be confirmed.” (opens the source at this quote in a new tab)
“As anticipated, Parts II and III that covered patient perceptions of motor function and the objective examination were more highly correlated (r = 0.66).” (opens the source at this quote in a new tab)
“These combined results preclude using a total MDS-UPDRS score or scores based on combinations of parts.” (opens the source at this quote in a new tab)
“In this light, we recommend that each of the parts (I–IV) should be reported separately and not collapsed into a single ‘‘Total MDS-UPDRS’’ summary score.” (opens the source at this quote in a new tab)

Minimal clinically important difference for the Parts II and III combined score

“Because of the presence of a major neurocognitive disorder, the data of 49 patients were excluded; therefore, the data of 452 patients with 1,113 sequenced examinations were analyzed.” (opens the source at this quote in a new tab)
“Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change.” (opens the source at this quote in a new tab)
“should apply the threshold of –4.9 and +4.2 points for revealing improvement or deterioration.” (opens the source at this quote in a new tab)
“Hauser and colleagues estimated the MCID thresholds for UPDRS 2 + 3 as being – 8.0 and –8.1 points in early PD and –7.1 and -8.8 points for advanced PD.” (opens the source at this quote in a new tab)
“Of note, our thresholds are considerably smaller, which may be partly explained by the different structures of these scales.” (opens the source at this quote in a new tab)
“Although our data support the concept of the usage of various composite scores, we also have to mention that the MCID thresholds for the individual MDS-UPDRS Parts have generally better discriminative abilities than those of the composite scores. Therefore, the analysis of the changes in the individual subscales is advised cardinally unless the clinical situation or the study aims require the utilization of the composite scores.” (opens the source at this quote in a new tab)

Minimal clinically important differences for Part III and Part II

“Therefore, 728 paired follow-up visits of 260 patients were utilized for the analyses.” (opens the source at this quote in a new tab)
“The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening.” (opens the source at this quote in a new tab)
“Based on the ROC analysis, the best cut-off values discriminating no change from minimal clinical improvement and no change from minimal clinical worsening were −3.5 and +4.5, respectively (Table 3).” (opens the source at this quote in a new tab)

“Nine hundred eighty-five paired investigations of 365 patients were reviewed, implementing three different techniques simultaneously.” (opens the source at this quote in a new tab)
“In reference to Part II, the smallest changes considered clinically relevant were 3.05 and 2.51 points for improvement and deterioration, respectively.” (opens the source at this quote in a new tab)

Investigators' interpretation of the observed change against the threshold

“Selection of the MDS-UPDRS Parts II and III combined scores as the primary endpoint was informed by previous clinimetric research” (opens the source at this quote in a new tab)
“The reduction in MDS-UPDRS Parts II and III combined scores observed with once-daily dosing of tavapadon relative to placebo at week 26 (−9·1 points) was approximately twice as large as the minimum clinically important difference (>4·9-point improvement) in MDS-UPDRS Parts II and III combined scores as derived from meta-analyses of published Parkinson’s disease trials.” (opens the source at this quote in a new tab)

Endpoint on which the prescribing information bases efficacy

“Efficacy was determined based on the change from baseline in the MDS-UPDRS Part II score at Week 26.” (opens the prescribing information at this quote)

Planned sample size and power

“A sample size of 148 subjects per group (total, 296 subjects) will provide at least 90% power to detect a change in the primary outcome measure (change from baseline in the MDS-UPDRS Parts II and III combined score) of 4 points, with a standard deviation of 9, 2-sided alpha level = 0.05, and assuming a 27% dropout rate.” (opens the source at this quote in a new tab)

Participants screened, randomized, and analyzed

“Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened; of these, 304 were randomly assigned to receive tavapadon 5–15 mg (n=151) or placebo (n=153). All 304 participants received one dose or more of study treatment and were included in the safety analysis set, and 301 met the criteria for the mITT population (figure 2).” (opens the source at this quote in a new tab)

Participants analyzed in the registry results

Analysis	Placebo	Tavapadon
Primary endpoint at week 26, participants analyzed	“133”	“99”
MDS-UPDRS Part II at week 26, participants analyzed	“134”	“99”
Safety (full analysis set), participants analyzed	“153”	“151”

Analysis population for the primary endpoint in the registry

“mITT Population includes subjects who receive at least 1 dose of study drug and have both a baseline and at least 1 postbaseline MDS-UPDRS assessment, and had available data for analysis.” (opens the source at this quote in a new tab)

Efficacy and safety populations

“Efficacy analyses were done with a mixed model for repeated measures (MMRM) approach on the basis of the modified intention-to-treat (mITT) population (ie, randomly assigned participants who received one dose or more of the study drug and had both a baseline and ≥1 post-baseline MDS-UPDRS assessments).” (opens the source at this quote in a new tab)
“The safety analysis set comprised all participants who received one dose or more of tavapadon or placebo.” (opens the source at this quote in a new tab)

Hierarchical testing and mixed model for repeated measures

“Primary and key secondary endpoints were assessed for tavapadon versus placebo by use of a hierarchical testing procedure, with comparison of MDS-UPDRS Parts II and III combined scores (primary endpoint), followed by comparison of MDS-UPDRS Part II scores (key secondary endpoint), and then the proportion of PGIC responders (key secondary endpoint).” (opens the source at this quote in a new tab)
“An MMRM approach was used for analyses of MDS-UPDRS Parts II and III combined scores (primary endpoint) and MDS-UPDRS Part II scores (key secondary endpoint), including fixed effects of treatment, visits, interaction between treatment and visit, and concomitant use of MAO-B inhibitors, with baseline scores included as a covariate and participant included as a random effect. The proportion of PGIC responders (key secondary endpoint) from each post-baseline visit (as a repeated measure) was analysed with a generalised linear mixed-model analysis with logit link with the same model specification as the MMRM described above. An unstructured covariance structure was used for the primary and key secondary analyses. Statistical comparisons for other continuous secondary endpoints were analysed in a manner similar to the primary endpoint.” (opens the source at this quote in a new tab)

Protocol definitions of analysis populations

Population	Description	Analysis
ITT	“All randomized subjects”	“Demographic and Baseline Characteristics”
FAS	“All randomized subjects who receive at least 1 dose of IMP. This will be the safety analysis set.”	“Safety analysis”
mITT	“All randomized subjects who receive at least 1 dose of IMP and have both a baseline and at least 1 postbaseline MDS-UPDRS assessment”	“Primary analysis set for efficacy”
Endpoint completers	“All subjects in the mITT population who have an MDS-UPDRS assessment at baseline and endpoint”	“Sensitivity analysis for efficacy”

Sequential testing of the primary and key secondary hypotheses

“A sequential testing approach depicted below will be taken to control the overall Type I error rate. The primary endpoint of the tavapadon will be compared with that of placebo (H1) with full α of 0.05 and, if successful, the available α will be passed along fully (r=1) to the secondary hypothesis H2. If H2 is successful, the full α will be available to the secondary hypothesis H3. The sequence will break if one of the hypotheses fails at α level of 0.05.” (opens the source at this quote in a new tab)

Mixed model covariates, stratification errors, and missing data

“The randomization is stratified by concurrent use of MAO-B inhibitor. This factor is planned to be included as a covariate in the efficacy analyses. However, due to isolated administrative errors at a few sites during randomization through IRT system, 15 subjects were randomized to the incorrect strata (2 non-MAO-B inhibitor users were randomized to the MAO-B inhibitor use stratum and 13 MAO-B inhibitor users were randomized to the non-user stratum; details in Section 9.7).” (opens the source at this quote in a new tab)
“The missing values, including missing due to missed visits or early termination due to COVID-19 control measures, are assumed to be missing at random (MAR) in the main MMRM analysis. Sensitivity analyses will be performed to assess the impact of deviation from MAR assumptions on the analysis results.” (opens the source at this quote in a new tab)

Discontinuation by treatment group

“80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo).” (opens the source at this quote in a new tab)

Screening and randomization

Screening outcome	Participants
Assessed for eligibility	“473”
Excluded	“169”
Did not meet inclusion or exclusion criteria	“140”
Withdrew	“13”
Lost to follow-up	“3”
Did not meet continuation criteria	“1”
Other reasons	“12”
Randomized	“304”

Trial profile by treatment group

Milestone or reason	Placebo	Tavapadon 5 to 15 mg
Assigned	“153”	“151”
Received ≥1 dose as randomized	“153”	“151”
Prematurely discontinued study	“23”	“57”
Adverse events	“6”	“36”
Withdrew	“5”	“6”
Site terminated by sponsor	“1”	“3”
Lack of efficacy	“2”	“2”
Lost to follow-up	“1”	“1”
Protocol deviation	“1”	“1”
Physician decision	Not reported	“1”
Non-adherence to study drug	Not reported	“1”
Use of prohibited concomitant medication	“3”	Not reported
Did not meet continuation criteria	“1”	Not reported
Other reasons	“3”	“6”
Completed study	“130”	“94”
Included in efficacy analysis (mITT)	“151”	“150”
Included in safety analysis set	“153”	“151”

Registry participant flow

Milestone or reason	Placebo	Tavapadon
Started	“153”	“151”
Completed	“130”	“94”
Not completed	“23”	“57”
Adverse event	“6”	“36”
Lack of efficacy	“2”	“2”
Lost to follow-up	“1”	“1”
Treatment with prohibited concomitant medications	“3”	“0”
Site terminated by sponsor	“1”	“3”
Withdrawal by subject	“5”	“6”
Other	“3”	“6”

Exposure to study drug

“Mean duration on study drug was 176.7 and 144.5 days for Placebo and Tavapadon, respectively. Median time on follow up (median time subjects were followed) was 200 and 198 days for Placebo and Tavapadon, respectively.” (opens the source at this quote in a new tab)

Demographic and disease characteristics of the randomized population

“The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62·9 (SD 9·2) years, and the mean disease duration was 0·86 (0·79) years.” (opens the source at this quote in a new tab)
“Demographics and baseline disease characteristics were similar across groups and consistent with that of a population with early-stage Parkinson’s disease (table 1). The mean duration since diagnosis was 0·86 (SD 0·79) years and the majority of participants (185 [61%] of 304) were mH&Y stage 2 at screening. Participants had a mean baseline MDS-UPDRS Parts II and III combined score of 30·5 (SD 11·2), and most (213 [70%] of 304) had not previously used MAO-B inhibitors.” (opens the source at this quote in a new tab)

Baseline characteristics by treatment group

Characteristic	Placebo (n = 153)	Tavapadon 5 to 15 mg (n = 151)	Overall (N = 304)
Age, mean (SD), years	“62·6 (9·4)”	“63·1 (9·0)”	“62·9 (9·2)”
Age <65 years, n (%)	“82 (54%)”	“77 (51%)”	“159 (52%)”
Age ≥65 years, n (%)	“71 (46%)”	“74 (49%)”	“145 (48%)”
Age ≥75 years, n (%)	“16 (10%)”	“12 (8%)”	“28 (9%)”
Male, n (%)	“85 (56%)”	“84 (56%)”	“169 (56%)”
Female, n (%)	“68 (44%)”	“67 (44%)”	“135 (44%)”
American Indian or Alaska Native, n (%)	“1 (1%)”	“0”	“1 (<1%)”
Asian, n (%)	“15 (10%)”	“17 (11%)”	“32 (11%)”
Black, n (%)	“2 (1%)”	“0”	“2 (1%)”
White, n (%)	“134 (88%)”	“134 (89%)”	“268 (88%)”
Other race, n (%)	“1 (1%)”	“0”	“1 (<1%)”
BMI, mean (SD), kg/m²	“27·0 (4·6)”	“26·6 (4·0)”	“26·8 (4·3)”
Years since initial diagnosis, mean (SD)	“0·85 (0·81)”	“0·88 (0·78)”	“0·86 (0·79)”
Disease duration <1 year, n (%)	“100 (65%)”	“100 (66%)”	“200 (66%)”
Disease duration 1 to <2 years, n (%)	“36 (24%)”	“31 (21%)”	“67 (22%)”
Disease duration 2 to <3 years, n (%)	“16 (10%)”	“20 (13%)”	“36 (12%)”
Modified Hoehn and Yahr stage 1, n (%)	“35 (23%)”	“38 (25%)”	“73 (24%)”
Modified Hoehn and Yahr stage 1.5, n (%)	“22 (14%)”	“24 (16%)”	“46 (15%)”
Modified Hoehn and Yahr stage 2, n (%)	“96 (63%)”	“89 (59%)”	“185 (61%)”
MDS-UPDRS Part I, mean (SD)	“4·6 (4·0)”	“5·3 (3·9)”	“5·0 (4·0)”
MDS-UPDRS Part II, mean (SD)	“6·9 (3·9)”	“7·4 (4·3)”	“7·1 (4·1)”
MDS-UPDRS Part III, mean (SD)	“23·1 (8·9)”	“23·6 (8·8)”	“23·4 (8·8)”
MDS-UPDRS Parts II and III, mean (SD)	“30 (11·1)”	“31·1 (11·2)”	“30·5 (11·2)”
MDS-UPDRS Parts I, II, and III, mean (SD)	“34·6 (13·1)”	“36·4 (13·3)”	“35·5 (13·2)”
MAO-B inhibitor use, n (%)	“45 (29%)”	“46 (30%)”	“91 (30%)”
No MAO-B inhibitor use, n (%)	“108 (71%)”	“105 (70%)”	“213 (70%)”

Baseline characteristics by treatment group in the registry

Characteristic	Placebo (n = 153)	Tavapadon (n = 151)	Total (N = 304)
Age, mean (SD), years	“62.6 (9.43)”	“63.1 (8.98)”	“62.9 (9.20)”
Female, count (%)	“68”( “44.4%”)	“67”( “44.4%”)	“135”( “44.4%”)
Male, count (%)	“85”( “55.6%”)	“84”( “55.6%”)	“169”( “55.6%”)
Hispanic or Latino, count (%)	“11”( “7.2%”)	“5”( “3.3%”)	“16”( “5.3%”)
Asian, count (%)	“15”( “9.8%”)	“17”( “11.3%”)	“32”( “10.5%”)
Black or African American, count (%)	“2”( “1.3%”)	“0”( “0.0%”)	“2”( “0.7%”)
White, count (%)	“134”( “87.6%”)	“134”( “88.7%”)	“268”( “88.2%”)
MDS-UPDRS Parts II and III combined, mean (SD)	“30.0 (11.11)”	“31.1 (11.21)”	“30.5 (11.16)”

Baseline demographics in the prescribing information

“Patients had a mean age of 62.9 years (range: 40 to 80 years), 56% were male, 88% were White, 11% were Asian, and 5% were Hispanic. The mean duration of PD at baseline was 0.9 years (range: 0 to 3 years). The mean MDS-UPDRS Part II score at baseline was 7.1 and was similar between treatment groups.” (opens the prescribing information at this quote)

Primary endpoint: MDS-UPDRS Parts II and III combined score at week 26

“The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10·3 [95% CI −12·2 to −8·3] points vs 1·2 [−2·9 to 0·6] points; LSM treatment difference −9·1 [95% CI −11·7 to −6·5]; p<0·0001).” (opens the source at this quote in a new tab)

Key secondary endpoints: MDS-UPDRS Part II and PGIC responders

“Treatment with tavapadon also resulted in a significant reduction from baseline to week 26 in the MDS-UPDRS Part II score compared with placebo (LSM change −1·5 [95% CI −2·1 to −0·8] points with tavapadon vs 0·0 [−0·6 to 0·6] points with placebo; LSM treatment difference −1·5 [95% CI −2·4 to −0·6]; p=0·0007).” (opens the source at this quote in a new tab)
“The proportion of participants with a PGIC response of “much improved” or “very much improved” at week 26 was also higher in the tavapadon group than in the placebo group (46 [46%] of 99 vs 25 [19%] of 134; odds ratio 3·94 [95% CI 2·21 to 7·04]; p<0·0001).” (opens the source at this quote in a new tab)

Onset of effect, multiplicity, and subgroup consistency

“Nominal improvements in MDS-UPDRS Parts II and III combined scores in tavapadon-treated versus placebo-treated participants were observed as early as week 5 and continued through the end of treatment (nominal p<0·0001; figure 3A).” (opens the source at this quote in a new tab)
“Initial improvements in the MDS-UPDRS Parts II and III combined scores were observed as early as week 5 during titration, with increasing separation from the placebo group continuing through approximately week 14; improvements versus placebo were then sustained through week 27. Improvements in MDS-UPDRS Part II scores and the proportion of PGIC responders in the tavapadon group relative to placebo were also first observed starting at week 8. Together, these early efficacy improvements suggest that tavapadon might provide benefit even with the lower doses received during initial titration.” (opens the source at this quote in a new tab)
“Nominal p values without multiplicity adjustment except for primary timepoint.” (opens the source at this quote in a new tab)
“The effect of tavapadon versus placebo on MDS-UPDRS Parts II and III combined scores was consistent at week 26 across subgroups by age (<65 years vs ≥65 years), sex, mH&Y staging at screening, baseline MDS-UPDRS Part II and III individual scores, concomitant use of an MAO-B inhibitor, disease duration (<1 year, 1 year to <2 years), and geographical region (appendix p 5).” (opens the source at this quote in a new tab)

Registry results for the primary and key secondary endpoints

Outcome at week 26	Placebo	Tavapadon
MDS-UPDRS Parts II and III, LSM change (SE)	“-1.2 (0.89)”	“-10.3 (0.99)”
MDS-UPDRS Part II, LSM change (SE)	“0.0 (0.30)”	“-1.5 (0.33)”
PGIC much or very much improved, participants analyzed	“134”	“99”
PGIC much or very much improved, count (%)	“25”( “18.7%”)	“46”( “46.5%”)

Change in MDS-UPDRS Part II in the prescribing information

MDS-UPDRS Part II	Juvmo (N = 150)	Placebo (N = 151)
Baseline (SD)	“7.4 (4.32)”	“6.8 (3.86)”
LS mean change (SE) from baseline to week 26	“-1.5 (0.33)”	“0.0 (0.30)”
LSMD vs placebo (95% CI)	“-1.5 (-2.4, -0.6)”	Not applicable
p-value	“0.0007”	Not applicable

Topline results announced by the sponsor

“The trial met its primary endpoint – patients treated with tavapadon experienced a statistically significant reduction (improvement) from baseline compared to placebo (placebo: -1.2; tavapadon 5-15 mg: -10.3; p-value <0.0001 versus placebo) in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III combined score at week 26” (opens the source at this quote in a new tab)
“The TEMPO-2 trial also met the key secondary endpoint, demonstrating a statistically significant and clinically meaningful improvement in motor aspects of experiences of daily living (MDS-UPDRS Part II) in the tavapadon group (5-15 mg) compared to placebo at week 26” (opens the source at this quote in a new tab)

Investigators' interpretation

“Tavapadon showed significant and clinically meaningful improvements in Parkinson’s disease motor symptoms, with low incidence of somnolence and impulse control disorders.” (opens the source at this quote in a new tab)

Pooled effect estimate for early-stage monotherapy

“In early-stage monotherapy, tavapadon improved the combined MDS-UPDRS Parts II and III score by 10.55 points versus placebo (95% CI − 13.11 to − 7.99; two trials).” (opens the source at this quote in a new tab)
“TEMPO-2 yielded a mean difference of − 9.10 points (95% CI − 11.70 to − 6.50).” (opens the source at this quote in a new tab)
“Between-study heterogeneity was moderate but not statistically significant (I² = 59.4%, τ² = 2.05, Q(1) = 2.46, p = 0.117), and with two trials the I² estimate is imprecise. A fixed-effect model gave a closely similar estimate of − 10.75 (95% CI − 12.34 to − 9.16).” (opens the source at this quote in a new tab)

Patient Global Impression of Change responders

“The Patient Global Impression of Change (PGIC) is a 7-point response scale. The participant response to the question, "Compared to your condition at the beginning of treatment, how much has your condition changed?" was assessed.” (opens the source at this quote in a new tab)

PGIC at week 26	Placebo	Tavapadon
Participants analyzed	“134”	“99”
Much improved or very much improved, count (%)	“25”( “18.7%”)	“46”( “46.5%”)

PGIC responders over time and any improvement at week 26

“There were significant improvements in the proportion of PGIC responders in the tavapadon group compared with the placebo group from week 8 until the end of the study (nominal p=0·0070 at week 8; p<0·0001 at weeks 11, 14, 18, 22, 26, and 27; appendix p 6). At week 26, 77 (78%) of 99 participants in the tavapadon group and 54 (40%) of 134 in the placebo group showed at least “minimal improvement” on the PGIC (appendix p 6).” (opens the source at this quote in a new tab)
“These findings are also reinforced by the higher proportion of participants who were considered responders on the PGIC based on the stringent criterion of “much improved” or “very much improved” in the tavapadon group compared with the placebo group (46% with tavapadon vs 19% with placebo), suggesting that symptom improvements were meaningful to participants.” (opens the source at this quote in a new tab)

