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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

Baseline Characteristics

Characteristic	Control	Active
N	255	252
Age - mean (SD)	64.1 (8.5) years	65.6 (8.4) years
Age <65 years	46.7%	41.3%
Age ≥65 years	53.3%	58.7%
Sex - Female	33.3%	40.1%
Sex - Male	66.7%	59.9%
Race - White	96.1%	97.6%
Race - Black	1.6%	0.8%
Race - Asian	0.8%	0.8%
Race - American Indian or Alaska Native	0.8%	0%
Race - Other	0.8%	0.8%
Weight - mean (SD) kg	79.9 (15.7)	79.5 (17.2)
BMI - mean (SD)	27.0 (4.4)	27.4 (5.1)
Time since initial diagnosis - mean (SD) years	6.4 (4.6)	6.9 (4.5)
Daily on-time without troublesome dyskinesia - mean (SD) hours	10.1 (2.6)	9.9 (2.6)
Daily off-time - mean (SD) hours	5.4 (2.5)	5.6 (2.2)
MoCA total score - mean (SD)	28.0 (1.3)	28.0 (1.3)
Modified H&Y Stage 2	57.3%	53.6%
Modified H&Y Stage 2.5	19.6%	25.0%
Modified H&Y Stage 3	23.1%	21.4%
MDS-UPDRS Part I score - mean (SD)	7.5 (4.9)	8.0 (5.1)
MDS-UPDRS Part II score - mean (SD)	12.5 (7.1)	13.3 (6.5)
MDS-UPDRS Part III score - mean (SD)	32.4 (14.3)	32.6 (14.3)
MDS-UPDRS Part II + III score - mean (SD)	44.9 (18.9)	45.9 (18.2)
Use of adjunctive PD medication	42.4%	45.6%
Amantadine use	15.7%	19.4%
COMT inhibitors use	7.5%	6.7%
Istradefylline use	0.8%	0.4%
MAO-B inhibitors use	30.2%	30.2%
Daily levodopa dose - mean (SD) mg	817.6 (644.0)	811.9 (451.4)

Arms

Field	Control	Tavapadon
N	255	252
Intervention	Placebo oral tablets once daily adjunctive to stable oral levodopa	Flexible-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.
Duration	27 weeks (8-week titration, 7-week dose adjustment, 12-week maintenance)	27 weeks (8-week titration, 7-week dose adjustment, 12-week maintenance)

Outcomes

Outcome	Type	Control	Intervention	P-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 diary	Primary	0.60 hours increase (LSM)	1.70 hours increase (LSM)	<.001
Change from baseline to week 26 in total daily off-time	Secondary	−0.93 hours (LSM)	−1.88 hours (LSM)	<.001
Change from baseline to week 26 in MDS-UPDRS Part II score	Secondary	−0.1 points (LSM)	−1.4 points (LSM)	.02 (nominal)
Change from baseline to week 26 in MDS-UPDRS Part III score	Secondary	−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 event	Safety	55.1%	71.7%
Serious adverse events	Safety	5.5%	6.8%
AE leading to discontinuation	Safety	9.1%	17.1%
Death	Safety	0%	0.4% (1 death, metastatic pancreatic carcinoma, unrelated to study drug)
Nausea	Safety	4.3%	14.3%
Dyskinesia	Safety	1.6%	10.0%
Dizziness	Safety	3.1%	7.6%
Headache	Safety	2.8%	6.8%
Fall	Safety	5.1%	6.4%
Orthostatic hypotension	Safety	1.2%	6.0%
Visual hallucination	Safety	1.2%	5.6%
COVID-19	Safety	3.5%	5.2%
Somnolence	Safety	4.3%	5.2%
Impulse control disorders	Safety	1.2%	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 mmHg				Adverse
Clinical laboratory, eye examinations, cardiovascular assessments				Adverse

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

Content summarized and formatted by NeuroTrials.ai.

TEMPO-3

(2026)

Objective

To evaluate the efficacy, safety, and tolerability of tavapadon as adjunctive therapy to oral levodopa in adults with Parkinson disease experiencing motor fluctuations.

Study Summary

• Tavapadon significantly increased daily good-on-time by 1.10 hours compared with placebo (1.70 vs 0.60 hours; 95% CI, 0.60-1.70; P <.001)
• Daily off-time was significantly reduced with tavapadon vs placebo (−1.88 vs −0.93 hours; difference, −0.94 hours; 95% CI, −1.48 to −0.41; P <.001)
• Most adverse events were nonserious (93.2%) and mild to moderate in severity; common AEs with tavapadon included nausea (14.3%), dyskinesia (10.0%), and dizziness (7.6%)

Intervention

Tavapadon 5-15 mg once daily (flexible-dose) vs placebo, both adjunctive to stable oral levodopa for 27 weeks

Inclusion Criteria

Adults aged 40-80 years with Parkinson disease (UK Brain Bank criteria), modified Hoehn & Yahr score 2-3 in on-state, ≥2.5 hours daily off-time, stable levodopa dose ≥400 mg/day (≥3-4 doses daily), good levodopa response

Study Design

Arms: Tavapadon 5-15 mg once daily vs Placebo

Patients per Arm: 252 (tavapadon), 255 (placebo)

Outcome

• Primary: Tavapadon increased daily good-on-time by 1.1 hours vs placebo (P <.001; Cohen d = 0.40)
• Key secondary: Tavapadon reduced daily off-time by 0.94 hours vs placebo (P <.001; Cohen d = 0.35)
• MDS-UPDRS Part II improved by 1.2 points with tavapadon vs placebo (P = .02); Part III improved by 2.4 points (P = .01)

Bottom Line

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

Study Design

Study Type: Phase 3, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial
Randomization: Yes
Blinding: Double-blind (participants, investigators, and all blinded sponsor personnel)
Sample Size: 507
Follow-up: 27 weeks treatment period plus 4-week safety follow-up (total ~35 weeks)
Centers: 148
Countries: 14 countries

Primary Outcome

Definition: Change from baseline to week 26 in total daily on-time without troublesome dyskinesia (good-on-time) based on 2-day average of Hauser diary

Control	Intervention	HR/OR	P-value
0.60 hours increase (LSM)	1.70 hours increase (LSM)	- (0.60 to 1.70)	<.001

Limitations & 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

Citation

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

View Original Publication →

TEMPO-3

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about TEMPO-3