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TEMPO-3

Tavapadon as Adjunctive Treatment for Parkinson Disease: The TEMPO-3 Randomized Clinical Trial

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Year of Publication: 2026

Authors: Hubert H. Fernandez, Stuart H. Isaacson, Robert A. Hauser, ..., Zoltan Mari

Journal: JAMA Neurology

Citation: JAMA Neurol. Published online March 20, 2026. doi:10.1001/jamaneurol.2026.0577

Link: https://doi.org/10.1001/jamaneurol.2026.0577

Clinical Question

Can once-daily tavapadon, a selective D1/D5 dopamine agonist, improve motor control and reduce off-time in Parkinson disease patients with motor fluctuations on levodopa while minimizing adverse events?

Bottom Line

In adults with Parkinson disease experiencing motor fluctuations on levodopa, adjunctive tavapadon (5-15 mg once daily) significantly increased daily good-on-time by 1.1 hours (P <.001) and reduced off-time by 0.94 hours (P <.001) compared with placebo, with a favorable safety profile characterized by mostly mild-to-moderate adverse events.

Major Points

  • Tavapadon significantly increased daily on-time without troublesome dyskinesia (good-on-time) by 1.10 hours vs placebo (1.70 vs 0.60 hours; P <.001; Cohen d = 0.40)
  • Daily off-time was significantly reduced with tavapadon vs placebo (−1.88 vs −0.93 hours; difference −0.94 hours; P <.001; Cohen d = 0.35)
  • The increase in good-on-time was primarily driven by increased on-time without dyskinesia
  • MDS-UPDRS Part II (activities of daily living) improved by 1.2 points with tavapadon vs placebo (nominal P = .02)
  • MDS-UPDRS Part III (motor function) improved by 2.4 points with tavapadon vs placebo (nominal P = .01)
  • Most adverse events (93.2%) were nonserious and mild-to-moderate in severity
  • Common AEs with tavapadon (≥5%) were nausea (14.3%), dyskinesia (10.0%), and dizziness (7.6%)
  • Discontinuation due to AEs was higher with tavapadon (17.1%) vs placebo (9.1%)
  • No notable differences between groups in rates of impulse control disorders, somnolence, or measured orthostatic hypotension

Design

Study Type: Phase 3, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial

Randomization: 1

Blinding: Double-blind (participants, investigators, and all blinded sponsor personnel)

Allocation: 1:1 randomization using computer-generated randomization scheme

Enrollment Period: September 2020 to February 2024

Follow-up Duration: 27 weeks treatment period plus 4-week safety follow-up (total ~35 weeks)

Centers: 148

Countries: 14 countries

Sample Size: 507

Analyzed: 487

Analysis: Modified intention-to-treat (mITT) population using mixed model for repeated measures (MMRM)

Power Calculation: Sample size of 184 participants per group provided ≥90% power to detect a 1-hour treatment difference at 2-sided .05 significance level with assumed SD of 2.5 hours; later increased to 500 total participants after interim analysis

Registration: ClinicalTrials.gov Identifier: NCT04542499

Inclusion Criteria

  • Adults aged 40 to 80 years
  • Diagnosis of PD consistent with UK Parkinson Disease Society Brain Bank criteria
  • Modified Hoehn & Yahr score of 2, 2.5, or 3 in the on-state
  • Minimum of 2.5 hours of daily off-time on 2 consecutive days during screening period
  • Minimum stable dose of 400 mg of levodopa per day divided at least 3 or 4 times daily
  • Good response to levodopa per investigator judgment
  • Acceptable ability to complete Hauser diary on concordance testing during screening
  • Montreal Cognitive Assessment score ≥26

Exclusion Criteria

  • Atypical or secondary parkinsonian syndrome
  • Previous or planned surgical intervention for PD
  • Montreal Cognitive Assessment score <26
  • History of or current diagnosis of clinically significant impulse control disorder
  • History of psychosis or hallucinations for ≤12 months
  • Current use (≤14 days of baseline) of dopamine agonists