Health-related quality of life endpoints specified in the protocol

“Change from baseline in PDQ-39 score” (opens the source at this quote in a new tab)
“Change from baseline in Schwab and England ADL score” (opens the source at this quote in a new tab)
“Change from baseline in the EQ-5D-5L index and VAS scores” (opens the source at this quote in a new tab)

PDQ-39 summary index and other quality of life endpoints

“There was no significant difference in the PDQ-39 summary index score between the tavapadon and placebo groups at week 26. Additional secondary endpoints are summarised in the appendix (p 3).” (opens the source at this quote in a new tab)
“The lack of improvement in the PDQ-39 summary index score with tavapadon relative to placebo might be explained by the relatively short observation period (6 months) or the low baseline scores in this early-stage Parkinson’s disease population.” (opens the source at this quote in a new tab)

Summary of adverse events in the safety analysis set

Adverse event, n (%)	Placebo (n = 153)	Tavapadon 5 to 15 mg (n = 151)
Any adverse event	“84 (55%)”	“115 (76%)”
Mild	“45 (29%)”	“51 (34%)”
Moderate	“38 (25%)”	“55 (36%)”
Severe	“1 (1%)”	“9 (6%)”
Related to study drug	“24 (16%)”	“82 (54%)”
Serious adverse events	“2 (1%)”	“7 (5%)”
Leading to discontinuation	“6 (4%)”	“36 (24%)”
Deaths	“0”	“0”
Nausea	“5 (3%)”	“45 (30%)”
Headache	“8 (5%)”	“25 (17%)”
Dizziness	“5 (3%)”	“24 (16%)”
Fatigue	“1 (1%)”	“12 (8%)”
Vomiting	“0”	“12 (8%)”
Dysgeusia	“0”	“12 (8%)”
Fall	“3 (2%)”	“10 (7%)”
Asthenia	“2 (1%)”	“8 (5%)”
Hallucination (safety topic of interest)	“0”	“6 (4%)”
Somnolence (safety topic of interest)	“6 (4%)”	“5 (3%)”
Orthostatic hypotension (safety topic of interest)	“1 (1%)”	“4 (3%)”
Impulse control disorders (safety topic of interest)	“0”	“2 (1%)”
Hypotension (safety topic of interest)	“0”	“6 (4%)”

Summary of serious and other adverse events in the registry

Adverse event, affected / at risk (%)	Placebo	Tavapadon
All-cause mortality	“0/153 (0.00%)”	“0/151 (0.00%)”
Serious adverse events, total	“2/153 (1.31%)”	“7/151 (4.64%)”
Fall (serious)	“0/153 (0.00%)”	“2/151 (1.32%)”
Reversible cerebral vasoconstriction syndrome (serious)	“0/153 (0.00%)”	“1/151 (0.66%)”
Other (not including serious) adverse events, total	“59/153 (38.56%)”	“99/151 (65.56%)”
Nausea	“5/153 (3.27%)”	“45/151 (29.80%)”
Headache	“8/153 (5.23%)”	“25/151 (16.56%)”
Dizziness	“5/153 (3.27%)”	“24/151 (15.89%)”
Vomiting	“0/153 (0.00%)”	“12/151 (7.95%)”
Fatigue	“1/153 (0.65%)”	“12/151 (7.95%)”
Dysgeusia	“0/153 (0.00%)”	“12/151 (7.95%)”
Asthenia	“2/153 (1.31%)”	“8/151 (5.30%)”
Fall	“3/153 (1.96%)”	“8/151 (5.30%)”
Hypotension	“0/153 (0.00%)”	“6/151 (3.97%)”
Somnolence	“6/153 (3.92%)”	“5/151 (3.31%)”
Abnormal dreams	“1/153 (0.65%)”	“5/151 (3.31%)”
Anxiety	“2/153 (1.31%)”	“5/151 (3.31%)”
Tremor	“13/153 (8.50%)”	“3/151 (1.99%)”

Overall adverse events, discontinuations, deaths, and timing by phase

“In the safety analysis set, 115 (76%) of 151 participants in the tavapadon group and 84 (55%) of 153 participants in the placebo group had at least one adverse event (table 2). Adverse events led to study drug discontinuation in 36 (24%) of 151 participants in the tavapadon group and six (4%) of 153 in the placebo group. Most adverse events were non-serious and mild to moderate in severity. No deaths occurred in either treatment group.” (opens the source at this quote in a new tab)
“Most adverse events were non-serious and mild to moderate in severity. More adverse events were observed with tavapadon than with placebo (115 [76%] of 151 participants vs 84 [55%] of 153 participants). The incidence of adverse events in the tavapadon group was higher during the titration phase (92 [61%] of 151) than during the dose adjustment (44 [37%] of 151) and maintenance (47 [43%] of 151) phases. The most commonly reported adverse events with tavapadon versus placebo (>10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]).” (opens the source at this quote in a new tab)

Adverse event counts and percentages for the dose adjustment and maintenance phases that do not agree with the denominator of 151

“The overall incidence of adverse events observed with tavapadon was highest during the titration phase (92 [61%] of 151) and decreased during dose adjustment (44 [37%] of 151) and maintenance (47 [43%] of 151; appendix p 4).” (opens the source at this quote in a new tab)

Somnolence and Epworth Sleepiness Scale

“The incidence of somnolence was comparable in the tavapadon group (five [3%] of 151) and the placebo group (six [4%] of 153); in the tavapadon group, most somnolence events occurred during titration, with none occurring during the maintenance phase. All adverse events of somnolence were non-serious, mild or moderate in severity, and resolved with no change to study treatment.” (opens the source at this quote in a new tab)
“The most robust indirect evidence for a differentiated safety profile remains the low incidence of somnolence, and changes from baseline to week 27 in ESS scores were also comparable between the tavapadon and placebo groups.” (opens the source at this quote in a new tab)

ESS total score, change from baseline to week 27	Placebo	Tavapadon 5 to 15 mg
LSM change (95% CI)	“−0·3 [−0·7 to 0·1]”	“−0·3 [95% CI −0·8 to 0·2]”
LSM treatment difference (95% CI)	Not applicable	“0·0 [95% CI −0·6 to 0·6]”
p value	Not applicable	“p=0·95”

Impulse control disorders and QUIP-RS scores

“The incidence of impulse control disorders in tavapadon-treated participants was low (two [1%] of 151; both hypersexuality). Both events were non-serious, mild in severity, and occurred during the titration phase. One event, assessed as not related to tavapadon, had not resolved by the end of the study. No action with tavapadon was taken in response to either event. Changes from baseline to week 27 in total QUIP-RS scores were comparable between the tavapadon and placebo groups (LSM change from baseline −2·0 [−2·7 to −1·2] with tavapadon vs −2·0 [95% CI −2·6 to −1·3] with placebo; LSM treatment difference 0·0 [95% CI −1·0 to 1·0]; p=0·99); mean total QUIP-RS scores at week 27 were 1·1 (3·94) in the tavapadon group and 1·1 (SD 3·71) in the placebo group.” (opens the source at this quote in a new tab)
“Furthermore, the mean scores on the QUIP-RS after 27 weeks of treatment (1·1 in the tavapadon group) were below the threshold of concern for impulsive or compulsive behaviours (≥10 points).” (opens the source at this quote in a new tab)

Hallucinations, peripheral edema, dyskinesia, and withdrawal symptoms

“Adverse events of hallucination occurred in six participants (six [4%] of 151) in the tavapadon group and none in the placebo group (table 2). All events were non-serious and mild or moderate in severity. Although most events resolved with no change in tavapadon treatment, one participant discontinued tavapadon due to an adverse event of hallucination. Peripheral oedema was also uncommon in the tavapadon group (two [1%] of 151 participants); both events were mild in severity. No adverse events of dyskinesia were observed in either group. There was no evidence of withdrawal symptoms reported during the study.” (opens the source at this quote in a new tab)

Blood pressure, laboratory, and cardiovascular findings

“Mean blood pressure decreased from baseline to the end of the study in tavapadon-treated participants, with a mean decrease in the tavapadon group of −10·8 (SD 14·08) mm Hg in standing systolic blood pressure (vs −3·8 [12·77] mm Hg with placebo) and −7·0 (9·61) mm Hg in standing diastolic blood pressure (vs −0·8 [8·56] mm Hg with placebo). However, changes in orthostatic blood pressure in the tavapadon group were not considered clinically significant; moreover, reported adverse events of hypotension and orthostatic hypotension were low (table 2). There were no clinically meaningful safety trends observed on the basis of clinical laboratory findings, vital signs, bodyweight, or cardiovascular assessments.” (opens the source at this quote in a new tab)

Daytime sleepiness, impulse control, and suicidality scales in the registry

Outcome	Placebo	Tavapadon
ESS at week 26, LSM change (SE)	“-0.1 (0.22)”	“-0.1 (0.24)”
QUIP-RS at week 26, LSM change (SE)	“-1.9 (0.31)”	“-2.0 (0.34)”
C-SSRS participants with any suicidal ideation at week 27, count (%)	“0”( “0.0%”)	“5”( “3.3%”)

Investigators' comparison with published dopamine agonist trials

“The safety profile of tavapadon was generally consistent with that of previous trials, and no new safety signals were identified.” (opens the source at this quote in a new tab)
“The frequency of certain adverse events in this study (eg, nausea, vomiting, and orthostatic hypotension) was higher with tavapadon versus placebo.” (opens the source at this quote in a new tab)
“The frequency of hallucinations observed in the tavapadon group was relatively low (4%) and was consistent with that of previous studies of D2 or D2/D3 dopamine agonists in participants with early-stage Parkinson’s disease (pramipexole [5%] and ropinirole [6%]; in the ropinirole study, “hallucinations” were defined as hallucinations, confusion, or delusions).” (opens the source at this quote in a new tab)
“These findings contrast with the higher incidence of somnolence reported in previous studies of D2 or D2/D3 dopamine agonists in participants with early-stage Parkinson’s disease treated with ropinirole (range 8–15% across studied doses) and rotigotine (range 18–24% across studied doses).” (opens the source at this quote in a new tab)

Pooled Study 1 and Study 2 adverse reactions in the prescribing information

“In Study 1 and Study 2 combined (n=833 total patients), the most common adverse reactions that occurred in ≥ 5% of patients treated with JUVMO were nausea, headache, dizziness, fatigue, dysgeusia, vomiting, dry mouth, and anxiety. Adverse reactions led to discontinuation of JUVMO in 100 of 505 patients (20%). Of the 100 patients receiving JUVMO who discontinued because of an adverse reaction, 85 (85%) did so during the titration and/or adjustment phases.” (opens the prescribing information at this quote)

Adverse reaction	Juvmo (N = 505), %	Placebo (N = 328), %
Nausea	“27”	“2”
Headache	“17”	“5”
Dizziness	“14”	“4”
Fatigue	“10”	“3”
Dysgeusia	“8”	“0”
Vomiting	“7”	“<1”
Dry mouth	“5”	“<1”
Anxiety	“5”	“2”
Hypotension	“4”	“1”
Dyspepsia	“4”	“1”
Abnormal dreams	“4”	“<1”
Orthostatic hypotension	“4”	“<1”
Hallucination	“3”	“0”
Gastroesophageal reflux disease	“3”	“<1”
Constipation	“3”	“1”

Pooled adverse event risk ratios from a meta-analysis

“Adverse events (RR 1.36, 1.09 to 1.71), nausea (6.38, 3.23 to 12.59), dizziness (3.03, 2.15 to 4.27) and discontinuation due to adverse events (2.72, 1.07 to 6.96) were more frequent with tavapadon. Serious adverse events were not increased (Peto OR 1.13, 0.69 to 1.85).” (opens the source at this quote in a new tab)
“Serious adverse events showed no excess on active drug (Peto odds ratio 1.13; 95% CI 0.69 to 1.85; six comparisons), and all-cause mortality was not increased (three deaths on placebo and two on tavapadon across all contributing trials).” (opens the source at this quote in a new tab)
“Adverse-event-related discontinuation was also markedly asymmetric: 36 of 151 tavapadon participants (23.8%) versus 6 of 153 receiving placebo (3.9%) in TEMPO-2, and 29 of 177 and 35 of 177 in the two TEMPO-1 tavapadon arms versus 6 of 175 on placebo.” (opens the source at this quote in a new tab)

Sleepiness, impulsivity, and suicidal ideation findings reported in a meta-analysis

“Consistent with this, neither pivotal monotherapy trial found a difference between arms on the Epworth Sleepiness Scale, and neither found a difference on the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale.” (opens the source at this quote in a new tab)
“In TEMPO-2, suicidal ideation on the Columbia Suicide Severity Rating Scale was reported in five tavapadon participants and none receiving placebo, with no suicidal behaviour in either arm; no comparable imbalance was reported in the other trials, but this is a signal requiring surveillance across the development programme.” (opens the source at this quote in a new tab)

Summary: limitations of TEMPO-2

TEMPO-2 compared flexible-dose tavapadon with placebo over 27 weeks, with the primary endpoint at week 26, and included no active comparator. The investigators state that head-to-head comparisons with D2/D3 dopamine agonists are not possible and that the 6-month duration does not allow conclusions on adverse events of special interest that take longer to manifest. Discontinuation was higher with tavapadon than with placebo (57 of 151 [38%] vs 23 of 153 [15%]); adverse events accounted for 36 (24%) and 6 (4%) discontinuations, and 21 (14%) tavapadon participants discontinued for reasons other than adverse events. The investigators report that the 38% discontinuation with tavapadon exceeds the withdrawal percentages in comparable trials of ropinirole (11% to 31%), piribedil (20%), and pramipexole (17% to 22%), and that the protocol requirement to discontinue participants who could not tolerate a titration step or a minimum dose of 5 mg may have confounded discontinuation during titration. Because each participant received the highest tolerated dose from 5 mg to 15 mg, the trial does not estimate the effect of a specific dose; the publication reports maintenance doses of 5 mg in 18 (12%), 10 mg in 13 (9%), and 15 mg in 94 (62%) participants, and separately states that 110 (73%) of 151 reached maintenance dosing. The registry results include week-26 primary endpoint data for 99 of 151 tavapadon participants and 133 of 153 placebo participants, and the statistical analysis plan assumes that missing values are missing at random in the primary mixed model. P values at timepoints other than the primary timepoint are nominal, without multiplicity adjustment, and the investigators acknowledge clinimetric critiques of summing the MDS-UPDRS Part II and Part III scores. The PDQ-39 summary index did not differ between groups at week 26; the numerical results for the other secondary endpoints, including MDS-UPDRS Part III, the CGI scales, the Schwab and England scale, and the EQ-5D-5L, are summarized in the supplementary appendix, which was not among the documents reviewed. The statistical analysis plan records that 15 participants were randomized to the incorrect MAO-B inhibitor stratum. White participants made up 268 of 304 (88%) of the population. The prescribing information bases efficacy on MDS-UPDRS Part II, where the placebo-adjusted difference was -1.5 points (95% CI, -2.4 to -0.6). AbbVie funded the trial and participated in its design, data analysis, and interpretation.

Strengths and limitations stated by the investigators

“However, the short observation period limits conclusions about long-term tolerability. An ongoing extension study aims to confirm its long-term safety and efficacy.” (opens the source at this quote in a new tab)
“The main strength of this study was its rigorous, multicentre, double-blind, randomised design. However, there are several limitations to this study. First, direct head-to-head comparisons with D2/D3 dopamine agonists or other therapies for Parkinson’s disease are not possible. Additionally, given the relatively short (6-month) duration of the trial, conclusions could not be drawn around the effects of tavapadon on certain adverse events of special interest in this patient population that require a longer duration to manifest. Thus, more research is needed to confirm the long-term safety and efficacy of tavapadon in people with early Parkinson’s disease.” (opens the source at this quote in a new tab)

Titration requirement and discontinuation rates

“The incidence of adverse events leading to discontinuation decreased substantially after the titration, although discontinuation percentages during the titration phase might also be confounded by the strict protocol requirements for discontinuation of participants unable to tolerate a given titration step or tolerate a minimum of 5 mg of tavapadon.” (opens the source at this quote in a new tab)
“The percentage of discontinuations with tavapadon in this study (38%) was higher than the withdrawal percentages observed in comparable trials of the D2 or D2/D3 dopamine agonists ropinirole (range 11–31%), piribedil (20%), and pramipexole (17–22%).” (opens the source at this quote in a new tab)
“Possible factors for the observed discontinuation rate with tavapadon include the large number of non-adverse event discontinuations (21 [14%] of 151) and the forced titration schedule, which might have limited the ability to adequately mitigate the development of adverse events.” (opens the source at this quote in a new tab)

Limits on cross-trial comparison

“Although head-to-head comparisons with other dopamine agonists cannot be made, the low incidence of certain adverse events (eg, somnolence) in the current study are suggestive of a differentiated mechanism of action with tavapadon compared with currently approved D2/D3 receptor-targeting dopamine agonists.” (opens the source at this quote in a new tab)
“More data are required to compare tavapadon with approved D2/D3 dopamine agonists.” (opens the source at this quote in a new tab)

Clinimetric critique of the combined Parts II and III score

“However, it is important to acknowledge recent clinimetric critiques about the summation of these parts (Part II, patient based; Part III, rater based), which might” (opens the source at this quote in a new tab)
“not be sound without specific monitoring of tremor and non-tremor components.” (opens the source at this quote in a new tab)
“Although this suggests a need for more granular analysis of these data in future research, the validity of the findings from the current trial is supported by the fact that treatment with tavapadon led to significant improvements in the individual MDS-UPDRS Parts II and III scores.” (opens the source at this quote in a new tab)

Need for longer-term data

“However, certain adverse events associated with D2/D3 dopamine agonists (eg, oedema and impulse control disorders) might not be apparent during 27 weeks of treatment; therefore, monitoring for these adverse events remains important until long-term data are available.” (opens the source at this quote in a new tab)
“Additionally, dyskinesias might not appear within the first few months of treatment, further underscoring the importance of long-term data.” (opens the source at this quote in a new tab)

Sponsor funding and role

“Funding for this study was provided by AbbVie. Cerevel is now a part of AbbVie. AbbVie funded this study and participated in study design, research, data analysis, data collection, data interpretation, and supported the authors in the writing of the report and their decision to submit the manuscript for publication.” (opens the source at this quote in a new tab)

Absence of active-comparator and longer-duration trials

“Its proposed neuropsychiatric advantage over D2/D3 agonists remains untested: no trial used an active comparator or exceeded 27 weeks.” (opens the source at this quote in a new tab)
“Impulse control disorder (RR 2.02, 0.51 to 8.00; nine events, one trial) and somnolence (1.20, 0.37 to 3.92) were rated at very low certainty. No outcome reached high certainty.” (opens the source at this quote in a new tab)

Risk of bias and certainty of evidence appraised in a meta-analysis

“B7601003 was rated as raising some concerns for missing outcome data, reflecting its termination at approximately half of planned enrolment, and for selection of the reported result, since it is reported only as a registry results posting. TEMPO-2 was rated as raising some concerns in the latter domain because its results were available only as a registry results posting rather than as a peer-reviewed report.” (opens the source at this quote in a new tab)
“Although the primary analyses used mixed models for repeated measures, which are valid under a missing-at-random assumption, dropout driven predominantly by adverse events in the active arms may not satisfy that assumption and could bias the treatment effect away from the null.” (opens the source at this quote in a new tab)
“Certainty was moderate for three outcomes: the primary outcome of combined MDS-UPDRS Parts II and III in early-stage monotherapy, good ON-time without troublesome dyskinesia in the adjunctive setting, and dizziness. Each was rated down by a single level for risk of bias, arising from the registry-only reporting of TEMPO-2 and B7601003, the early termination of B7601003, and substantial differential attrition in the monotherapy trials.” (opens the source at this quote in a new tab)

Discontinuation and open questions raised in a commentary on TEMPO-2

“the unusually high premature dropout rate observed in the tavapadon group (38%), far above that reported in comparable D2 agonist trials (around 20–25%).” (opens the source at this quote in a new tab)
“Is this specific to tavapadon, or could this be mitigated by a more flexible and less aggressive titration, or by targeting a lower dose (<15 mg/day)? This question requires clarification before tavapadon is made available in clinical practice.” (opens the source at this quote in a new tab)
“Despite this clear positive efficacy signal, TEMPO-2 does not answer some essential questions that are mandatory to anticipate the future positioning of tavapadon among other antiparkinsonian dopaminergic options in clinical practice, especially D2 agonists and L-DOPA. This missing evidence is due to the absence of an active comparator in the trial, its limited sample size, and a short follow-up.” (opens the source at this quote in a new tab)
“The frequency of hallucinations (4%) and impulse control disorders (1%) was low with tavapadon in TEMPO-2 (as in comparable D2 agonist trials), but none occurred on placebo. Longer and larger cohorts are therefore needed to better assess the true difference between tavapadon and D2 agonists in this regard.” (opens the source at this quote in a new tab)

