TEMPO-3 Trial: Tavapadon Adjunctive Therapy in Fluctuating Parkinson Disease
Key Takeaways
- Adjunctive tavapadon was associated with more daily good-on-time and less off-time than placebo at week 26 in adults receiving stable levodopa.
- Adverse events and adverse-event-related discontinuations were more frequent with tavapadon, while serious adverse event rates were similar and most events were mild to moderate.
- Levodopa remained stable, some long-standing adjunctive Parkinson medicines were allowed, and the trial was not designed to compare tavapadon with other adjunctive therapies in a broad population.
This phase 3, double-blind, placebo-controlled, parallel-group randomized clinical trial ran from September 2020 to February 2024 at 148 sites in 14 countries. Among screened adults, 507 were randomized; mean age was 64.9 years, 63% were male, mean disease duration was 6.7 years, and mean baseline off-time was 5.5 hours. Eligible adults were 40 to 80 years old with on-state modified Hoehn and Yahr stage 2, 2.5, or 3, along with at least 2.5 hours of daily off-time, stable oral levodopa of at least 400 mg/day, good levodopa response, and ability to complete the Hauser diary. Randomization was 1:1 to tavapadon or placebo, with blinded titration to 5 mg over 6 weeks and to the highest tolerated dose by week 14. Levodopa remained fixed, and COMT inhibitors, MAO-B inhibitors, amantadine, istradefylline, or anticholinergics were permitted only when started more than 90 days before baseline.
The primary endpoint was change from baseline to week 26 in daily on-time without troublesome dyskinesia by Hauser diary, and the key secondary endpoint was change in total daily off-time. Good-on-time changed by 1.70 hours with tavapadon and 0.60 hours with placebo, for a treatment difference of 1.10 hours (95% CI, 0.60 to 1.70; P<.001). Off-time changed by -1.88 hours with tavapadon and -0.93 hours with placebo, for a treatment difference of -0.94 hours (95% CI, -1.48 to -0.41; P<.001). Separation in good-on-time and off-time was apparent by week 8 and persisted through week 26, and predefined sensitivity analyses were consistent. The gain mainly reflected more on-time without dyskinesia; nominal differences in MDS-UPDRS II, III, and II+III favored tavapadon, while PDQ-39 and EQ-5D-5L showed no notable between-group differences.
In the safety population, at least one adverse event occurred in 71.7% of tavapadon participants and 55.1% of placebo participants, and most events were nonserious and mild to moderate. Adverse-event-related discontinuation occurred in 17.1% versus 9.1%, most often during titration, while serious adverse event rates were similar at 6.8% and 5.5%. Common tavapadon adverse events were nausea 14.3%, dyskinesia 10.0%, dizziness 7.6%, headache 6.8%, falls 6.4%, orthostatic hypotension 6.0%, visual hallucination 5.6%, COVID-19 5.2%, and somnolence 5.2%. There was no evidence of increased suicidality and no clinically relevant laboratory, eye, or cardiovascular safety findings. Blood pressure decreases were observed with tavapadon, while measured orthostatic hypotension frequency was comparable between groups; the main safety difference was more frequent generally nonserious dopaminergic-type events and discontinuation.
The trial was not designed to compare tavapadon with D2/D3 agonists or other adjunctive Parkinson therapies. Participants were predominantly White at 96.8% and were selected for stable levodopa response and Hauser diary competence, narrowing the population represented by these findings. Treatment lasted 27 weeks with a 4-week safety follow-up, so longer-term durability and safety were not addressed. Nonadverse discontinuations included participant withdrawal and site terminations related to the war in Ukraine, and the findings reflect a 27-week adjunctive trial with a primary week 26 comparison in a selected levodopa-treated population.