Arms

FieldControlTavapadon
N255252
InterventionPlacebo oral tablets once daily adjunctive to stable oral levodopaFlexible-dose tavapadon 5-15 mg once daily (oral tablets) adjunctive to stable oral levodopa. Titration: 0.25 mg escalating to 5 mg over 8 weeks. Dose adjustment: 5-15 mg over 7 weeks. Maintenance: maximum tolerated dose for 12 weeks.
Duration27 weeks (8-week titration, 7-week dose adjustment, 12-week maintenance)27 weeks (8-week titration, 7-week dose adjustment, 12-week maintenance)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline to week 26 in total daily on-time without troublesome dyskinesia (good-on-time) based on 2-day average of Hauser diaryPrimary0.60 hours increase (LSM)1.70 hours increase (LSM)<.001
Change from baseline to week 26 in total daily off-timeSecondary−0.93 hours (LSM)−1.88 hours (LSM)<.001
Change from baseline to week 26 in MDS-UPDRS Part II scoreSecondary−0.1 points (LSM)−1.4 points (LSM).02 (nominal)
Change from baseline to week 26 in MDS-UPDRS Part III scoreSecondary−4.6 points (LSM)−7.0 points (LSM).01 (nominal)
Change from baseline to week 26 in MDS-UPDRS Part II + III combined score (exploratory)Secondary−4.7 points (LSM)−8.4 points (LSM).005 (nominal)
Any adverse eventSafety55.1%71.7%
Serious adverse eventsSafety5.5%6.8%
AE leading to discontinuationSafety9.1%17.1%
DeathSafety0%0.4% (1 death, metastatic pancreatic carcinoma, unrelated to study drug)
NauseaSafety4.3%14.3%
DyskinesiaSafety1.6%10.0%
DizzinessSafety3.1%7.6%
HeadacheSafety2.8%6.8%
FallSafety5.1%6.4%
Orthostatic hypotensionSafety1.2%6.0%
Visual hallucinationSafety1.2%5.6%
COVID-19Safety3.5%5.2%
SomnolenceSafety4.3%5.2%
Impulse control disordersSafety1.2%2.4%
Placebo 25.6%, Tavapadon 31.9%Adverse
Placebo 25.2%, Tavapadon 32.7%Adverse
Placebo 4.3%, Tavapadon 7.2%Adverse
Placebo 21.3%, Tavapadon 41.8%Adverse
93.2%Adverse
Placebo 7%, Tavapadon 11%Adverse
Mean decrease in standing systolic BP 8.6 mmHg (tavapadon) vs 0.8 mmHg (placebo); standing diastolic BP 6.0 mmHg vs 1.8 mmHgAdverse
Clinical laboratory, eye examinations, cardiovascular assessmentsAdverse

Subgroup Analysis

Not explicitly reported in the document provided

Criticisms

  • Study population was predominantly White (96.8%), limiting generalizability to other racial and ethnic groups
  • 27-week treatment duration may not fully capture long-term safety and efficacy, particularly for adverse events that emerge with prolonged treatment (e.g., impulse control disorders)
  • Higher discontinuation rate in tavapadon group (36.9%) vs placebo (19.2%), primarily due to adverse events
  • No direct comparison with currently available D2/D3 dopamine agonists or other adjunctive therapies
  • Trial conducted during COVID-19 pandemic, which may have affected enrollment times and discontinuation rates
  • No significant differences observed in quality of life measures (PDQ-39, EQ-5D-5L)
  • MDS-UPDRS assessments conducted 2-3 hours after last levodopa dose may not fully capture peak effects
  • Secondary outcome analyses not corrected for multiplicity; P-values should be interpreted as nominal

Funding

Cerevel Therapeutics (now part of AbbVie Inc)

Based on: TEMPO-3 (JAMA Neurology, 2026)

Authors: Hubert H. Fernandez, Stuart H. Isaacson, Robert A. Hauser, ..., Zoltan Mari

Citation: JAMA Neurol. Published online March 20, 2026. doi:10.1001/jamaneurol.2026.0577

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