Trial objective: adjunctive tavapadon in levodopa-treated adults with motor fluctuations

“To evaluate the efficacy, safety, and tolerability of tavapadon as adjunctive therapy to oral levodopa in adults with PD experiencing motor fluctuations.” (opens the source at this quote in a new tab)
“The Flexible-Dose, Adjunctive Therapy Trial in Adults With Parkinson Disease With Motor Fluctuations (TEMPO-3) was designed to evaluate the efficacy, safety, and tolerability of flexible-dose tavapadon (5-15 mg once daily) as an adjunctive therapy for PD in levodopa-treated adults experiencing off-time fluctuations.” (opens the source at this quote in a new tab)

Research question stated by the investigators

“Can adjunctive tavapadon—an oral, once-daily, selective dopamine (D) D1/D5 agonist—improve motor control for people with Parkinson disease (PD) experiencing motor fluctuations while minimizing risk of adverse events?” (opens the source at this quote in a new tab)

Registry statement of purpose

“The purpose of this study is to assess the effect of tavapadon on the change from baseline in total daily hours of "on" time without troublesome dyskinesia in L-Dopa-treated participants with Parkinson's Disease (PD) who are experiencing motor fluctuations.” (opens the source at this quote in a new tab)

Protocol rationale for the trial

“By targeting the D1R subtype, tavapadon aims to improve motor control symptoms while minimizing adverse events (AEs) that may be mechanistically linked to D2/D3 dopamine receptor agonists (notably, dose-limiting hypotension, impulse control disorders, sleep disorders, and, potentially, some forms of hallucinations).” (opens the source at this quote in a new tab)
“This prospective, Phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group, 27-week trial will evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of flexible doses of tavapadon (5 mg to 15 mg once daily [QD]) as adjunctive therapy for PD in levodopa (L-Dopa)-treated adults with motor fluctuations to further define and confirm the magnitude of efficacy and risk/benefit profile of this target dose range.” (opens the source at this quote in a new tab)

Summary: sites, countries, and enrollment period

The primary publication reports 148 sites in 14 countries and a trial period of September 2020 to February 2024. The registry record for NCT04542499 lists 146 locations in the same 14 countries: the United States (54), Poland (13), Germany (11), Spain (11), Italy (10), Ukraine (8), Bulgaria (7), France (6), Israel (6), Australia (5), Czechia (5), Hungary (4), Serbia (4), and Canada (2). The registry gives an actual start date of September 23, 2020, an actual primary completion date of January 29, 2024, and an actual study completion date of February 15, 2024. The protocol (CVL-751-PD-003) names Cerevel Therapeutics, LLC as sponsor; the registry now lists AbbVie.

Number of sites, countries, and study period

“This was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted between September 2020 and February 2024 with a 4-week safety follow-up. Participants were recruited from 148 sites across 14 countries.” (opens the source at this quote in a new tab)
“The trial was conducted from September 2020 to February 2024. Participation lasted approximately 35 weeks, including a 4-week maximum screening period, a 27-week treatment period, and a 4-week safety follow-up period (Figure 1A).” (opens the source at this quote in a new tab)

Randomized, double-blind, placebo-controlled, parallel-group design

“The TEMPO-3 trial was a prospective, phase 3, multicenter, double-blind, placebo-controlled, parallel-group, 27-week randomized clinical trial conducted at 148 clinical sites across 14 countries (the trial protocol and statistical analysis plan are available in Supplement 1 and Supplement 2, respectively).” (opens the source at this quote in a new tab)
“The trial was conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation Good Clinical Practice guidelines, and was approved by independent ethics committees before initiation; participants or their representatives provided written informed consent before screening and enrollment. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.” (opens the source at this quote in a new tab)

Registered official title and masking

“A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Flexible-Dose, 27-Week Trial to Evaluate the Efficacy, Safety, and Tolerability of Tavapadon as Adjunctive Therapy for Parkinson's Disease in Levodopa-Treated Adults With Motor Fluctuations (TEMPO-3 Trial)” (opens the source at this quote in a new tab)

Maintenance of blinding

“Participants, investigators, and all blinded sponsor personnel remained blinded until final database lock.” (opens the source at this quote in a new tab)
“All participants took 3 tablets of tavapadon, placebo, or a combination of tavapadon and placebo once daily during the treatment period; all tablets and packaging were identical in appearance for blinded dose adjustment.” (opens the source at this quote in a new tab)

Scientific rationale for the design stated in the protocol

“The randomized, double-blind, placebo-controlled, parallel-group trial design is widely accepted as one that minimizes the risk of bias and that is appropriate for evaluating the effects of a trial treatment in indications in which use of a placebo is ethical (US FDA, 2001).” (opens the source at this quote in a new tab)

Visit schedule, diary collection, and entry into the open-label extension

“Assessments will be conducted in the clinic at the end of Weeks 2, 5, 8, 11, 14, 18, 22, 26, and 27. Subjects will complete the Hauser diary on 2 consecutive days within the 7 days before each scheduled postbaseline clinic visit.” (opens the source at this quote in a new tab)
“Subjects who complete through Week 27 of the trial may have the opportunity to enter an open-label extension trial (Protocol CVL-751-PD-004).” (opens the source at this quote in a new tab)

Design described in the prescribing information

“The efficacy of JUVMO for the treatment of PD as adjunctive therapy to levodopa was established in a 27-week, double-blind, randomized, placebo-controlled, parallel-group, flexible-dose trial, Study 3 (NCT04542499).” (opens the prescribing information at this quote)

Place of the trial in the phase 3 program

“The TEMPO clinical development program is evaluating the efficacy, safety and tolerability of tavapadon across a broad Parkinson’s population, including two monotherapy Phase 3 trials (TEMPO-1 and TEMPO-2) and one adjunctive Phase 3 trial (TEMPO-3). Cerevel is also conducting a fourth, open-label extension (OLE) trial (TEMPO-4) to assess the long-term safety and tolerability of tavapadon.” (opens the source at this quote in a new tab)

Key inclusion criteria reported in the primary publication

“Eligible participants included adults aged 40 to 80 years with a diagnosis of PD consistent with the UK Parkinson Disease Society Brain Bank criteria, a modified Hoehn & Yahr score of 2, 2.5, or 3 in the on-state (ie, good mobility, smoother movement, fewer motor/nonmotor symptoms), a minimum of 2.5 hours of daily off-time on 2 consecutive days during the screening period (ie, return/worsening of motor/nonmotor symptoms often experienced between medication doses), a minimum stable dose of 400 mg of levodopa per day divided at least 3 or 4 times daily, and a good response to levodopa per investigator judgment.” (opens the source at this quote in a new tab)
“Participants were required to demonstrate an acceptable ability to complete the Hauser diary” (opens the source at this quote in a new tab)
“on concordance testing during the screening period, and to maintain the same levodopa dose and frequency for the trial duration.” (opens the source at this quote in a new tab)

Key exclusion criteria and permitted concomitant medications

“Exclusion criteria included atypical or secondary parkinsonian syndrome, previous or planned surgical intervention for PD, Montreal Cognitive Assessment score less than 26, history of or current diagnosis of a clinically significant impulse control disorder, history of psychosis or hallucinations for 12 months or less, or current use (≤14 days of baseline) of DAs.” (opens the source at this quote in a new tab)
“Previous and concurrent use of catechol-O-methyl transferase inhibitors, monoamine oxidase inhibitor B inhibitors, amantadine, istradefylline, or anticholinergic drugs was permitted if initiated more than 90 days before the baseline visit; dosage changes for concurrent PD medications were not permitted.” (opens the source at this quote in a new tab)

Levodopa regimen and diary requirements as registered

“Participants who return a completed self-reported home diary for motor function status (Hauser diary) during the screening period (after diary training and concordance testing has occurred), with recordings for 2 consecutive days (ie, 2 consecutive 24-hour periods) showing at least 2 and half hours of "off" time on each of the 2 days.” (opens the source at this quote in a new tab)
“Participants who are on a stable dose of L-Dopa for at least 4 weeks prior to screening and are taking a minimum total daily dose of 400 milligram (mg) divided in at least 4 doses per day of standard carbidopa/levodopa or divided in at least 3 doses per day of extended-release carbidopa/levodopa capsules. The carbidopa/levodopa dose and frequency must be maintained for the duration of the trial.” (opens the source at this quote in a new tab)

Registered exclusion criteria: psychiatric, cardiovascular, and drug interaction conditions

“Participants with a history of psychosis or hallucinations within the previous 12 months.” (opens the source at this quote in a new tab)
“Participants who are currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors(except for topical administration).” (opens the source at this quote in a new tab)
“Participants with clinically significant orthostatic hypotension (eg, syncope).” (opens the source at this quote in a new tab)
“Participants with moderate or severe renal impairment (creatinine clearance as estimated by Cockcroft-Gault formula <30 mL/min or on dialysis).” (opens the source at this quote in a new tab)

Randomization, flexible dosing, and fixed levodopa dose

“Participants were randomized 1:1 to receive flexible-dose tavapadon (5-15 mg once daily) or placebo as adjunct to levodopa, using a computer-generated randomization scheme.” (opens the source at this quote in a new tab)
“Tavapadon was gradually titrated to the maximum tolerated dose (up to 15 mg once daily) over the first 14 weeks of the trial during the dose titration and dose adjustment phases (eTable 1 in Supplement 3). Further adjustments during the maintenance phase were not permitted. For both treatment groups, the levodopa dose was fixed, without dose adjustments for the duration of the trial.” (opens the source at this quote in a new tab)

Tavapadon and placebo dosing schedule

Trial day	Titration step	Blinded treatment assignment
Blinded dose titration phase	“Days 1-4”	“0.25 mg of tavapadon or placebo QD”
Blinded dose titration phase	“Days 5-8”	“0.5 mg of tavapadon or placebo QD”
Blinded dose titration phase	“Days 9-12”	“0.75 mg of tavapadon or placebo QD”
Blinded dose titration phase	“Days 13-16”	“1 mg of tavapadon or placebo QD”
Blinded dose titration phase	“Days 17-20”	“1.5 mg of tavapadon or placebo QD”
Blinded dose titration phase	“Days 21-24”	“2.25 mg of tavapadon or placebo QD”
Blinded dose titration phase	“Days 25-40”	“3 mg of tavapadon or placebo QD”
Blinded dose titration phase	“Days 41-56”	“5 mg of tavapadon or placebo QD”
Blinded dose adjustment phase	“Days 57-72”	“10 mg of tavapadon or placebo QD”
Blinded dose adjustment phase	“Days 73-104”	“15 mg of tavapadon or placebo QD”
Blinded maintenance phase	“Days 105-189”	“Maximum tolerated dose of tavapadon (5-15 mg) or placebo QD”

Maintenance doses achieved

“Participants received the highest tolerated dose level that was achieved during the dose adjustment phase (5 mg, 22 participants [8.8%]; 10 mg, 32 participants [12.7%]; 15 mg, 169 participants [67.3%]). No adjustment in the tavapadon dose was allowed during the maintenance phase.” (opens the source at this quote in a new tab)

Dose reduction and rechallenge rules

“A reduction in dose (from 15 mg QD to 10 mg QD or from 10 mg QD to 5 mg QD) will be allowed based on individual subject tolerability. Subjects who require a dose reduction may be rechallenged with the higher dose, at the discretion of the investigator, to address symptomatic needs.” (opens the source at this quote in a new tab)
“Subjects will receive the highest tolerated dose level that is achieved during the Dose Adjustment Phase for the duration of the subsequent 13-week Maintenance Phase. Adjustments in the dose of tavapadon will not be allowed during the Maintenance Phase. Subjects who cannot tolerate their maintenance dose will be discontinued from the trial.” (opens the source at this quote in a new tab)

Justification for the 5 mg to 15 mg dose range

“These data suggest that doses <5 mg QD are unlikely to deliver clinically meaningful benefit over placebo in motor symptom control to most patients with PD.” (opens the source at this quote in a new tab)
“The safety and pharmacokinetic data from this Phase 1 trial suggest that doses >15 mg QD are unlikely to have an optimal risk/benefit profile for patients with PD.” (opens the source at this quote in a new tab)
“Taken together, these findings suggest that an optimal dose range of tavapadon for the treatment of PD may reasonably be between 5 and 15 mg QD for the individual patient, based on symptomatic needs and tolerability thresholds.” (opens the source at this quote in a new tab)

Dosing described in the prescribing information

“Patients in Study 3 were on a fixed dose of levodopa and were titrated to JUVMO 15 mg once daily unless prevented by intolerance, resulting in maintenance doses between 5 mg and 15 mg (n=251), compared to placebo (n=254).” (opens the prescribing information at this quote)

Primary, key secondary, and other secondary endpoints

“The primary end point was the change from baseline to week 26 in total daily on time without troublesome dyskinesia (referred to as good-on-time) based on the 2-day average of the Hauser diary.” (opens the source at this quote in a new tab)
“The key secondary end point was change from baseline to week 26 in total daily off-time. Other secondary end points included change from baseline in good-on-time and off-time at all time points, change from baseline in Movement Disorder Society-Unified Parkinson Disorder Rating Scale (MDS-UPDRS) parts I, II, and III individual and combined scores (week 26 and all time points), Parkinson Disease Questionnaire (PDQ) 39 score,” (opens the source at this quote in a new tab)
“and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) index and visual analog scale (VAS) scores.” (opens the source at this quote in a new tab)
“MDS-UDPRS assessments were conducted approximately 2 to 3 hours after the last dose of levodopa, and participant scores could have been collected during on or off status.” (opens the source at this quote in a new tab)

Exploratory, post hoc, and safety end points

“Change from baseline in MDS-UDPRS parts II+III scores was a predefined exploratory end point. Additionally, a post hoc analysis evaluated changes from baseline to week 26 (the end of treatment) in additional motor states (eg, on-time with nontroublesome dyskinesia, on-time without dyskinesia) across the normal waking day as recorded in the Hauser diary.” (opens the source at this quote in a new tab)
“Safety end points included AEs, clinical laboratory values, vital signs (including orthostatic values), and electrocardiograms. Columbia-Suicide Severity Rating Scale (C-SSRS),” (opens the source at this quote in a new tab)
“Epworth Sleepiness Scale (ESS),” (opens the source at this quote in a new tab)
“and Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease-Rating Scale (QUIP-RS)” (opens the source at this quote in a new tab)
“scores were also assessed at each visit.” (opens the source at this quote in a new tab)

Registered primary outcome measure and diary categories

“Change From Baseline in the Total "On" Time Without Troublesome Dyskinesia Based on the 2-day Average of the Self-completed Home Diary for Motor Function Status (Hauser Diary)” (opens the source at this quote in a new tab)
“The Hauser diary asks participants to rate their mobility for each 30-minute period and to record their status for the majority of the period in 1 of 5 categories as: "on" time without dyskinesia, "on" time with nontroublesome dyskinesia, "on" time with troublesome dyskinesia, "off" time, or asleep.” (opens the source at this quote in a new tab)

Registered MDS-UPDRS secondary outcome and score ranges

“The MDS-UPDRS rating tool was used to follow longitudinal course of Parkinson's Disease. It was made up of 4 parts: Part 1: Non-motor aspects of experiences of daily living (13 items. Score range: 0-52); Part 2: Motor aspects of experiences of daily living (13 items. Score range: 0-52); Part 3: Motor examination (18 items. Score range: 0-132); Part 4: Motor complications (6 items. Score range: 0-24. Part 4 was not collected in this trial). Each item has 0-4 rating on scale from 0 (normal) to 4 (severe). Higher values represent a worse outcome.” (opens the source at this quote in a new tab)

Protocol rationale for the Hauser diary and the clinically important difference in off time

“The minimum clinically important difference (smallest change that is meaningful to patients) for a reduction in “off” time (key secondary efficacy endpoint) has been reported to be 1.0 hour (Hauser et al, 2011; Hauser et al, 2014).” (opens the source at this quote in a new tab)
“The MDS-UPDRS is a comprehensive assessment that is designed to monitor the burden and extent of PD across the longitudinal disease course and provides a clinical endpoint in therapy trials (Goetz et al, 2008).” (opens the source at this quote in a new tab)

Diary recording procedure in the protocol

“Subjects will record diary entries at home at 30-minute intervals for 24 hours on 2 consecutive days within the 7 days before randomization at the Baseline Visit and at 30-minute intervals for 24 hours on 2 consecutive days within the 7 days before each postbaseline clinic visit.” (opens the source at this quote in a new tab)

Phase 2 effect size that informed the trial

“In a Phase 2 trial of tavapadon in L-Dopa-treated subjects with PD who were experiencing motor fluctuations (Trial B7601003), analysis of the change from baseline in average daily “on” time without troublesome dyskinesia showed that the magnitude of benefit of tavapadon 15 mg QD, relative to placebo, was approximately 1 hour at Week 10.” (opens the source at this quote in a new tab)

Development of the diary: dyskinesia categories and patient-defined good and bad time

“In both studies, patients concurrently completed a test and a reference diary.” (opens the source at this quote in a new tab)
“In Study II, we evaluated a new home diary designed to separate dyskinesia that had a negative impact on patient-defined functional status from dyskinesia that did not. There were 816 evaluable time periods from 17 patients; 84.9% of off time and 89.9% of on time with troublesome dyskinesia was considered bad time while 85.5% of on time without dyskinesia and 93.8% of on time with nontroublesome dyskinesia was considered good time.” (opens the source at this quote in a new tab)
“In evaluating the efficacy of an intervention, assessment of change in off time and change in on time with troublesome dyskinesia provides a more accurate reflection of clinical response than change in off time alone.” (opens the source at this quote in a new tab)

Validation of good on time as a trial outcome

“In the current study, PD patients with motor fluctuations and dyskinesia (present more than 25% of the awake day and at least moderately disabling) completed daily diaries on 3 consecutive days in each of 2 consecutive weeks.” (opens the source at this quote in a new tab)
“Three hundred two patients from 10 countries participated.” (opens the source at this quote in a new tab)
“Mean age was 65.5 years (range, 37–89 years), and 48% of patients were women.” (opens the source at this quote in a new tab)
“They were instructed to place a tick mark on a daily diary card every 30 minutes reflecting their predominant status over the prior half-hour period.” (opens the source at this quote in a new tab)
“Seventy-six percent of the missing or duplicate entries occurred after Day 3.” (opens the source at this quote in a new tab)
“Coefficients of reliability as calculated by Cronbach's alpha were as follows: 2 days, r = 0.806; 3 days, r = 0.868; 4 days, r = 0.918; 5 days, r = 0.934; 6 days, r = 0.946.” (opens the source at this quote in a new tab)
“Mean percentages of the awake day (± SD) for each of the diary categories for all patients over the 6 days were as follows: off, 24.7 ± 15.2; on without dyskinesia, 27.4 ± 19.8; on with nontroublesome dyskinesia, 26.7 ± 14.9; and on with troublesome dyskinesia, 21.2 ± 16.0. Mean percent of the awake day spent in good on time (ONG%) was 54.1 ± 19.1.” (opens the source at this quote in a new tab)
“Mean ONG% was observed to be very stable in time (repeated measurement ANOVA, P = 0.9939).” (opens the source at this quote in a new tab)
“The mean correlation for any pair of days was r = 0.74 (SD = 0.06, range = 0.65,0.85). Between any 2 consecutive days, the mean correlation was r = 0.79 (SD = 0.04, range = 0.71,0.82).” (opens the source at this quote in a new tab)
“Under these conditions, the point estimate ICC was 0.715, and the 95% one-sided lower limit was found to be 0.710. The standard error of measurement (SEM) was calculated to be 10.75%.” (opens the source at this quote in a new tab)
“Sample size calculations ranged from N = 42 (4 days of diaries at baseline and endpoint, alpha = 0.05, beta = 0.2, one tail) to N = 99 (2 days of diaries at baseline and endpoint, α = 0.05, β = 0.1, two tails).” (opens the source at this quote in a new tab)
“Of note, the VAS response to the question “How much of the day today did you experience a good response?” more strongly correlated with ONG% (0.41) than ON% (0.24).” (opens the source at this quote in a new tab)
“The maximum error (at the 95% level) as determined by the standard error of measurement was 15.2% for 2 days of diaries, 12.4% for 3 days, and 10.8% for 4 days.” (opens the source at this quote in a new tab)
“Test-retest reliability was good, and reliability increased with increasing number of diary days but compliance diminished beyond 3 days. Good on time (ONG = on time without dyskinesia or with nontroublesome dyskinesia) most strongly correlated with patients' perceived duration of a good response through the day and is an important outcome variable.” (opens the source at this quote in a new tab)
“We anticipate that most clinical trials will use 2 to 4 days of diaries for each assessment point. Having more diary days provides greater reliability but increases cost and effort and potentially reduces compliance. This diary provides good test–retest reliability at 2 days and increasing reliability with increasing number of days. However, most of the diary errors occurred after 3 days. Perhaps the most important determinant in selecting the number of diary days is the anticipated efficacy of the intervention, as more diary days allows detection of smaller changes.” (opens the source at this quote in a new tab)
“Although patients received training regarding the definitions of the various diary designations, the study did not include external validation to assess the accuracy of patient responses.” (opens the source at this quote in a new tab)

