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)