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)