Minimal important difference in good on time by number of diary days

Diary days	Minimal important difference in good on time, % of the awake day
1	“21.5”
2	“15.2”
3	“12.4”
4	“10.8”
5	“9.6”
6	“8.8”

Minimal clinically important change in off time: rasagiline trial data

“PRESTO included 472 levodopa-treated PD subjects with motor fluctuations who were randomized to rasagiline, 0.5 or 1.0 mg/day, or matching placebo and followed for 6 months.” (opens the source at this quote in a new tab)
“The PRESTO study utilized home diaries to capture subject-rated ‘‘on,’’ ‘‘off,’’ and asleep time every half hour for 3 days prior to the baseline, week 6, week 14, and week 26 visits.” (opens the source at this quote in a new tab)
“Subject and investigator CGI-I were determined at week 26; both were used for this analysis, however, we considered subject-rated CGI-I to be the better measure of clinically important change.” (opens the source at this quote in a new tab)
“The Spearman correlation coefficient between CGI-I and change in ‘‘off’’ time at week 26 for advanced PD subjects in the PRESTO study was 0.46 (all P < .001).” (opens the source at this quote in a new tab)
“Based on subject-rated CGI-I, mean (SD) changes in ‘‘off’’ time for subjects in an active treatment group of the PRESTO study were −1.9 (2.2) hours for those rated minimally improved and −0.5 (2.2) hours for those rated minimally worse. Corresponding values for subjects in the placebo group were −1.9 (2.7) and 0.3 (2.3) hours.” (opens the source at this quote in a new tab)
“The optimal cutoff for change in ‘‘off’’ time to distinguish rasagiline-treated subjects rated minimally improved versus unchanged was −1.2 hours; the optimal cutoff for placebo subjects was −1.8 hours.” (opens the source at this quote in a new tab)
“The optimal cutoff to distinguish rasagiline-treated subjects rated minimally worse versus unchanged was 0.2 hours; the optimal cutoff for placebo subjects was −0.7 hours.” (opens the source at this quote in a new tab)
“In general, values for no change, minimally improved, and minimally worse were very similar to those derived using subject-rated CGI-I.” (opens the source at this quote in a new tab)
“In addition, we found an MCIC for reduction in "off" time of 1.0 hours as defined by mean reduction in "off" time in active treated subjects self-rated as minimally improved on CGI-I minus mean reduction in "off" time in placebo-treated subjects self-rated as unchanged (1.9-0.9 hours).” (opens the source at this quote in a new tab)
“As defined by mean change in subjects rated minimally improved on CGI-I, we found the MCIC for reduction in ‘‘off’’ time in patients with motor fluctuations to be 1.9 hours in both actively and placebo-treated subjects. However, we also note that there was a mean reduction in ‘‘off’’ time of 0.9 hours in placebo-treated subjects and 0.7 hours in actively treated subjects self-rated as unchanged on the CGI-I. This suggests that there may be a greater placebo effect on diary-recorded ‘‘off’’ hours than on CGI-I (in both placebo and active treatment groups).” (opens the source at this quote in a new tab)
“Similarly, we found that a reduction in ‘‘off’’ time of 1.2 hours best distinguished active treatment subjects rated minimally improved from those rated unchanged.” (opens the source at this quote in a new tab)
“By definition, MCICs derived from ROC cutoffs are smaller than those derived using mean scores. Whether one approach is superior to the other to MCIC is unknown.” (opens the source at this quote in a new tab)
“We hypothesize that many methodological factors can influence determination of the MCIC, and a range of values is likely to emerge from multiple studies.” (opens the source at this quote in a new tab)
“There are multiple limitations of our analyses. There could potentially be bias in the external anchor, in this case, the CGI-I.” (opens the source at this quote in a new tab)
“In our study, there was moderately good correlation between change in ‘‘off’’ time and subject-rated CGI-I scores, but the correlations between change in UPDRS scores and investigator-rated CGI-I scores, although acceptable, were not as strong.” (opens the source at this quote in a new tab)

Change in off time by subject-rated global impression, and receiver operating characteristic cutoffs: rasagiline trial data

Treatment group and subject-rated global impression of improvement	Sample size	Change in off time, hours, mean (SD)	ROC curve cutoff, hours	Sensitivity	Specificity	Area under curve
Rasagiline, very much improved	“26”	“−3.3 (2.2)”	“−2.2”	“0.73”	“0.71”	“0.8”
Rasagiline, much improved	“54”	“−3.5 (2.6)”	“−2.5”	“0.65”	“0.78”	“0.79”
Rasagiline, minimally improved	“69”	“−1.9 (2.2)”	“−1.2”	“0.71”	“0.57”	“0.65”
Rasagiline, no change	“63”	“−0.7 (2.2)”	Not applicable	Not applicable	Not applicable	Not applicable
Rasagiline, minimally worse	“48”	“−0.5 (2.2)”	“0.2”	“0.42”	“0.68”	“0.54”
Rasagiline, much worse	“12”	“−0.6 (2.6)”	“0.3”	“0.58”	“0.7”	“0.52”
Placebo, much improved	“16”	“−1.9 (1.9)”	“−1.7”	“0.75”	“0.66”	“0.67”
Placebo, minimally improved	“27”	“−1.9 (2.7)”	“−1.8”	“0.56”	“0.66”	“0.65”
Placebo, no change	“44”	“−0.9 (2.5)”	Not applicable	Not applicable	Not applicable	Not applicable
Placebo, minimally worse	“43”	“0.3 (2.3)”	“−0.7”	“0.74”	“0.52”	“0.63”
Placebo, much worse	“8”	“1.7 (4.3)”	“0.2”	“0.88”	“0.64”	“0.72”

Minimal clinically important difference in off time: pramipexole extended-release trial data

“In the APD trial, we calculated the MCID for OFF time to be −1.0 hours in the pramipexole ER group and −1.3 hours in the pramipexole IR group.” (opens the source at this quote in a new tab)
“In surveying the literature to date, studies suggest that the lower limit of MCID for total UPDRS (I + II + III) is −3.8 and for change on OFF time is −1.0 hour” (opens the source at this quote in a new tab)

Minimal clinically important differences for MDS-UPDRS Parts I, II, and III

“Nine hundred eighty-five paired investigations of 365 patients were reviewed, implementing three different techniques simultaneously.” (opens the source at this quote in a new tab)
“Any improvement greater than 2.64 points or any worsening more than 2.45 points on MDS-UPDRS Part I represent a minimal, yet clinically meaningful change.” (opens the source at this quote in a new tab)
“In reference to Part II, the smallest changes considered clinically relevant were 3.05 and 2.51 points for improvement and deterioration, respectively.” (opens the source at this quote in a new tab)

“Therefore, 728 paired follow-up visits of 260 patients were utilized for the analyses.” (opens the source at this quote in a new tab)
“The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening.” (opens the source at this quote in a new tab)

“Based on our calculations, the MCID thresholds for the MDS-UPDRS I+II+III are –6.7 and +5.2 points for identifying clinically relevant improvement and worsening.” (opens the source at this quote in a new tab)
“Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change.” (opens the source at this quote in a new tab)

Investigators' interpretation of the observed off-time reduction against the clinically important difference

“Improvements in good-on-time are associated with better clinical outcomes, improved quality of life, and reduced economic burden.” (opens the source at this quote in a new tab)
“The LSM decrease in off-time from baseline to week 26 observed in the tavapadon group (−1.88 hours) is comparable with improvements in off-time seen with other adjunctive PD therapies, including D2/D3 agonists, and surpasses the previously reported minimum clinically important difference for a reduction in off-time of approximately 1.0 hour.” (opens the source at this quote in a new tab)

Planned sample size, power, and interim sample size increase

“A sample size of 184 participants per group provided greater than or equal to 90% power to detect a 1-hour treatment difference in the primary outcome measure at a 2-sided .05 significance level, with an assumed SD of 2.5 hours. Because sample size assumptions were based on a preliminary trial with limited sample size and a different dosing schedule, an interim analysis to assess the adequacy of the sample size assumption was performed by an independent external review committee, and the target trial sample size subsequently increased from 368 to 500 participants to maintain statistical power at 90%.” (opens the source at this quote in a new tab)

Protocol sample size assumptions

“A sample size of 184 subjects per group (total, 368 subjects) will provide at least 90% power to detect a change in the primary outcome measure (change from baseline in “on” time without troublesome dyskinesia) of 1 hour with a standard deviation of 2.5, a 2-sided alpha level = 0.049, and assuming a 27% dropout rate.” (opens the source at this quote in a new tab)
“This analysis will be conducted by an independent Interim Analysis Review Committee (IARC), which may make a recommendation to increase the overall sample size up to a maximum of 528 subjects.” (opens the source at this quote in a new tab)

Participants screened, randomized, and analyzed

“Of 842 screened individuals, 507 (mean [SD] age, 64.9 [8.5] years; 186 female [37%]; 321 male [63%]) were randomized to receive tavapadon (n = 252) or placebo (n = 255) in addition to levodopa (randomization by site shown in eTable 2 in Supplement 3); 505 received at least 1 dose of study treatment and were included in the safety analysis, and 487 met criteria for the mITT population (Figure 1B).” (opens the source at this quote in a new tab)

Number screened stated in the abstract

“After screening 824 adults with PD, 507 participants (mean [SD] age, 64.9 [8.5] years; 321 male [63%]; mean [SD] disease duration, 6.7 [4.5] years; mean [SD] baseline daily off-time, 5.5 [2.4] hours) were enrolled and received tavapadon (n = 252) or placebo (n = 255).” (opens the source at this quote in a new tab)

Participants analyzed for the primary and key secondary end points

Measure	Tavapadon	Placebo
Participants in the primary and key secondary analysis (prescribing information, Table 10)	“(N = 242)”	“(N = 245)”

Participants with week 26 data in the registry results

Measure	Placebo	Tavapadon
Overall number of participants analyzed, week 26 on time without troublesome dyskinesia	“201”	“153”
Least squares mean (SE) change from baseline, hours	“0.619(0.188)”	“1.721(0.207)”

Modified intention-to-treat and safety analysis sets and the analysis model

“Efficacy analyses were conducted using a mixed model for repeated measures (MMRM) approach based on a modified intention-to-treat (mITT) population (ie, randomized participants who received ≥1 dose of the assigned treatment and had both baseline and ≥1 postbaseline Hauser diary entries). For the primary and key secondary analyses, MMRM included fixed effects of treatment, visits, and interaction between treatment and visit with baseline total daily on-time or off-time (for the primary and key secondary analysis, respectively) included as a covariate and participant included as a random effect. Statistical comparisons for other secondary end points were not corrected for multiplicity; therefore, P values should be interpreted as nominal. The safety analysis set included all participants who received 1 or more doses of tavapadon or placebo.” (opens the source at this quote in a new tab)

Analysis populations defined in the protocol

Population	Description	Analysis
ITT	“All randomized subjects”	“Demographic and Baseline Characteristics”
FAS	“All randomized subjects who receive at least 1 dose of IMP. This will be the safety analysis set.”	“Safety analysis”
mITT	“All randomized subjects who receive at least 1 dose of IMP and have both a baseline and at least 1 postbaseline Hauser diary entry”	“Primary analysis set for efficacy”
Endpoint completers	“All subjects in the mITT population who complete the Hauser diary at endpoint”	“Sensitivity analysis for efficacy”
PK analysis set	“All randomized subjects who receive at least 1 dose of IMP and have at least 1 measurable tavapadon (CVL-751) concentration”	“PK analysis”

Hierarchical testing and alpha adjustment for the interim analysis

“The hypothesis testing will be done in hierarchical order from the primary endpoint onward.” (opens the source at this quote in a new tab)
“hypothesis will be tested at an α level of 0.049 (2-sided) to ensure that the overall Type I error rate is below 0.05. Subsequent testing in the secondary endpoints will be conducted at an α level of 0.05 (2-sided).” (opens the source at this quote in a new tab)

Handling of intercurrent events and missing data

“A hypothetical strategy will be used to address the intercurrent events of discontinuation or use of prohibited medications with the data post intercurrent events treated as censored.” (opens the source at this quote in a new tab)
“Sensitivity analyses for the primary and secondary endpoints will be conducted with different assumptions on missing mechanism. Sensitivity analysis will also be conducted on the endpoint completer set with MMRM.” (opens the source at this quote in a new tab)

Missing-at-random assumption in the statistical analysis plan

“The missing values are assumed to be missing at random for the main analysis, including missing due to missed visits or early termination due to COVID-19 control measures.” (opens the source at this quote in a new tab)
“A pattern mixture model (PMM) approach will be used to address potentially MNAR patterns.” (opens the source at this quote in a new tab)

Discontinuation by treatment group

“A total of 142 participants (28.0%) discontinued the trial, including 93 (36.9%) in the tavapadon group and 49 (19.2%) in the placebo group. Discontinuation reasons included both AEs and non-AE related reasons, such as withdrawal by participant and site terminations due to the war in Ukraine (Figure 1B).” (opens the source at this quote in a new tab)

Participant flow and reasons for not completing the trial

Milestone or reason	Placebo	Tavapadon
Started	“255”	“252”
Completed	“206”	“159”
Not completed	“49”	“93”
Adverse event	“23”	“43”
Lack of efficacy	“5”	“2”
Lost to follow-up	“3”	“4”
Failure to meet continuation criteria	“0”	“1”
Treatment with prohibited concomitant medications	“1”	“0”
Non-compliance with study drug	“0”	“2”
Physician decision	“0”	“1”
Site terminated by sponsor	“3”	“5”
Withdrawal by subject	“12”	“33”
Other	“2”	“2”

Exposure and follow-up duration

“All-cause mortality were reported from enrollment to the end of study, median time on follow up (median time subjects were followed) was 190 and 189 days for Placebo and Tavapadon, respectively. Treatment-emergent adverse events and serious adverse events were collected from first dose of study drug until 4 weeks after the last dose of study drug; mean duration on study drug was 169.6 and 151.7 days for Placebo and Tavapadon, respectively.” (opens the source at this quote in a new tab)

Timing of discontinuations due to adverse events

“AEs led to treatment discontinuation in 17.1% of participants in the tavapadon group compared with 9.1% in placebo; discontinuations due to AEs occurred most commonly during the titration phase (placebo, 17 [7%]; tavapadon, 28 [11%]).” (opens the source at this quote in a new tab)

“Of the 43 patients receiving JUVMO who discontinued because of an adverse reaction, 38 (88%) did so during the titration and adjustment phases. The most common adverse reactions leading to discontinuation included nausea, dyskinesia, visual hallucination, and dizziness.” (opens the prescribing information at this quote)

Demographic and disease characteristics of the randomized population

“Demographics and baseline disease characteristics were similar between groups and reflective of a population with PD and motor fluctuations (Table 1); the mean (SD) duration since diagnosis was 6.7 (4.5) years, and participants experienced a mean (SD) of 5.52 (2.37) hours of daily off-time and 10.02 (2.60) hours of daily on-time without troublesome dyskinesia at baseline. Participants self-reported the following races and ethnicities: 2 American Indian or Alaska Native (0.4%), 4 Asian (0.8%), 6 Black (1.2%), 491 White (96.8%), and 4 other (0.8%).” (opens the source at this quote in a new tab)

Baseline demographics and disease characteristics by treatment group

Characteristic	Placebo QD (n = 255)	Tavapadon 5-15 mg QD (n = 252)	Overall (N = 507)
Age, mean (SD) [range], y	“64.1 (8.5) [43-80]”	“65.6 (8.4) [43-80]”	“64.9 (8.5) [43-80]”
Age <65 y, No. (%)	“119 (46.7)”	“104 (41.3)”	“223 (44.0)”
Age ≥65 y, No. (%)	“136 (53.3)”	“148 (58.7)”	“284 (56.0)”
Female, No. (%)	“85 (33.3)”	“101 (40.1)”	“186 (36.7)”
Male, No. (%)	“170 (66.7)”	“151 (59.9)”	“321 (63.3)”
American Indian or Alaska Native, No. (%)	“2 (0.8)”	“0”	“2 (0.4)”
Asian, No. (%)	“2 (0.8)”	“2 (0.8)”	“4 (0.8)”
Black, No. (%)	“4 (1.6)”	“2 (0.8)”	“6 (1.2)”
White, No. (%)	“245 (96.1)”	“246 (97.6)”	“491 (96.8)”
Other race, No. (%)	“2 (0.8)”	“2 (0.8)”	“4 (0.8)”
Weight, mean (SD), kg	“79.9 (15.7)”	“79.5 (17.2)”	“79.7 (16.5)”
BMI, mean (SD) [range]	“27.0 (4.4) [16.6-40.2]”	“27.4 (5.1) [16.6-42.4]”	“27.2 (4.7) [16.2-46.4]”
Time since initial diagnosis, mean (SD), y	“6.4 (4.6)”	“6.9 (4.5)”	“6.7 (4.5)”
Daily on-time without troublesome dyskinesia, mean (SD), h	“10.1 (2.6)”	“9.9 (2.6)”	“10.0 (2.6)”
Daily off-time, mean (SD), h	“5.4 (2.5)”	“5.6 (2.2)”	“5.5 (2.4)”
MoCA total score, mean (SD)	“28.0 (1.3)”	“28.0 (1.3)”	“28.0 (1.3)”
Modified H&Y stage 2, No. (%)	“146 (57.3)”	“135 (53.6)”	“281 (55.4)”
Modified H&Y stage 2.5, No. (%)	“50 (19.6)”	“63 (25.0)”	“113 (22.3)”
Modified H&Y stage 3, No. (%)	“59 (23.1)”	“54 (21.4)”	“113 (22.3)”
MDS-UPDRS part I score, mean (SD)	“7.5 (4.9)”	“8.0 (5.1)”	“7.7 (5.0)”
MDS-UPDRS part II score, mean (SD)	“12.5 (7.1)”	“13.3 (6.5)”	“12.9 (6.8)”
MDS-UPDRS part III score, mean (SD)	“32.4 (14.3)”	“32.6 (14.3)”	“32.5 (14.3)”
MDS-UPDRS part II + III score, mean (SD)	“44.9 (18.9)”	“45.9 (18.2)”	“45.4 (18.5)”
Adjunctive PD medication added to levodopa: yes, No. (%)	“108 (42.4)”	“115 (45.6)”	“223 (44.0)”
Amantadine, No. (%)	“40 (15.7)”	“49 (19.4)”	“89 (17.6)”
COMT inhibitors, No. (%)	“19 (7.5)”	“17 (6.7)”	“36 (7.1)”
Istradefylline, No. (%)	“2 (0.8)”	“1 (0.4)”	“3 (0.6)”
MAO-B inhibitors, No. (%)	“77 (30.2)”	“76 (30.2)”	“153 (30.2)”
Adjunctive PD medication added to levodopa: no, No. (%)	“147 (57.6)”	“137 (54.4)”	“284 (56.0)”
Daily levodopa dose, mean (SD), mg	“817.6 (644.0)”	“811.9 (451.4)”	“814.8 (556.1)”

Timing of baseline MDS-UPDRS assessments

“Assessments conducted approximately 2 to 3 hours after last dose of levodopa and collected during on or off status.” (opens the source at this quote in a new tab)

Baseline characteristics stated in the prescribing information

“Patients had a mean age of 64.9 years (range: 43 to 80 years), 63% were male, 97% were White, and 5% were Hispanic. The mean duration of PD at baseline was 6.7 years (range: 0.1 to 30.9 years). The mean total ON time without troublesome dyskinesia at baseline was 10.0 hours and was similar between treatment groups.” (opens the prescribing information at this quote)

Primary end point: change in good-on-time at week 26

“The study met its primary end point, with the tavapadon group demonstrating a statistically significant increase of 1.1 hours in total daily good-on-time from baseline to week 26 compared with the placebo group (least-squares mean [LSM] increase of 1.70 hours with tavapadon vs 0.60 hours with placebo; LSM treatment difference, 1.1; 95% CI, 0.6-1.7; P < .001; Cohen d = 0.40). The increase in daily good-on-time from baseline was observed starting at week 2, and separation between tavapadon and placebo was observed as early as week 8 and sustained through week 26 and end of treatment (week 27) (Figure 2A).” (opens the source at this quote in a new tab)

Key secondary end point: change in off-time at week 26

“The tavapadon group experienced a statistically significant reduction from baseline to week 26 in the key secondary end point of off-time compared with the placebo group (LSM decrease of 1.88 vs 0.93 hours, respectively; LSM treatment difference, −0.94 hours; 95% CI, −1.48 to −0.41; P < .001; Cohen d = 0.35). Reductions in off-time with tavapadon relative to placebo were observed starting at week 8 and continued to end of treatment (Figure 2B). Predefined sensitivity analyses were consistent with the primary analysis for both primary and key secondary end points (data not shown).” (opens the source at this quote in a new tab)

Change from baseline to week 26 in primary and key secondary measures

Measure	Juvmo (N = 242)	Placebo (N = 245)
On time without troublesome dyskinesia, baseline mean (SD), hours	“9.9 (2.58)”	“10.2 (2.58)”
On time without troublesome dyskinesia, week 26 mean (SD) change from baseline, as printed	“1.7 (0.21)”	“0.6 (0.19)”
Off time, baseline mean (SD), hours	“5.6 (2.26)”	“5.4 (2.36)”
Off time, week 26 mean (SD) change from baseline, as printed	“-1.9 (0.20)”	“-0.9 (0.18)”

Treatment differences for the primary and key secondary measures in the prescribing information

Measure	Juvmo vs placebo
On time without troublesome dyskinesia, LS mean (SE) difference, as printed	“1.1 (0.6, 1.7)”
On time without troublesome dyskinesia, p-value	“<0.0001”
Off time, LS mean (SE) difference, as printed	“-0.9 (-1.5, -0.4)”
Off time, p-value	“0.0006”

MDS-UPDRS parts II and III and the combined score

“Treatment with tavapadon also resulted in an improvement from baseline in MDS-UPDRS part II scores at week 26 compared with placebo (LSM decrease, 1.4 vs 0.1 points, respectively; LSM treatment difference, −1.2 points; 95% CI, −2.2 to −0.2; nominal P = .02), with significant reductions observed starting at week 11 and continuing to end of treatment (eFigure in Supplement 3). Reductions in MDS-UPDRS part III scores at week 26 were also significantly greater in participants treated with tavapadon vs placebo (LSM decrease, 7.0 vs 4.6 points, respectively; LSM treatment difference, −2.4 points; 95% CI, −4.3 to −0.5; nominal P = .01) (eFigure in Supplement 3).” (opens the source at this quote in a new tab)
“The exploratory analysis of change from baseline in MDS-UPDRS part II+III combined scores demonstrated a significant reduction in the tavapadon group vs the placebo group at week 26 (LSM decrease, 8.4 vs 4.7 points; LSM treatment difference, −3.7; 95% CI, −6.3 to −1.1; nominal P = .005) (eFigure in Supplement 3).” (opens the source at this quote in a new tab)

Pooled good on-time estimate across two adjunctive trials in a meta-analysis

“B7601003 at its 15 mg dose reported + 1.04 h at Week 10 (95% CI − 0.53 to 2.61), an estimate in the same direction and of almost identical magnitude but not statistically significant in a trial terminated at half enrolment.” (opens the source at this quote in a new tab)
“The pooled estimate was + 1.09 h per day (95% CI 0.57 to 1.61; p < 0.001) with no heterogeneity whatsoever (I² = 0.0%, Q(1) = 0.01, p = 0.944)” (opens the source at this quote in a new tab)

TEMPO-3 good on-time confidence interval that differs between the text and figure 6 of a meta-analysis

“Fernandez et al. [12] reported a gain of + 1.10 h per day with tavapadon versus placebo (95% CI 0.60 to 1.70; p < 0.001)” (opens the source at this quote in a new tab)
“Fernandez et al. 2026 242 245 89.1% 1.10 [0.55; 1.65]” (opens the source at this quote in a new tab)

Post hoc analysis: motor states across the waking day

“In a post hoc analysis, a comparison of changes from baseline in motor states across the waking day revealed the improvements in total daily good-on-time at week 26 were primarily driven by the increase in total daily on-time without dyskinesia (Figure 3).” (opens the source at this quote in a new tab)
“Analysis of normal waking day was based on normalized waking hours of 16 hours per day for each individual patient.” (opens the source at this quote in a new tab)

Post hoc motor state results presented at a congress

“Participants receiving adjunctive tavapadon (n=252) demonstrated a significant increase of 0.7 hours in ON time without dyskinesia during the normal waking day versus placebo (n=255; 1.6 hours vs 0.9 hours, respectively; P=0.0426).” (opens the source at this quote in a new tab)
“Change from baseline in OFF time during the normal waking day also showed a significant reduction of 0.8 hours with tavapadon vs placebo (1.1 hours vs 1.9 hours, respectively; P=0.0022). Participants receiving tavapadon experienced a marginal decrease from baseline in ON time with troublesome dyskinesia versus placebo (−0.008 hours vs 0.1 hours; P=0.3397), and an increase in ON time with nontroublesome dyskinesia versus placebo (0.3 hours vs 0.05 hours; P=0.1815).” (opens the source at this quote in a new tab)

Results first presented at a congress

“Adults aged 40–80 years (N=507) were enrolled. Treatment with tavapadon (5–15 mg once daily) significantly increased total daily ON time without troublesome dyskinesia by 1.1 hours relative to placebo (1.7 hours vs 0.6 hours, respectively; P<0.0001). A significant reduction versus placebo in change from baseline in daily OFF time was also observed.” (opens the source at this quote in a new tab)

Topline results announced by the sponsor

“The trial met its primary endpoint – patients treated with tavapadon adjunctive to LD experienced a clinically meaningful and statistically significant increase of 1.1 hours in total “on” time without troublesome dyskinesia compared to those treated with LD and placebo (1.7 hours vs. 0.6 hours, p <0.0001). A statistically significant reduction in “off” time, the key secondary endpoint, was also observed for the tavapadon treatment arm.” (opens the source at this quote in a new tab)

PDQ-39, EQ-5D-5L, and MDS-UPDRS part I

“There were no notable differences in MDS-UPDRS part I, PDQ-39, or EQ-5D-5L Index and VAS scores (data not shown).” (opens the source at this quote in a new tab)
“Finally, participants treated with tavapadon showed nominally significantly greater reductions in MDS-UPDRS parts II and III scores, corresponding to improvements in activities of daily living and investigators’ evaluations of motor function, respectively. No significant differences between groups were observed in the PDQ-39, EQ-5D-5L index, and VAS scores.” (opens the source at this quote in a new tab)

Patient-reported daytime sleepiness on the Epworth Sleepiness Scale

“In TEMPO-3, LSM decrease in ESS total score from baseline was 0.9 with tavapadon and 0.7 points with placebo (LSM difference from placebo [95% CI], −0.2 [−0.8, 0.4]; P=0.53). Item-level scores related to sleepiness on the Movement Disorder Society-Unified Parkinson’s Disorder Rating Scale and Parkinson’s Disease Questionnaire-39, including frequency of unexpectedly falling asleep during the day, did not differ from placebo.” (opens the source at this quote in a new tab)

Summary of adverse events in the safety population

Safety outcome	Placebo QD (n = 254)	Tavapadon 5-15 mg QD (n = 251)
AEs, No. (%)	“140 (55.1)”	“180 (71.7)”
Mild	“65 (25.6)”	“80 (31.9)”
Moderate	“64 (25.2)”	“82 (32.7)”
Severe	“11 (4.3)”	“18 (7.2)”
AE related to study drug	“54 (21.3)”	“105 (41.8)”
AEs with onset in titration phase, No./No. (%)	“83/254 (32.7)”	“100/251 (39.8)”
AEs with onset in adjustment phase, No./No. (%)	“54/237 (22.8)”	“100/214 (46.7)”
AEs with onset in maintenance phase, No./No. (%)	“65/220 (29.5)”	“71/188 (37.8)”
Serious AEs	“14 (5.5)”	“17 (6.8)”
AE leading to discontinuation	“23 (9.1)”	“43 (17.1)”
Death	“0”	“1 (0.4)”
Nausea	“11 (4.3)”	“36 (14.3)”
Dyskinesia	“4 (1.6)”	“25 (10.0)”
Dizziness	“8 (3.1)”	“19 (7.6)”
Headache	“7 (2.8)”	“17 (6.8)”
Fall	“13 (5.1)”	“16 (6.4)”
Orthostatic hypotension	“3 (1.2)”	“15 (6.0)”
Hallucination, visual	“3 (1.2)”	“14 (5.6)”
COVID-19	“9 (3.5)”	“13 (5.2)”
Somnolence	“11 (4.3)”	“13 (5.2)”

Overall adverse events, serious adverse events, and death

“In the safety population, 180 participants (71.1%) in the tavapadon group and 140 participants (55.1%) in the placebo group experienced at least 1 AE (Table 2). Most AEs were nonserious (93.2%) and mild to moderate in severity. Rates of serious AEs (Table 2) were similar between groups. Serious AEs reported in 2 or more participants in the tavapadon group were fall (n = 3) and abdominal pain (n = 2). Severe AEs observed in 2 or more participants in the tavapadon group were dyskinesia (3 [1.2%]), abdominal pain (3 [1.2%]), dizziness (2 [0.8%]), and nausea (2 [0.8%]). One AE of death due to metastatic pancreatic carcinoma reported in the tavapadon group was considered unrelated to study treatment.” (opens the source at this quote in a new tab)

Adverse events by treatment phase

“For the tavapadon group, the percentage of participants experiencing AEs was higher during the dose titration (39.8%) and adjustment (46.7%) phases compared with the maintenance (37.8%) phase. The most common AEs reported in the tavapadon group (≥5% incidence) were nausea (14.3%), dyskinesia (10.0%), dizziness (7.6%), headache (6.8%), falls (6.4%), and orthostatic hypotension (6.0%) (Table 2). Rates of nausea, dyskinesia, dizziness, and headache were higher during the titration phase and decreased with continued exposure. Rates of visual hallucinations and orthostatic hypotension were higher during the dose adjustment and maintenance phases compared with the titration phase.” (opens the source at this quote in a new tab)

Somnolence, fatigue, and daytime sleepiness

“Incidence rates of somnolence (tavapadon, 5.2%; placebo, 4.3%) and fatigue (tavapadon, 4.0%; placebo, 4.3%) were similar between treatment groups. Mean change from baseline to the last visit in ESS total score and subscores were also similar in the tavapadon and placebo groups, with a numerically lower percentage of participants reporting a score greater than or equal to 10 (sleepy) in the tavapadon groups vs the placebo group.” (opens the source at this quote in a new tab)

Impulse control disorders and suicidality

“Overall, 9 participants (tavapadon, 6 [2.4%]; placebo, 3 [1.2%]) experienced AEs suggestive of ICDs. Of the 6 participants in the tavapadon group, all events were nonserious and mild to moderate in severity; 1 event led to tavapadon discontinuation. All events but 1 were resolved by the end of the trial. Mean changes from baseline to the last visit in QUIP-RS total scores were similar between the tavapadon and placebo groups (data not shown). There was no evidence of increased suicidality with tavapadon based on the C-SSRS (data not shown).” (opens the source at this quote in a new tab)

Blood pressure and orthostatic hypotension

“Blood pressure decreases in the tavapadon group were observed. At the end of the study (week 27), a mean (SD) decrease of 8.6 (16.3) mm Hg was observed in standing systolic blood pressure (vs 0.8 [15.2] mm Hg with placebo) and a mean (SD) decrease of 6.0 (10.8) mm Hg was observed in standing diastolic blood pressure (vs 1.8 [9.7] mm Hg with placebo), with similar changes observed for supine blood pressures. The frequency of measured orthostatic hypotension was comparable between treatment groups (eTable 3 in Supplement 3), but the incidence of orthostatic hypotension reported as an AE was higher in the tavapadon group (6.0%) compared with the placebo group (1.2%) (Table 2). There were no clinically relevant safety findings in clinical laboratory findings, eye examinations, or cardiovascular assessments.” (opens the source at this quote in a new tab)
“Of tavapadon-treated participants experiencing falls, only 1 was receiving treatment for orthostatic hypotension.” (opens the source at this quote in a new tab)

Measured orthostatic hypotension

Measure	Placebo QD (N = 254)	Tavapadon 5-15 mg QD (N = 251)
Systolic blood pressure ≥20 mm Hg decrease upon standing compared to supine, n (%)	“51 (20.1)”	“45 (17.9)”
Diastolic blood pressure ≥10 mm Hg decrease upon standing compared to supine, n (%)	“57 (22.4)”	“64 (25.5)”

Adverse reactions in Study 3 in the prescribing information

Adverse reaction	Juvmo (N = 251), %	Placebo (N = 254), %
Nausea	“14”	“4”
Dyskinesia	“10”	“2”
Dizziness	“8”	“3”
Headache	“7”	“3”
Hallucination	“7”	“1”
Orthostatic hypotension	“6”	“1”
Hypotension	“4”	“<1”
Abdominal pain	“3”	“<1”
Asthenia	“3”	“0”

Warnings and precautions: rates observed in Study 3

“In Study 3 in patients taking JUVMO as adjunctive therapy to fixed dose levodopa [see Clinical Studies (14.2)], orthostatic hypotension was reported in 8% of patients treated with JUVMO compared to 2% of patients on placebo. Hypotension was reported in 4% of patients treated with JUVMO compared to 0.4% on placebo.” (opens the prescribing information at this quote)
“In Study 3, impulse control disorders were reported in 2% of patients treated with JUVMO compared to 1% of patients on placebo.” (opens the prescribing information at this quote)
“In Study 3, when added as an adjunct to a fixed dose of levodopa, hallucination was reported in 7% of patients treated with JUVMO compared to 1% of patients on placebo.” (opens the prescribing information at this quote)
“In Study 3, among patients 65 years of age and older, hallucination was reported in 9% of patients treated with JUVMO compared to 1% of patients on placebo.” (opens the prescribing information at this quote)
“In Study 3, 10.0% of patients treated with JUVMO reported dyskinesia compared to 2% on placebo. Consider decreasing the dosage of JUVMO or other dopaminergic medications if dyskinesia occurs.” (opens the prescribing information at this quote)

Serious adverse events and deaths in the registry results

Measure	Placebo	Tavapadon
All-cause mortality, affected / at risk (%)	“0/255 (0.00%)”	“1/252 (0.40%)”
Serious adverse events, affected / at risk (%)	“14/255 (5.49%)”	“17/252 (6.75%)”

Investigators' interpretation of the safety findings

“The safety profile of tavapadon was favorable and consistent with earlier-phase tavapadon trials” (opens the source at this quote in a new tab)
“most AEs were nonserious, mild or moderate in severity, and allowed participants to remain on treatment. Rates of discontinuation due to AEs were higher for tavapadon vs placebo. Common dopaminergic AEs (eg, nausea, dyskinesia, dizziness) reported in participants treated with tavapadon were expected.” (opens the source at this quote in a new tab)
“In this 27-week trial, there were no notable differences between tavapadon and placebo in the incidence of ICDs or the QUIP-RS total score.” (opens the source at this quote in a new tab)

Summary: limitations of TEMPO-3

TEMPO-3 compared tavapadon with placebo for 27 weeks and included no active comparator, so it provides no direct comparison with D2/D3 dopamine agonists or other adjunctive therapies; the investigators note that adverse events such as impulse control disorders may emerge with longer treatment. Discontinuation was unequal between groups: 93 of 252 participants (36.9%) receiving tavapadon and 49 of 255 (19.2%) receiving placebo discontinued, including 43 and 23 for adverse events and 33 and 12 by participant withdrawal. The registry results report week 26 primary end point data for 153 tavapadon and 201 placebo participants, compared with 242 and 245 in the modified intention-to-treat population, and the primary analysis treated data after discontinuation as censored under a hypothetical strategy with a missing-at-random assumption. The target sample size was increased from 368 to 500 participants after an interim analysis, and the primary hypothesis was tested at a 2-sided alpha of 0.049. Comparisons for secondary end points other than off-time were not corrected for multiplicity, so MDS-UPDRS results carry nominal P values, and MDS-UPDRS assessments were performed 2 to 3 hours after the last levodopa dose in either the on or off state. The levodopa dose and dosing frequency were held fixed for the whole trial. The population was 96.8% White, excluded people with a Montreal Cognitive Assessment score below 26, a clinically significant impulse control disorder, or psychosis or hallucinations within 12 months, and excluded users of moderate or strong CYP3A4 inhibitors or inducers. The trial ran during the COVID-19 pandemic and the war in Ukraine, which led to site terminations. The prescribing information reports orthostatic hypotension in 8% versus 2% in its warnings section and 6% versus 1% in its adverse reaction table, and the publication reports 6.0% versus 1.2%. The primary publication gives two screening counts (842 in the results and 824 in the abstract) and two percentages for any adverse event with tavapadon (71.1% in the text and 71.7% in the table).

Limitations stated by the investigators

“The 27-week treatment duration was comparable with other phase 3 trials investigating therapies for PD with motor fluctuations” (opens the source at this quote in a new tab)
“however, as people with PD in real-world settings may receive treatment for years,” (opens the source at this quote in a new tab)
“research is needed to support the long-term safety and efficacy of tavapadon. This study was not designed to compare tavapadon with D2/D3 DAs or other adjunctive therapies for PD. The study population was predominantly White (96.8%), and further study of tavapadon in underrepresented populations may be needed. This trial was held during the height of the COVID-19 pandemic, which may have contributed to the longer-than-usual times to complete enrollment, and the discontinuation rate.” (opens the source at this quote in a new tab)
“As some AEs associated with dopaminergic treatment, such as ICDs, may emerge with prolonged treatment, additional data from the long-term extension trial” (opens the source at this quote in a new tab)
“of tavapadon may further the understanding about the safety of tavapadon adjunctive to levodopa in people with PD and motor fluctuations.” (opens the source at this quote in a new tab)

Sample size assumptions based on a trial with a different dosing schedule

“Given that the assumptions for the sample size were based on a preliminary study using a different dosing schedule, it is unknown if these assumptions are appropriate for this study as designed.” (opens the source at this quote in a new tab)

Absence of active comparator and trials longer than 27 weeks across the evidence base

“Its proposed neuropsychiatric advantage over D2/D3 agonists remains untested: no trial used an active comparator or exceeded 27 weeks.” (opens the source at this quote in a new tab)

Power of TEMPO-3 to detect a difference in impulse control disorders

“Impulse control disorder (RR 2.02, 0.51 to 8.00; nine events, one trial) and somnolence (1.20, 0.37 to 3.92) were rated at very low certainty.” (opens the source at this quote in a new tab)
“The point estimate is above unity and the interval is compatible with anything from a halving to an eight-fold increase in risk; with nine events in total, this trial had approximately 18% power to detect a doubling of the observed placebo rate. No inference about impulse control disorder risk, in either direction, is supported by these data.” (opens the source at this quote in a new tab)
“For impulse control disorder the evidence was rated down one level for indirectness, because the 27-week maximum exposure of the included trials is short relative to the multi-year latency over which these disorders typically emerge, and two levels for imprecision, because nine events across a single trial yield a confidence interval spanning a halving to an eight-fold increase in risk.” (opens the source at this quote in a new tab)

Trial objective: long-term safety and efficacy of flexible-dose tavapadon

“The purpose of this study is to evaluate the safety and efficacy of long-term administration of flexible doses of tavapadon in participants with Parkinson's Disease.” (opens the source at this quote in a new tab)

Objective as stated in the interim analysis

“The TEMPO-4 trial (NCT04760769) evaluated the long-term safety and efficacy of tavapadon in adults with PD.” (opens the source at this quote in a new tab)

Role of TEMPO-4 in the new drug application

“The submission is also based on an interim data cut from TEMPO-4, an open-label extension (OLE) trial to assess the long-term clinical benefit of tavapadon.” (opens the source at this quote in a new tab)

Summary: sponsor, identifiers, sites, and study dates

The registry record for NCT04760769 gives AbbVie as lead sponsor, CVL-751-PD-004 as the sponsor protocol number, and 2019-002952-17 as the EudraCT number. The actual study start date was 24 February 2021, and the actual primary completion and study completion dates were both 1 December 2025; the overall status is completed. The record lists 140 study locations in 14 countries: the United States (52 sites), Poland (12), Spain (11), Italy (10), Germany (9), Bulgaria (7), France (7), Ukraine (7), Australia (6), Czechia (5), Israel (5), Serbia (4), Hungary (3), and Canada (2). As of September 2026, no results had been posted to the registry.

Presentation of the interim analysis

“The interim analysis, presented as a late-breaker at the 2025 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9, in Honolulu, Hawaii, included 468 patients who rolled over, and 524 previously untreated participants (placebo rollover: n = 471; de novo; n = 53).” (opens the source at this quote in a new tab)

Open-label design, treatment duration, and follow-up

“Participants who completed the TEMPO-1, TEMPO-2, or TEMPO-3 trial, as well as newly enrolled participants with PD (modified Hoehn and Yahr stage 1, 1.5, 2, 2.5, or 3) on a stable dose of levodopa were enrolled in the phase 3, open-label TEMPO-4 trial. Participants received tavapadon (5 to 15 mg once daily) for up to 58 weeks (85 total weeks of exposure for those who had previously received tavapadon in the TEMPO-1, -2, and -3 trials), followed by a 10-day safety/withdrawal assessment period and 20-day safety follow-up period.” (opens the source at this quote in a new tab)

Registry design record

Design element	Quoted record
Official title	“58-Week Open-label Trial of Tavapadon in Parkinson's Disease (TEMPO-4 Trial)”
Phase	“Phase 3”
Enrollment (actual)	“992”

Source cohorts described by the sponsor

“An open-label extension study (TEMPO-4) is ongoing to assess the long-term safety and efficacy of tavapadon through 58 weeks of treatment. TEMPO-4 enrolled patients who completed participation in TEMPO-1 through 3, as well as patients on stable doses of levodopa who had not been in prior TEMPO trials.” (opens the source at this quote in a new tab)

Summary: age and sex eligibility

The registry record sets an age range of 40 to 80 years, accepts participants of all sexes, and does not accept healthy volunteers.

Inclusion criteria for rollover participants

“Participants who complete the 27-week double-blind Treatment Period of Trial CVL-751-PD-001 (NCT04201093) or Trial CVL-751 PD-003 (NCT04542499) or the 27-week double-blind Treatment Period and 10-day Safety/Withdrawal Assessment Period of Trial CVL-751-PD-002 (NCT04223193) and enter this trial within 72 hours after completing the last trial visit in the double-blind trial. Rollover participants from Trial CVL-751-PD-003 must continue to use levodopa/carbidopa (or levodopa/benserazide) for the duration of the trial.” (opens the source at this quote in a new tab)
“Participants who are willing and able to refrain from any PD medications that are not permitted by the protocol (including dopaminergic agents) throughout participation in the trial.” (opens the source at this quote in a new tab)

Exclusion criteria for rollover participants

“Participants who do not enroll in this open-label trial within 72 hours after completing the last trial visit in the double-blind trial” (opens the source at this quote in a new tab)
“Participants who had previously been enrolled in this open-label trial and had subsequently withdrawn.” (opens the source at this quote in a new tab)

Newly enrolled participants

“newly enrolled participants with PD (modified Hoehn and Yahr stage 1, 1.5, 2, 2.5, or 3) on a stable dose of levodopa” (opens the source at this quote in a new tab)

Tavapadon dose and duration

“Participants will receive a Tavapadon tablet at a dose of 5 milligrams (mg) to 15 mg once daily (QD) orally during 58-week treatment period.” (opens the source at this quote in a new tab)

Levodopa use by source cohort

“The TEMPO-4 trial enrolled levodopa-naive participants from TEMPO-1 and TEMPO-2, participants receiving stable levodopa treatment from TEMPO-3, and de novo participants receiving stable levodopa treatment.” (opens the source at this quote in a new tab)

Safety outcome measures

“Number of Participants With Treatment Emergent Adverse Events (TEAEs)” (opens the source at this quote in a new tab)
“Any AE occurring following the start of treatment or occurring before treatment but increasing in severity afterward were counted as treatment-emergent AE (TEAE). Clinically significant abnormalities in Clinical Laboratory Evaluations, Vital Signs, Physical and Neurological evaluations and ECGs will be reported as TEAEs.” (opens the source at this quote in a new tab)
“Number of Participants Who Discontinued Study Treatment” (opens the source at this quote in a new tab)

Impulse control, sleepiness, suicidality, and withdrawal assessments

“QUIP-RS is a global screening instrument that assesses impulse control disorders (ICDs) and related disorders (punding, hobbyism, and dopamine dysregulation syndrome) in participants with PD.” (opens the source at this quote in a new tab)
“ESS is a scale that is intended to measure daytime sleepiness.” (opens the source at this quote in a new tab)
“C-SSRS rates an individual's degree of suicidal ideation (SI) on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent."” (opens the source at this quote in a new tab)
“SMWQ is a questionnaire to assess withdrawal symptoms subsequent to completion of dosing with Investigational medicinal product (IMP).” (opens the source at this quote in a new tab)

Efficacy outcome measures

“Change From Baseline in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I, II and III” (opens the source at this quote in a new tab)
“Change From Baseline in the Hauser diary” (opens the source at this quote in a new tab)
“Change From Baseline in the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Index” (opens the source at this quote in a new tab)

Outcome time frames

“62 Weeks” (opens the source at this quote in a new tab)
“58 Weeks” (opens the source at this quote in a new tab)
“Baseline (Day 1), Weeks 32 and 58” (opens the source at this quote in a new tab)

Participants enrolled by source cohort

“Of 992 enrolled participants, 468 had previously received tavapadon in the TEMPO-1, -2, and -3 trials; 524 were previously untreated (placebo rollover, n=471; newly enrolled, n=53).” (opens the source at this quote in a new tab)

Pooled safety population in the interim analysis

“Pooling both cohorts (n = 991)” (opens the source at this quote in a new tab)

Post hoc levodopa analysis populations

“This TEMPO-4 post hoc analysis assessed levodopa initiation in participants enrolled from TEMPO-1 and TEMPO-2 and levodopa dose adjustments in participants enrolled from TEMPO-3 and de novo participants.” (opens the source at this quote in a new tab)

Completion, ongoing treatment, and discontinuation at the interim analysis

“In this interim analysis, 484 (48.8%) participants completed the study, 223 (22.5%) were receiving treatment, and 285 (28.7%) discontinued treatment. Adverse events (AEs; n=136 [13.7%]) and withdrawal by subject (n=71 [7.2%]) were the most common reasons for treatment discontinuation.” (opens the source at this quote in a new tab)

Data cutoff of the interim analysis

“less than half (48.8%) of the participants completed the trial as of October 25, 2024, while 28.7% (n = 285) discontinued treatment and 22.5% (n = 223) were still on the study drug” (opens the source at this quote in a new tab)

Prior treatment in the antecedent trials

“468 had previously received tavapadon in the TEMPO-1, -2, and -3 trials; 524 were previously untreated (placebo rollover, n=471; newly enrolled, n=53)” (opens the source at this quote in a new tab)

Demographic and disease characteristics at open-label baseline

No evidence found.

Motor function with continued treatment

“Participants who received tavapadon in the TEMPO-1, -2, and -3 trials had stable improvements in motor function with continued tavapadon treatment. Placebo rollover and de novo participants showed motor improvements, which remained stable with continued treatment over 58 weeks.” (opens the source at this quote in a new tab)
“This interim analysis demonstrated that tavapadon has a favorable long-term safety profile and provides stable efficacy with continued treatment.” (opens the source at this quote in a new tab)

Levodopa initiation in the early Parkinson's disease cohorts (post hoc)

“In the early PD cohorts (TEMPO-1 and TEMPO-2 extensions), most participants (86.4% to 94.0%) avoided initiating levodopa over the treatment period (previously treated, 85 weeks of treatment; previously untreated, 58 of weeks treatment).” (opens the source at this quote in a new tab)

Levodopa dose changes in the adjunctive cohorts (post hoc)

“For those already receiving tavapadon adjunctive to levodopa (TEMPO-3 extension or newly enrolled participants), the drug rarely necessitated dose adjustments. Most patients (81.3% to 87.6%) kept their levodopa dose stable. When modifications were needed, patients were twice as likely to reduce their levodopa dose (∼10%) than to increase it (∼5%), keeping the mean daily dose under 1000 mg.” (opens the source at this quote in a new tab)
“After a total of 14-20 months of tavapadon treatment, ~90% of participants did not require levodopa initiation or dose increases.” (opens the source at this quote in a new tab)

MDS-UPDRS and Hauser diary values by cohort

No evidence found.

EuroQol 5 Dimension 5 Level as a prespecified outcome measure

“Change From Baseline in the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Index” (opens the source at this quote in a new tab)
“Change From Baseline in the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scores (VAS)” (opens the source at this quote in a new tab)

Reported patient-reported outcome results

No evidence found.

Overall safety profile at the interim analysis

“The safety profile was consistent with previous studies; most AEs were non-serious and mild-to-moderate in severity (Table 1). There were low rates of AEs of interest , including AEs associated with currently approved D2/D3 receptor agonists. No new safety concerns were identified, including vital signs, laboratory/electrocardiogram results, or Columbia-Suicide Severity Rating Scale scores.” (opens the source at this quote in a new tab)

Most common treatment-emergent adverse events, pooled cohorts

“Pooling both cohorts (n = 991), the most common treatment-emergent adverse event (TEAE) observed with tavapadon was nausea (11.0%), followed by dizziness (10.6%), headache (9.6%), fall (9.2%), COVID-19 (9.1%), and constipation (5.5%).” (opens the source at this quote in a new tab)

Severity of treatment-emergent adverse events

“When pooling both patients who rolled over and de novo participants, mild, moderate, and severe TEAEs occurred in 29.5%, 36.3%, and 9.5% of patients.” (opens the source at this quote in a new tab)

Discontinuation due to treatment-emergent adverse events

“In the interim analysis, 14.1% of patients discontinued the study drug because of TEAEs.” (opens the source at this quote in a new tab)

Adverse events of special interest: hallucination, somnolence, hypotension, and impulse control disorders

“Outside of the aforementioned TEAEs, there were a few safety topics of special interest, including reports of hallucination (6.3%), somnolence (4.6%), hypotension (4.1%), orthostatic hypotension (3.7%), and impulse control disorders (1.4%).” (opens the source at this quote in a new tab)

Selectivity for D1/D5 receptors and adverse events of interest

“Selective D1/D5 agonism may offer a differentiated safety profile compared with D2/D3 agonists, as supported by the low rates of AEs of interest.” (opens the source at this quote in a new tab)

Pooled or integrated safety analyses across the TEMPO trials including TEMPO-4

No evidence found.

Summary: limitations of the available TEMPO-4 evidence

As of September 2026, TEMPO-4 results are available only from an interim analysis (data as of 25 October 2024) presented as a late-breaking abstract at the 2025 International Congress of Parkinson's Disease and Movement Disorders, a 2026 World Parkinson Congress abstract, a 2026 American Academy of Neurology abstract, and secondary news reports. The registry record lists the study as completed on 1 December 2025 but carries no posted results, and no peer-reviewed publication has been identified. The trial had a single open-label tavapadon arm with no control group, so the reported motor improvements and levodopa outcomes cannot be attributed to tavapadon by randomized comparison. Enrollment was drawn mainly from participants who completed the 27-week double-blind TEMPO-1, TEMPO-2, and TEMPO-3 trials, which may enrich the population for participants who tolerated treatment; 53 of 992 participants were newly enrolled. At the interim analysis, 285 participants (28.7%) had discontinued treatment, 136 (13.7%) because of adverse events. The levodopa analyses were post hoc. The abstracts report motor outcomes descriptively without MDS-UPDRS or Hauser diary values, and the adverse event table in the congress abstract is an image; the event rates quoted here come from a news report of the late-breaking presentation, which gives the pooled safety population as 991 participants and the rate of discontinuation due to adverse events as 14.1%, against 992 participants and 13.7% in the abstract.

Trial objective: flexible-dose PF-06649751 in early Parkinson's disease

“The purpose of this study is to evaluate the efficacy, safety and tolerability of PF-06649751 in Parkinson's disease patients at early stage of the disease.” (opens the source at this quote in a new tab)

Objective as stated in the publication

“A 15-week, phase II, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy and safety of flexible-dose PF-06649751 in subjects with early stage Parkinson’s disease (ClinicalTrials.gov identifier: NCT02847650).” (opens the source at this quote in a new tab)

Summary: sponsor, identifiers, and registry status

The registry record for NCT02847650 gives Pfizer as sponsor and B7601011 as the sponsor study number. The actual study start date was 17 October 2016 and the actual study completion date was 29 January 2018. The overall status is terminated, with 57 participants enrolled, and results have been posted.

Study period, sites, and countries

“This phase II, double-blind, randomized, placebo-controlled, flexible-dose, 15-week study in subjects with early stage Parkinson’s disease was conducted from October 2016 (first subject first visit) to January 2018 (last subject last visit) at 23 sites in the United States, France, Germany, and Israel (ClinicalTrials.gov identifier: NCT02847650).” (opens the source at this quote in a new tab)

Screening, dose optimization, maintenance, and follow-up periods

“The study consisted of a 30-day screening period, a 15-week double-blind treatment period (9 week dose optimization and 6 week dose maintenance), and a 28-day follow-up period.” (opens the source at this quote in a new tab)

Randomization and stratification

“At Visit 1, subjects were stratified by region and randomized (1:1) in a double-blind manner to either oral (tablet) PF-06649751 or matching placebo.” (opens the source at this quote in a new tab)

Inclusion criteria

“Study inclusion criteria were as follows: males agreeing to use contraception or females of nonchildbearing potential; aged 45–80; a clinical diagnosis of Parkinson’s disease (Hoehn & Yahr Stage I–III); an MDS-UPDRS Part III score ⩾10; treatment naïve or history of prior incidental treatment with dopaminergic agents for no more than 28 days and not within at least 7 days prior to randomization; a Mini-Mental State Examination (MMSE) score ⩾26; body mass index (BMI) of 17.5–35 kg/m2; and a total body weight ⩾45 kg.” (opens the source at this quote in a new tab)

Exclusion criteria

“Key exclusion criteria included: history or clinical features consistent with an atypical Parkinsonian syndrome (e.g. progressive supranuclear palsy, multiple system atrophy, and cortico basal degeneration); significant psychiatric disease (except minor or treated stable depression); risk of suicide; current malignancy (except nonmetastatic basal or squamous cell carcinoma of the skin); significant cardiovascular disease; cognitive impairment that would interfere with ability to comply with study procedures; pregnancy; currently breastfeeding; male subjects with pregnant partner; 12 lead electrocardiogram (ECG) demonstrating a QTcF interval >450 ms (>470 ms for females) or a QRS interval >120 ms.” (opens the source at this quote in a new tab)

Permitted and prohibited concomitant medications

“MAO B inhibitors, amantadine, and anticholinergic drugs were permitted if subjects were on stable doses of these anti-parkinsonian medications for at least 42 days prior to Visit 1.” (opens the source at this quote in a new tab)
“Prior treatment with levodopa or dopamine receptor agonists for more than 28 days, or any treatment with these agents within 7 days of Visit 1, was prohibited. Rescue anti-parkinsonian medication use after first dose of study treatment was not permitted.” (opens the source at this quote in a new tab)

Titration schedule and dose adjustment

“Subjects administered medication once-daily (morning) and recorded administration in a dosing diary.” (opens the source at this quote in a new tab)
“The recommended dosing schedule was as follows: 0.25 mg (days 1–7), 0.75 mg (days 8–14), 1.5 mg (days 15–21), 3 mg (days 22–28), 5 mg (days 29–35), 7 mg (days 36–42), 11 mg (days 43–49), and 15 mg (from day 50 onward). A dose increase from 0.25 mg to 0.75 mg was mandatory at Visit 2, and subjects who could not tolerate 0.25 mg were discontinued. Dosing decisions (increase/decrease/stay at current dose) were made on a weekly basis thereafter, up to Visit 10, based on investigator assessment of an individual subject achieving an optimal balance of motor symptom control and tolerability. Dosing adjustments after week 10 required consultation with the sponsor’s study clinician. The minimum recommended dose level was 3 mg.” (opens the source at this quote in a new tab)

Maintenance doses achieved

“The maintenance dose (defined as the dose received for at least the last 4 weeks of the maintenance phase) for subjects in the PF-06649751 group was as follows: 0.75 mg (n = 1), 1.5 mg (n = 1), 3 mg (n = 5), 5 mg (n = 1), 7 mg (n = 2), 11 mg (n = 4), and 15 mg (n = 11).” (opens the source at this quote in a new tab)

Primary endpoint definition

“The primary study endpoint was the change, from baseline, in MDS-UPDRS Part III score at week 15.” (opens the source at this quote in a new tab)
“MDS-UPDRS Part III scores were also compared between treatment groups at weeks 3, 5, 7, 9, and 12.” (opens the source at this quote in a new tab)

Efficacy threshold derived from the minimal clinically important difference

“The target MDS-UPDRS Part III efficacy threshold for PF-06649751 (change from baseline relative to placebo) in the current trial was 3.6 points, and was based on an internal meta-analysis of historical studies in subjects with early Parkinson’s disease, which utilized the traditional Unified Parkinson’s Disease Rating Scale (UPDRS). The minimal clinically important difference in traditional UPDRS Part III score is considered to be approximately 2.5 points.” (opens the source at this quote in a new tab)
“Therefore, we sought to set our efficacy criteria as PF-06649751 having at least a 3 point improvement over placebo in traditional UPDRS Part III score after 15 weeks of treatment. This corresponds to an improvement of at least 3.6 points in the newer MDS-UPDRS Part III.” (opens the source at this quote in a new tab)

Safety and exploratory outcome measures

“Safety and tolerability measures included AE reporting, clinical laboratory parameters, vital signs, ECG parameters, the Beck Depression Inventory-II (BDI-II), Epworth Sleepiness Scale (ESS), the Columbia Suicide Severity Rating Scale (C-SSRS), the Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS), and the Physician Withdrawal Checklist (PWC-20).” (opens the source at this quote in a new tab)
“Change, from baseline, in exploratory endpoint measures was assessed at weeks 9 and 15, and included Patient Global Impression-Severity (PGI-S), Patient Global Impression-Improvement (PGI-I), Parkinson’s Disease Questionnaire (PDQ-39), EuroQol 5 Dimension (EQ-5D-5L), Oral Symbol Digit Modality Test (OSDMT), Modified Clinical Global Impression-Severity (MCGI-S), Modified Clinical Global Impression-Improvement (MCGI-I), and MDS-UPDRS total and component scores.” (opens the source at this quote in a new tab)

Sample size and decision criteria

“The decision criteria for efficacy were: (1) a ⩾50% confidence that the PF-06649751 effect is at least 3.6 points better than placebo (i.e. a mean improvement of at least 3.6 points over placebo), and (2) a ⩾95% confidence that the PF-06649751 effect over placebo is greater than 0.” (opens the source at this quote in a new tab)
“It was estimated that 34 subjects per arm would give sufficient precision to meet both criteria, and, assuming that 23% of subjects would fail to complete the study or optimize the dose, 44 subjects per arm were planned.” (opens the source at this quote in a new tab)

Participants randomized against the planned sample

“Overall, 57 subjects were enrolled instead of the 88 that were planned.” (opens the source at this quote in a new tab)

Full Analysis Set and statistical model

“All efficacy analyses were based on the Full Analysis Set, defined as all subjects who received at least one dose of study medication and had baseline and at least one post-baseline MDS-UPDRS Part III score.” (opens the source at this quote in a new tab)
“Efficacy comparisons for this model were based on the treatment difference versus placebo using least squares means and hypothesis testing utilized a one-sided α of 0.05, corresponding to a statistical significance threshold of p < 0.1 in two-sided values.” (opens the source at this quote in a new tab)

Early termination linked to the companion trial in advanced Parkinson's disease

“This study was terminated early. However, the decision to terminate was not based on, and did not consider, data from the study itself. Prior to the start of this study, a strategic linkage was established with a concurrent study in more advanced PD (ClinicalTrials.gov NCT02687542). When the interim analysis of data from the more advanced PD study showed a low probability that it would reach a target efficacy threshold, (which was not a comparison with placebo, but a more stringent placebo-adjusted target value) that study was terminated, triggering a decision to terminate this trial early as well.” (opens the source at this quote in a new tab)

Registry statement of the reason for termination

“Study B7601011 was terminated on 29 Jan 2018 due to lack of efficacy in moderate/advanced Parkinson's disease.” (opens the source at this quote in a new tab)

Randomized, treated, and completing participants

“Overall, 57 subjects were randomized and received study treatment (placebo = 28 and PF-06649751 = 29; Figure 2). Of these, 22 (78.6%) and 25 (86.2%) completed the study in the placebo and PF-06649751 groups, respectively.” (opens the source at this quote in a new tab)
“The number of subjects reaching the dose maintenance phase was 22 (78.6%) in the placebo group and 26 (89.7%) in the PF-06649751 group.” (opens the source at this quote in a new tab)

Demographics and baseline disease characteristics

Characteristic	Placebo (n = 28)	PF-06649751 (n = 29)
Age, years, mean (SD)	“63.36 (9.16)”	“64.76 (8.34)”
Female, n (%)	“14 (50.0)”	“9 (31.0)”
White, n (%)	“25 (89.3)”	“28 (96.6)”
Duration since Parkinson's disease onset, years, mean (SD)	“1.61 (1.92)”	“1.42 (1.73)”
Baseline MDS-UPDRS Part III score, mean (SD)	“25.8 (10.5)”	“23.9 (12.3)”

Concomitant Parkinson's disease medication

“Overall, 16/29 subjects in the PF-06649751 group and 16/28 subjects in the placebo group received concomitant medication to treat PD symptoms. The medications most frequently taken were rasagiline/rasagiline mesylate (taken by 13/29 subjects in the PF-06649751 group and by 10/28 subjects in the placebo group) and amantadine (taken by 4/29 subjects in the PF-06649751 group and 6/28 subjects in the placebo group).” (opens the source at this quote in a new tab)

Primary endpoint: change in MDS-UPDRS Part III score at week 15

“The PF-06649751 group exhibited a mean (SE) change, from baseline to week 15, in MDS-UPDRS Part III score of −9.0 (1.54) compared with −4.3 (1.65) for placebo (Figure 3). This corresponds to a least squares mean (SE) (90% CI) improvement over placebo of 4.8 (2.26) (1.0, 8.6) for the PF-06649751 group (2-sided p = 0.0407). PF-06649751, therefore, met the first predefined efficacy criteria by demonstrating an observed mean treatment effect over placebo of greater than 3.6 points. The probability that this observed treatment effect over placebo was greater than 0 was determined to be 98%; thus, PF-06649751 also met the second prespecified primary efficacy criteria and the overall primary endpoint.” (opens the source at this quote in a new tab)

Onset of effect by week 3

“Statistically significant improvements in MDS-UPDRS Part III scores were also evident in the PF-06649751 group, compared with placebo, at all timepoints prior to week 15 (weeks 3, 5, 7, 9, and 12; all 2-sided p < 0.1; Figure 3).” (opens the source at this quote in a new tab)

Exploratory endpoints: combined MDS-UPDRS scores and other scales

“Exploratory analyses demonstrated statistically significant (2-sided p < 0.1) improvements in combined MDS-UPDRS scores (Part II + III, Part I + II + III, and total) at all timepoints assessed (weeks 9 and 15) in the PF-06649751 group compared with placebo (data not shown), driven in large part by changes in MDS-UPDRS Part III score.” (opens the source at this quote in a new tab)
“However, there was no statistically significant difference between treatment groups for any of the following scales at weeks 9 and 15: MDS-UPDRS Part I, MDS-UPDRS Part II, PDQ-39 global score, EQ-5D-5L, OSDMT, MCGI-I, MCGI-S, and PGI-S (all data not shown).” (opens the source at this quote in a new tab)

Patient Global Impression of Improvement

“Exploratory assessment of PGI-I scores at weeks 9 and 15 demonstrated statistically significant improvement (lower score) in the PF-06649751 group compared with placebo. Mean/median PGI-I scores were 3.0/3.0 in the PF-06649751 group at week 9 compared with 3.5/4 for placebo (2-sided p = 0.055) and 2.5/2.0 in the PF-06649751 group at week 15 compared with 3.2/3.5 for placebo (2-sided p = 0.039).” (opens the source at this quote in a new tab)

Parkinson's Disease Questionnaire and EuroQol 5 Dimension

“there was no statistically significant difference between treatment groups for any of the following scales at weeks 9 and 15: MDS-UPDRS Part I, MDS-UPDRS Part II, PDQ-39 global score, EQ-5D-5L, OSDMT, MCGI-I, MCGI-S, and PGI-S (all data not shown)” (opens the source at this quote in a new tab)

Summary of adverse events

Measure	Placebo (n = 28)	PF-06649751 (n = 29)
Participants with at least 1 all-causality AE, n (%)	“18 (64.3)”	“25 (86.2)”
Participants with at least 1 treatment-related AE, n (%)	“10 (35.7)”	“22 (75.9)”
Participants with at least 1 serious AE, n (%)	“0”	“1 (3.4)”
Participants discontinued due to AE, n (%)	“4 (14.3)”	“2 (6.9)”
Deaths, n (%)	“0”	“0”

Most common adverse events

Adverse event	Placebo (n = 28), n (%)	PF-06649751 (n = 29), n (%)
Nausea	“2 (7.1)”	“9 (31.0)”
Headache	“2 (7.1)”	“7 (24.1)”
Dry mouth	“0”	“5 (17.2)”
Somnolence	“1 (3.6)”	“4 (13.8)”
Tremor	“2 (7.1)”	“4 (13.8)”
Hypotension	“0”	“2 (6.9)”
Dizziness	“1 (3.6)”	“2 (6.9)”

Serious adverse event: suicidal ideation

“One serious AE (suicidal ideation) occurred in a subject in the PF-06649751 group. This event started and resolved on day 64, but led to study discontinuation on day 70.” (opens the source at this quote in a new tab)

Blood pressure and orthostatic hypotension

“More subjects treated with PF-06649751 met categorization criteria for standing diastolic BP decrease of ⩾20 mmHg (8 versus 2), standing systolic BP decrease ⩾30 mmHg (4 versus 1), supine diastolic BP decrease ⩾20 mmHg (9 versus 1), and supine systolic BP decrease ⩾30 mmHg (5 versus 0) than subjects treated with placebo. Regarding orthostatic hypotension, there was a difference between treatment groups for the incidence of diastolic BP postural difference >10 mmHg (3 for PF-06649751 versus 1 for placebo) and there was no apparent increase in orthostatic hypotension-related AEs such as dizziness, fainting, or lightheadedness. No subjects met criteria for significant ECG changes.” (opens the source at this quote in a new tab)

Sleepiness, impulse control, depression, suicidality, and withdrawal scales

“There was no apparent difference between treatment groups on the BDI-II, ESS, QUIP-RS, C-SSRS, and PWC-20 at weeks 9 and 15 (data not shown).” (opens the source at this quote in a new tab)

Laboratory safety

“There were no clinically meaningful effects of PF-06649751, relative to placebo, for standard laboratory safety assessments, including blood chemistry and liver function.” (opens the source at this quote in a new tab)

Summary: limitations of the NCT02847650 evidence

Enrollment stopped early after a linked phase 2 trial in advanced Parkinson's disease (NCT02687542) met futility criteria at an interim analysis, so 57 of the 88 planned participants were randomized (29 to PF-06649751 and 28 to placebo). Efficacy testing used a one-sided alpha of 0.05, equivalent to a two-sided threshold of p < 0.1, and the primary result was reported with a 90% confidence interval of 1.0 to 8.6 points. The double-blind period was 15 weeks. The PF-06649751 group had a lower proportion of women (31.0%) than the placebo group (50.0%). Maintenance doses ranged from 0.75 mg to 15 mg, with 11 participants maintained on 15 mg. Most exploratory scale results were reported as data not shown.

Limitations stated by the authors

“Though PF-06649751 met the primary efficacy endpoint, some limitations of the study should be noted. Foremost, enrollment in the study was terminated early by the sponsor. Overall, 57 subjects were enrolled instead of the 88 that were planned.” (opens the source at this quote in a new tab)
“It should be noted that, although PF-06649751 consistently and significantly improved MDS-UPDRS Part III scores during the current trial, the trial was focused on subjects with early stage Parkinson’s disease and there remains a need to assess the safety and efficacy of PF-06649751 in other stages of the disease.” (opens the source at this quote in a new tab)

Trial objective: PF-06649751 in Parkinson's disease with motor fluctuations

“The purpose of this study is to evaluate the efficacy, safety and tolerability of PF-06649751 in Parkinson's disease patients who experience motor-fluctuations.” (opens the source at this quote in a new tab)

Official title

“A 15-WEEK, PHASE 2, DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED, DOSE RANGING STUDY TO INVESTIGATE THE EFFICACY, SAFETY AND TOLERABILITY OF PF-06649751 IN SUBJECTS WITH MOTOR FLUCTUATIONS DUE TO PARKINSON'S DISEASE” (opens the source at this quote in a new tab)

Summary: sponsor, identifiers, sites, and study dates

The registry record for NCT02687542 gives Pfizer as sponsor, B7601003 as the sponsor study number, 2015-004912-39 as the EudraCT number, and A-ROSE as an alias study number. The actual study start date was 3 March 2016, and the actual primary completion and study completion dates were both 10 November 2017. The record lists 57 study locations in 6 countries: the United States (33 sites), France (6), Spain (6), Germany (5), Japan (5), and Canada (2). Results were first posted on 24 December 2018.

Reason for termination

“Terminated 25Sep17 due to insufficient efficacy. Not due to safety reasons.” (opens the source at this quote in a new tab)

Randomized, placebo-controlled, parallel-group dose-ranging design

“The study has a randomized, double-blind, placebo-controlled parallel group design. Approximately 198 subjects will be randomized to 5 treatment groups. Each subject will participate in the study for approximately 23 weeks including a 30 day screening period, 15 week double blind treatment period, and an approximately 28 day follow-up period.” (opens the source at this quote in a new tab)

Treatment periods

“Duration of treatment was 15 weeks including: 3-week titration of PF-06649751 administered QD to the randomized target dose; 2-week stabilization period for dose adjustment after reaching the target dose; 5-week Period A of PF-06649751 administered QD adjunctive to stable doses of L-Dopa; 5-week Period B (maintenance period) of PF-06649751 administered QD adjunctive to stable doses of L-Dopa.” (opens the source at this quote in a new tab)

Inclusion criteria

“Females of non-childbearing potential and/or male subjects between the ages of 40 and 85 years, inclusive.” (opens the source at this quote in a new tab)
“Clinical diagnosis of Parkinson's disease.” (opens the source at this quote in a new tab)
“Able to refrain from any Parkinson's disease medication not permitted by the protocol.” (opens the source at this quote in a new tab)

Exclusion criteria

“History or presence of atypical Parkinsonian syndrome.” (opens the source at this quote in a new tab)
“History of surgical intervention for Parkinson's disease.” (opens the source at this quote in a new tab)
“Severe acute or chronic medical or psychiatric condition or laboratory abnormality.” (opens the source at this quote in a new tab)

Treatment groups

Arm	Quoted record
Placebo	“Placebo”
Low dose	“PF-06649751 low dose level (1 mg QD)”
Lower middle dose	“PF-06649751 lower middle dose 1 (3 mg QD)”
Higher middle dose	“PF-06649751 higher middle dose 2 (7 mg QD)”
High dose	“PF-06649751 high dose (15 mg QD)”

Administration

“The participants swallowed 3 tablets QD at approximately the same time each morning within approximately 5 minutes without being manipulated or chewed prior to being swallowed.” (opens the source at this quote in a new tab)

Primary outcome measure: Hauser diary OFF time at week 10

“Change From Baseline in Daily OFF Time at Week 10” (opens the source at this quote in a new tab)
“A paper Hauser diary was utilized to record motor state for half-hour intervals. Participants completed the diary by answering whether they had been OFF for 3 consecutive days in the week prior to each visit (except Day 28 visit), including 3 consecutive days during the week prior to Day 0 (Randomization).” (opens the source at this quote in a new tab)
“The daily OFF time was calculated as the average of the 3 consecutive daily OFF hours from the Hauser diary at each visit.” (opens the source at this quote in a new tab)

Secondary outcome measures

“Change From Baseline in Daily ON Time With Troublesome Dyskinesia” (opens the source at this quote in a new tab)
“Change From Baseline in Daily ON Time Without Troublesome Dyskinesia” (opens the source at this quote in a new tab)
“Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III” (opens the source at this quote in a new tab)
“Change From Baseline in Total Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale (QUIP-RS)” (opens the source at this quote in a new tab)

Differences in endpoint and design from the early Parkinson's disease trial

“In addition to the target levels of the primary analysis, there are several other factors that may explain the apparent discrepancy in efficacy between these studies, including the stage of Parkinson’s disease (early versus advanced), dosing approach (flex-dosing monotherapy versus fixed-dose add-on), length of titration (9 weeks versus 3 weeks), primary endpoint (MDS-UPDRS Part III versus subject reported OFF time), and other operational aspects.” (opens the source at this quote in a new tab)

Planned and actual enrollment

Measure	Quoted record
Planned randomization	“Approximately 198 subjects will be randomized to 5 treatment groups.”
Actual enrollment	“108”

Participants analyzed for the primary endpoint

Group	Participants analyzed
Placebo	“21”
PF-06649751 1 mg QD	“7”
PF-06649751 3 mg QD	“9”
PF-06649751 7 mg QD	“9”
PF-06649751 15 mg QD	“41”

Interim analysis at approximately 50% enrollment

“The primary analysis in that phase II trial was based on a specific, prespecified, target level of efficacy for PF-06649751 over placebo, which was deemed unlikely to be achieved by the interim analysis. However, as that study was terminated at approximately 50% enrollment, there was insufficient data to make any firm statistical conclusion about PF-06649751 efficacy versus placebo.” (opens the source at this quote in a new tab)

Full Analysis Set and Safety Analysis Set

“Full Analysis Set consisted of all participants randomized who completed at least 1 post-dose efficacy measurement (Hauser home diary).” (opens the source at this quote in a new tab)
“Safety Analysis Set included all participants who received at least 1 dose of PF-06649751 or placebo.” (opens the source at this quote in a new tab)

Participants starting, completing, and discontinuing

Disposition	Placebo	PF-06649751 1 mg QD	PF-06649751 3 mg QD	PF-06649751 7 mg QD	PF-06649751 15 mg QD
Started	“23”	“13”	“15”	“13”	“44”
Completed	“15”	“1”	“1”	“3”	“24”
Not completed	“8”	“12”	“14”	“10”	“20”
Adverse event	“3”	“1”	“3”	“2”	“9”
Other	“5”	“9”	“10”	“6”	“5”

Limitations and caveats recorded with the results

“The study was terminated prematurely due to insufficient efficacy and not due to safety reasons.” (opens the source at this quote in a new tab)

Age by treatment group

Group	Age, years, mean (SD)
Placebo	“66.04(8.79)”
PF-06649751 1 mg QD	“66.92(8.79)”
PF-06649751 3 mg QD	“63.80(7.76)”
PF-06649751 7 mg QD	“67.77(9.36)”
PF-06649751 15 mg QD	“63.41(8.47)”
Total	“64.97(8.60)”

Disease duration and baseline OFF time

No evidence found.

Primary endpoint: change from baseline in daily OFF time at week 10

Group	Participants analyzed	Least squares mean change, hours (standard error)
Placebo	“21”	“-0.969(0.4092)”
PF-06649751 1 mg QD	“7”	“-1.173(0.3482)”
PF-06649751 3 mg QD	“9”	“-1.316(0.3289)”
PF-06649751 7 mg QD	“9”	“-1.480(0.3460)”
PF-06649751 15 mg QD	“41”	“-1.663(0.4297)”

Caution on week 15 results

“Results at Week 15 should be interpreted with caution given almost half the participants were not available for this analysis at Week 15 as compared to Week 10 and the complicated nature of protocol changes that impacted the study design after Week 10.” (opens the source at this quote in a new tab)

Interim futility analysis

“When the interim analysis of data from the more advanced PD study showed a low probability that it would reach a target efficacy threshold, (which was not a comparison with placebo, but a more stringent placebo-adjusted target value) that study was terminated” (opens the source at this quote in a new tab)

Adverse events, serious adverse events, discontinuations, and deaths

Measure	Placebo (n=23)	PF-06649751 1 mg QD (n=13)	PF-06649751 3 mg QD (n=15)	PF-06649751 7 mg QD (n=13)	PF-06649751 15 mg QD (n=44)
All-cause mortality, affected/at risk (%)	“1/23 (4.35%)”	“0/13 (0.00%)”	“0/15 (0.00%)”	“0/13 (0.00%)”	“1/44 (2.27%)”
Serious adverse events, affected/at risk (%)	“1/23 (4.35%)”	“1/13 (7.69%)”	“0/15 (0.00%)”	“0/13 (0.00%)”	“2/44 (4.55%)”
Other adverse events, affected/at risk (%)	“15/23 (65.22%)”	“7/13 (53.85%)”	“11/15 (73.33%)”	“10/13 (76.92%)”	“31/44 (70.45%)”

Selected non-serious adverse events

Adverse event	Placebo (n=23)	PF-06649751 1 mg QD (n=13)	PF-06649751 3 mg QD (n=15)	PF-06649751 7 mg QD (n=13)	PF-06649751 15 mg QD (n=44)
Nausea	“1/23 (4.35%)”	“2/13 (15.38%)”	“2/15 (13.33%)”	“1/13 (7.69%)”	“11/44 (25.00%)”
Headache	“0/23 (0.00%)”	“2/13 (15.38%)”	“1/15 (6.67%)”	“3/13 (23.08%)”	“11/44 (25.00%)”
Dyskinesia	“2/23 (8.70%)”	“1/13 (7.69%)”	“1/15 (6.67%)”	“3/13 (23.08%)”	“7/44 (15.91%)”
Dizziness	“0/23 (0.00%)”	“0/13 (0.00%)”	“1/15 (6.67%)”	“2/13 (15.38%)”	“4/44 (9.09%)”
Irritability	“0/23 (0.00%)”	“0/13 (0.00%)”	“0/15 (0.00%)”	“0/13 (0.00%)”	“4/44 (9.09%)”
Orthostatic hypotension	“0/23 (0.00%)”	“0/13 (0.00%)”	“1/15 (6.67%)”	“0/13 (0.00%)”	“2/44 (4.55%)”
Hallucination	“0/23 (0.00%)”	“0/13 (0.00%)”	“0/15 (0.00%)”	“1/13 (7.69%)”	“0/44 (0.00%)”

Serious adverse events in the 15 mg group

“Allergic oedema” (opens the source at this quote in a new tab)
“Dermatitis allergic” (opens the source at this quote in a new tab)

Summary: limitations of the NCT02687542 evidence

NCT02687542 was terminated on 25 September 2017 for insufficient efficacy after an interim analysis, with 108 of approximately 198 planned participants randomized, and no peer-reviewed publication of its results has been identified; results are available only from the ClinicalTrials.gov record and from the discussion in the publication of the linked early Parkinson's disease trial. Groups were unbalanced (44 participants in the 15 mg group and 13 to 23 in each other group), and 1 of 13 and 1 of 15 participants completed treatment in the 1 mg and 3 mg groups. The primary endpoint was analyzed in 87 participants with a Bayesian dose-response model. The registry cautions that week 15 results are affected by missing data and protocol changes after week 10. Doses were fixed at 1, 3, 7, or 15 mg once daily after a 3-week titration.

Limitation stated in the publication of the linked trial

“However, as that study was terminated at approximately 50% enrollment, there was insufficient data to make any firm statistical conclusion about PF-06649751 efficacy versus placebo.” (opens the source at this quote in a new tab)

Trial objective: multiple ascending doses in Parkinson's disease with motor fluctuations

“A Phase 1b, 2-period, Open Label, Multicenter, Dose Escalation Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-06649751 In Subjects With Parkinson's Disease And Motor Fluctuations” (opens the source at this quote in a new tab)

Primary and secondary objectives

“The primary objective of these studies was to evaluate the safety and tolerability of PF-06649751 in subjects with Parkinson’s disease. The pharmacokinetics of PF-06649751 was a secondary objective. Additionally, in both studies, we sought to explore the pharmacodynamic effects of PF-06649751 on motor performance and dyskinesia using the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III)” (opens the source at this quote in a new tab)

Summary: sponsor, identifiers, and study dates

The registry record for NCT02224664 gives Pfizer as sponsor and B7601005 as the sponsor study number. The study started in October 2014 and was completed in March 2016, with 50 participants enrolled; results were first posted on 27 March 2017.

Study centers

“a multiple ascending dose (MAD) study (NCT02224664) was conducted at 10 centers in the USA” (opens the source at this quote in a new tab)

Open-label dose escalation in sequential cohorts

“In the open-label MAD study, PF-06649751 was administered once daily (QD) over 21 days (days 3–23) to sequential cohorts of subjects with Parkinson’s disease (Table 2). PF-06649751 was up-titrated to achieve the target dose by day 14 (11 days of dosing).” (opens the source at this quote in a new tab)
“Cohorts 3, 4, and 6 targeted doses of 5 mg, 15 mg, and 25 mg QD, respectively, and in each case a separate up-titration scheme was employed to allow for 10 days of dosing at the target dose (days 14–23).” (opens the source at this quote in a new tab)
“Cohort 5 was designed to test doses up to 15 mg QD, specifically in Parkinson’s disease patients with l-dopa-induced dyskinesia (LID).” (opens the source at this quote in a new tab)

Levodopa down-titration during PF-06649751 up-titration

“During up-titration of PF-06649751 in period 2 in the MAD study, there was concomitant gradual down-titration of l-dopa, with the option of l-dopa rescue therapy as determined by the study investigators (Table 2).” (opens the source at this quote in a new tab)

Inclusion and exclusion criteria

“Both the SAD and MAD studies admitted male or female subjects of non-childbearing potential between the ages of 30 and 85 years (SAD study) or 30 and 80 years (MAD study), inclusive, with a body mass index of 17.5–38.0 kg/m2 and a total body weight greater than 50 kg, and with a clinical diagnosis of idiopathic Parkinson’s disease, including the presence of at least two out of three cardinal characteristics (tremor, rigidity, and/or bradykinesia). For both studies, subjects were excluded if they had a history of or clinical features consistent with an atypical parkinsonian syndrome, or a history of surgical intervention for Parkinson’s disease (pallidotomy, thalamotomy, deep brain stimulation, etc.).” (opens the source at this quote in a new tab)

Prohibited concomitant medications

“In the MAD study, amantadine (except cohort 5), apomorphine, anticholinergics, catechol-O-methyl transferase inhibitors, and dopamine agonists were not permitted at any time (days 0–24).” (opens the source at this quote in a new tab)

Dose titration by cohort

Cohort	Quoted record
5 mg target	“Dose levels were titrated from 0.25 mg up to a maximum dose level of 5 mg.”
15 mg target	“Dose levels were titrated from 1.0 mg up to a maximum dose of 15 mg.”
15 mg target, levodopa-induced dyskinesia	“Dose levels were titrated from 1 mg up to a maximum dose level of 15 mg.”
25 mg target	“Dose levels were titrated from 1 mg up to a maximum dose level of 25 mg.”

Primary safety outcome

“Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)” (opens the source at this quote in a new tab)

Pharmacodynamic assessment with the MDS-UPDRS Part III

“In the MAD study, MDS-UPDRS-III assessments took place each study day and at intervals of 0.5, 1, 1.5, 2, 4, 8, and 12 h on intensive pharmacokinetic/pharmacodynamic study days (days 7, 13, and 22).” (opens the source at this quote in a new tab)

Planned sample size

“A sample size of approximately nine (SAD study) and eight (MAD study) completers per cohort was chosen on the basis of the need to minimize exposure of humans to a new chemical entity and the requirement to provide adequate safety and tolerability information at each dose.” (opens the source at this quote in a new tab)

Participants assigned and treated

“For the MAD study, a total of 50 subjects were assigned to study treatment (l-dopa) in period 1. Of the 50 subjects, 45 subjects met the criteria for enrollment to period 2, and five subjects were discontinued from the study as they did not meet the period 2 entrance criteria. Forty-five subjects distributed across cohorts 3–6 were treated with PF-06649751.” (opens the source at this quote in a new tab)

Descriptive pharmacodynamic analysis

“In the MAD study, no formal inferential statistics were applied to the pharmacodynamic analysis, and results were descriptive only, with comparisons generally made to baseline, as appropriate.” (opens the source at this quote in a new tab)

Safety analysis set

“Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2.” (opens the source at this quote in a new tab)

Dose escalation period

Disposition	PF-06649751 5 mg	PF-06649751 15 mg	PF-06649751 15 mg, levodopa-induced dyskinesia	PF-06649751 25 mg
Started	“9”	“11”	“6”	“19”
Completed	“9”	“9”	“3”	“8”
Not completed	“0”	“2”	“3”	“11”
Adverse event	“0”	“2”	“2”	“7”

Permanent discontinuations due to adverse events

“Eleven subjects permanently discontinued the study owing to AEs: two in cohort 4 (PF-06649751 15 mg), two in cohort 5 (PF-06649751 LID), and seven in cohort 6 (PF-06649751 25 mg).” (opens the source at this quote in a new tab)

Sex, race, and age

“Of the 50 subjects in the study, 31 were male and 19 were female; the majority of the subjects were white (44/50 subjects) and the age range was 44–76 (Supplementary Table 2).” (opens the source at this quote in a new tab)

Mean age

Population	Age, years, mean (SD)
Overall study (n=50)	“64.2(6.9)”

Change in MDS-UPDRS Part III total score at 12 hours after dosing on day 22

“On day 22, at 12 h post dose the mean change of MDS-UPDRS-III scores from baseline was 2.25 ± 6.50 (80% CI, –1.0, 5.50), –20.0 ± 12.90 (80% CI, –27.02, –12.98), and –9.33 ± 14.60 (80% CI, –18.13, –0.54) for cohorts 3, 4, and 6 (PF-06649751 5 mg, 15 mg, and 25 mg), respectively.” (opens the source at this quote in a new tab)

Levodopa-free days

“In addition, 44% (4/9), 78% (7/9), and 50% (4/8) of the completed subjects in cohorts 3 (PF-06649751 5 mg), 4 (PF-06649751 15 mg), and 6 (PF-06649751 25 mg), respectively, experienced more than 10 l-dopa-free days (Fig. 2, bottom panel).” (opens the source at this quote in a new tab)

Levodopa-induced dyskinesia cohort

“There was a lack of an observed pharmacodynamic effect in cohort 5 (PF-06649751 LID), although numbers in this cohort were small (n = 3).” (opens the source at this quote in a new tab)

Steady-state pharmacokinetics

“On day 22 (steady-state), following administration of multiple oral doses of PF-06649751 from 5 mg to 25 mg, mean Cmax for PF-06649751 occurred at approximately 2.0–4.0 h post dose. The PF-06649751 exposures (geometric means of Cmax and AUCtau) increased with an increase of dose. On the basis of average values in Parkinson’s disease subjects with motor fluctuations (cohort 4 vs cohort 6), the increase in AUCtau was less than dose proportional between 15 mg and 25 mg. The mean apparent clearance values ranged from 2.4 L/h to 3.5 L/h.” (opens the source at this quote in a new tab)

Adverse events and serious adverse events by cohort

Measure	PF-06649751 5 mg (n=9)	PF-06649751 15 mg (n=11)	PF-06649751 15 mg, levodopa-induced dyskinesia (n=6)	PF-06649751 25 mg (n=19)
Participants with AEs	“9”	“7”	“5”	“15”
Participants with SAEs	“0”	“0”	“0”	“1”

Most common adverse events, severity, and serious adverse events

“The most common AEs reported in all PF-06649751 treatment groups were headache, nausea, abnormal dreams, dizziness, and vomiting (Supplementary Table 6). The majority of the AEs were mild to moderate in severity, except for six AEs that were severe in nature. AEs in all treatment groups occurred in the up-titration phase (days 3–24 and follow-up) and appeared related to pace and increment of up-titration rather than maximum exposure, and they were generally self-limited. There was only one SAE (palpitations), which occurred in cohort 6 on study day 3 when the PF-06649751 dose was 1 mg.” (opens the source at this quote in a new tab)

Electrocardiogram, laboratory, and suicidality assessments

“Despite these observations in the SAD study, no QTcF prolongation was observed in the MAD study, where higher PF-06649751 exposures were achieved, and no subject had a QTcF ≥ 500 ms or an increase of QTcF ≥ 60 ms.” (opens the source at this quote in a new tab)
“For both studies, there were no notable findings in clinical laboratory, physical, and neurological examinations, vital signs, or in suicidal ideation and behavior assessments.” (opens the source at this quote in a new tab)

Summary: limitations of the NCT02224664 evidence

The study was open label, had no placebo group during the dose escalation period, and treated 45 participants for 21 days across 4 cohorts of 6 to 19 participants. Pharmacodynamic results were descriptive, and participants who needed levodopa rescue were excluded from the pharmacodynamic analysis. In the 25 mg cohort, 11 of 19 participants did not complete dosing, 7 because of adverse events. The levodopa-induced dyskinesia cohort had 3 completers, too few to assess an effect on dyskinesia. Levodopa was down-titrated while PF-06649751 was up-titrated.

Limitations stated by the authors

“The multi-dose study was conducted in an open-label fashion, which does not facilitate direct and quantitative comparison of efficacy results with established agents.” (opens the source at this quote in a new tab)
“The relatively short duration of the studies described herein can only provide limited data on potential efficacy and address acute rather than long-term safety.” (opens the source at this quote in a new tab)

Trial objective: single ascending doses in idiopathic Parkinson's disease

“A Phase 1, Double Blind, Sponsor Open, Randomized, Placebo-controlled, Single Ascending Dose Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-06649751 In Subjects With Idiopathic Parkinson's Disease” (opens the source at this quote in a new tab)

Study summary

“This is a study with two sequential cohorts, each with three treatment periods. Single doses of PF-06649751 will be tested in this study, starting at a low dose and escalating to a dose projected to be under the current limits for drug concentration. Each cohort will aim to achieve approximately 9 completers. Primary endpoint is safety and tolerability, secondary endpoint is MDS-UPDRS part III.” (opens the source at this quote in a new tab)

Summary: sponsor, identifiers, and study dates

The registry record for NCT02373072 gives Pfizer as sponsor and B7601009 as the sponsor study number. The study started in March 2015, reached primary completion in February 2016, and was completed in March 2016, with 18 participants enrolled. No results have been posted to the registry.

Study sites

“A single ascending dose (SAD) study (NCT02373072) was conducted at five sites in the USA and one site in Belgium” (opens the source at this quote in a new tab)

Randomized, placebo-substitution, three-way crossover design

“The SAD study was a randomized, double-blind, sponsor-open, placebo-controlled, placebo-substitution study with three-way crossover design in subjects with idiopathic Parkinson’s disease (Table 1). After overnight washout of l-dopa (no l-dopa administration after 8 PM), study drug or placebo was administered once during each of three treatment periods, with an at least 7-day study drug washout phase between treatment periods.” (opens the source at this quote in a new tab)

Inclusion and exclusion criteria

“Both the SAD and MAD studies admitted male or female subjects of non-childbearing potential between the ages of 30 and 85 years (SAD study) or 30 and 80 years (MAD study), inclusive, with a body mass index of 17.5–38.0 kg/m2 and a total body weight greater than 50 kg, and with a clinical diagnosis of idiopathic Parkinson’s disease, including the presence of at least two out of three cardinal characteristics (tremor, rigidity, and/or bradykinesia).” (opens the source at this quote in a new tab)

Doses by cohort

“PF-06649751 doses were 0.75 mg, 1.5 mg, 3 mg, 6 mg, and 9 mg.” (opens the source at this quote in a new tab)
“All subjects in cohort 1 period 1 received either PF-06649751 (0.75 mg) or placebo, and dosing proceeded through two additional periods as outlined in Table 1.” (opens the source at this quote in a new tab)
“All subjects in cohort 2 received either a higher starting dose of PF-06649751 (3 mg) or placebo, and dosing for cohort 2 proceeded as outlined in Table 1.” (opens the source at this quote in a new tab)

Primary and secondary outcome measures

“Number and proportion of subjects with Adverse Events (AEs)” (opens the source at this quote in a new tab)
“Number of participants with ECG data that meet criteria of potential clinical concern” (opens the source at this quote in a new tab)
“MDS - Unified Parkinson's Disease Rating Scale Part III” (opens the source at this quote in a new tab)

Central rating of the MDS-UPDRS Part III

“All Part III assessments were performed by the local rater and, in the SAD study, rating sessions were video-recorded for evaluation by an independent central qualified rater.” (opens the source at this quote in a new tab)

Participants randomized and completing

“In the SAD study, a total of 18 subjects were randomized and assigned to study treatments. All subjects completed the treatment, except for one subject from cohort 2 who discontinued after two periods as they were no longer willing to participate.” (opens the source at this quote in a new tab)

Mixed-model analysis of MDS-UPDRS Part III

“In the SAD study, change from baseline in MDS-UPDRS-III total score was analyzed using a restricted maximum likelihood linear mixed-effect repeated measures model with fixed effects for treatment, time (visit), baseline MDS-UPDRS-III total motor score, and a random effect for subject.” (opens the source at this quote in a new tab)
“All subjects treated with study drugs were analyzed for pharmacodynamics and safety.” (opens the source at this quote in a new tab)

Discontinuation

“All subjects completed the treatment, except for one subject from cohort 2 who discontinued after two periods as they were no longer willing to participate.” (opens the source at this quote in a new tab)

Sex, race, age, weight, and body mass index

“The majority of the subjects were male (15/18) and white (16/18). The mean age (60.1 years, range 44–76 years), mean weight (81.0 kg, range 56.1–126.6 kg), and body mass index (27.8 kg/m2, range 18.3–37.5 kg/m2) were generally comparable across the two cohorts (Supplementary Table 1).” (opens the source at this quote in a new tab)

Change in MDS-UPDRS Part III total score after a single 9 mg dose

“In the SAD study, there was a statistically significant (p < 0.05) decrease in least squares (LS) mean change from baseline in MDS-UPDRS-III total motor score on day 1 at 1, 2, 4, 8, and 12 h in subjects in the PF-06649751 9-mg treatment group compared with placebo (Fig. 1). At 12 h post dose the LS mean change of MDS-UPDRS-III scores from baseline was –0.82 ± 3.26 (90% CI, –6.35, 4.71) and –11.96 ± 4.16 (90% CI, –18.88, –5.03) for placebo and PF-06649751 9 mg, respectively. The MDS-UPDRS-III demonstrated a statistically significant difference of –11.13 ± 3.68 (90% CI, –17.21, –5.06; p = 0.0028) in the PF-06649751 9-mg treatment group versus placebo.” (opens the source at this quote in a new tab)

Single 3 mg dose

“Similarly, there were greater decreases from baseline in LS mean total motor score on day 1 at 1, 2, 4, 8, and 12 h in subjects in the PF-06649751 3-mg treatment group versus placebo; however, the differences were not statistically significant.” (opens the source at this quote in a new tab)

Single-dose pharmacokinetics

“Following administration of single oral doses of PF-06649751 from 0.75 mg to 9 mg under fasted conditions, PF-06649751 Cmax occurred at approximately 3.0–4.0 h post dose (Supplementary Fig. 1 top panel and Supplementary Table 3). The half-life (t1/2) of PF-06649751 for the 3-mg group in cohort 2 was approximately 16 h.” (opens the source at this quote in a new tab)
“Both peak exposure (Cmax) and total exposure (AUClast) increased with increasing dose from 0.75 mg to 9 mg, and the increases appeared to be dose proportional as evidenced by similar dose-normalized AUClast and Cmax across all doses.” (opens the source at this quote in a new tab)

Adverse events

“In the SAD study, single doses of PF-06649751 up to 9 mg were safe and well tolerated by subjects with Parkinson’s disease. There were no deaths, serious AEs (SAE), severe AEs, discontinuations due to AEs, dose reductions, or temporary discontinuations due to AEs. A total of 46 all-causality treatment-emergent AEs (TEAEs) were reported, of which 35 were considered treatment related. All TEAEs were mild to moderate in severity (Supplementary Table 5). The most common TEAEs across all groups were headache, nausea, and vomiting (Supplementary Table 6).” (opens the source at this quote in a new tab)

QTcF changes after single doses

“There appeared to be a small dose-related increase in QT interval corrected for heart rate using Fridericia’s formula (QTcF) at the 2, 4, and 8 h post dose time points. The greatest increase from baseline in mean QTcF at any time point for any dose group was 11.7 ms.” (opens the source at this quote in a new tab)
“The reason for observed QTcF changes following single doses requires further investigation as PF-06649751 is expected to interact minimally with hERG (potassium ion) channels at clinically relevant concentrations.” (opens the source at this quote in a new tab)

Nausea and vomiting in healthy volunteer studies

“Healthy subject studies (single and multiple dose studies) with PF-06649751 were associated with nausea and vomiting, even at low doses, precluding evaluation of safety at projected clinically relevant doses (data on file).” (opens the source at this quote in a new tab)

Summary: limitations of the NCT02373072 evidence

The study enrolled 18 participants, gave single doses only, and assessed MDS-UPDRS Part III after an overnight levodopa washout, so it provides no information on repeated dosing or on use adjunctive to levodopa. The statistically significant motor effect was limited to the 9 mg dose, and the 3 mg dose did not differ significantly from placebo. Pharmacodynamic comparisons used 90% confidence intervals. The terminal half-life could not be characterized for most doses. No results have been posted to the registry.

Half-life characterization

“The t1/2 was not reportable for most treatments because the data were not sufficient for adequate characterization of the elimination phase.” (opens the source at this quote in a new tab)

Trial objective: effect of itraconazole on PF-06649751 exposure

“The purpose of this study is to evaluate the impact of CYP3A4 inhibitor, itraconazole, on plasma concentration of PF-06649751 in healthy subjects” (opens the source at this quote in a new tab)

Summary: sponsor, site, and study dates

The registry record for NCT03121664 gives Pfizer as sponsor and B7601006 as the sponsor study number, with a single site, the Pfizer Clinical Research Unit in Brussels, Belgium. The actual study start date was 7 April 2017 and the actual study completion date was 14 September 2017, with 11 participants enrolled. No results have been posted to the registry.

Open-label, fixed-sequence design

“A Phase 1, Open-label, Fixed-sequence Study To Estimate The Effects Of Multiple-dose Administration Of Itraconazole On The Steady-state Pharmacokinetics Of Pf-06649751 In Healthy Adult Subjects” (opens the source at this quote in a new tab)

Healthy adults

“Healthy female subjects of nonchildbearing potential and/or male subjects who, at the time of screening, are between the ages of 18 and 55 years, inclusive.” (opens the source at this quote in a new tab)

PF-06649751 titration and itraconazole coadministration

“PF-06649751 0.25 mg on Days 1,2,3 PF-06649751 0.5 mg on Days 4,5,6 PF-06649751 1 mg on Days 7 to Day 25 Itracoanzole 200 mg on Days 12 to Day 25” (opens the source at this quote in a new tab)

Primary pharmacokinetic outcome measures

“PF-06649751 and PF-06752844 steady state Cmax” (opens the source at this quote in a new tab)
“PF-06649751 and PF-06752844 steady state AUC24” (opens the source at this quote in a new tab)

Enrollment

Measure	Quoted record
Enrollment (actual)	“11”

Effect of strong CYP3A4 inhibition on tavapadon and metabolite exposure

“Tavapadon’s clearance is primarily via metabolism by cytochrome P450 (CYP450) 3A4 (CYP3A4). Coadministration with the potent CYP3A4 inhibitor itraconazole resulted in a 4- and 5-fold increase in peak and overall exposure, respectively; the major circulating hydroxylated metabolite exposure decreased by 36%.” (opens the source at this quote in a new tab)

Phase 1 pharmacokinetic summary across studies

“Following oral administration of tavapadon, PK was characterized by rapid absorption and average terminal elimination half-life of approximately 24 hours, supporting once-daily dosing. High-fat meals prior to dosing did not have clinically relevant impact on the rate or extent of absorption in healthy volunteers (a study in PD is ongoing).” (opens the source at this quote in a new tab)
“Due to low recovery of tavapadon in urine (<2%) and its extensive hepatic metabolism, planned studies will evaluate PK and safety in patients with severe renal impairment and patients with mild, moderate, or severe hepatic impairment.” (opens the source at this quote in a new tab)

Safety across phase 1 studies

“Although nausea and vomiting are the most frequent adverse events, there were no notable abnormalities in laboratory or electrocardiogram parameters across early-phase studies. Tavapadon is generally safe and well tolerated in a titrated dose of up to 15 mg in PD.” (opens the source at this quote in a new tab)

Summary: limitations of the NCT03121664 evidence

The itraconazole result is available only as one sentence in a 2022 congress abstract that summarizes several phase 1 studies without naming them; no registry results, confidence intervals, or individual pharmacokinetic parameters have been published. The study enrolled 11 healthy adults aged 18 to 55 years and used a 1 mg PF-06649751 dose; the same abstract describes titrated doses of up to 15 mg in Parkinson's disease.