Trial of Pimavanserin in Dementia-Related Psychosis (HARMONY)
(2021)Study Summary
• Pimavanserin significantly delayed psychosis relapse in dementia-related psychosis (DRP): relapse in 13% (pimavanserin) vs 28% (placebo) during randomized withdrawal phase (HR 0.35; 95% CI 0.17-0.73; P=0.005).
• First positive RCT for DRP across dementia types (AD, PD, LBD, vascular, FTD).
• Published NEJM 2021.
• 392 enriched → 194 randomized.
• First positive RCT for DRP across dementia types (AD, PD, LBD, vascular, FTD).
• Published NEJM 2021.
• 392 enriched → 194 randomized.
Intervention
Continue pimavanserin 34 mg daily vs Switch from pimavanserin to matching placebo
Study Design
Arms: Array
Outcome
Time from randomization to relapse of psychosis: 12/95 (13%) relapsed vs 28/99 (28%) relapsed (p=0.005)
Bottom Line
Pimavanserin significantly delayed psychosis relapse in dementia-related psychosis (DRP): relapse in 13% (pimavanserin) vs 28% (placebo) during randomized withdrawal phase (HR 0.35; 95% CI 0.17-0.73; P=0.005). First positive RCT for DRP across dementia types (AD, PD, LBD, vascular, FTD). Published NEJM 2021. 392 enriched → 194 randomized.
Major Points
- Relapse significantly delayed: 13% vs 28% (HR 0.35; 95% CI 0.17-0.73; P=0.005).
- Enrichment-randomized withdrawal design: 12-week open-label pimavanserin → responders randomized to continue vs placebo for 26 weeks.
- First positive trial in dementia-related psychosis spanning multiple dementia types.
- 392 enrolled open-label → 217 responded → 194 randomized (105 pimavanserin, 89 placebo).
- Dementia types: AD 67%, PD dementia 11%, LBD 7%, vascular 8%, FTD 4%, other 3%.
- Pimavanserin 34 mg once daily. Selective 5-HT2A inverse agonist — no D2 blockade.
- No worsening of cognition (MMSE stable) or motor function.
- AEs: headache 9% vs 4%, UTI 5% vs 2%, constipation 4% vs 1%. Falls similar.
- Stopped early for efficacy at prespecified interim analysis.
- Published NEJM 2021 (Tariot et al.). Acadia Pharmaceuticals sponsored. Led to FDA supplemental application.
Study Design
- Study Type
- Phase 3, double-blind, randomized, placebo-controlled discontinuation trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 392
- Follow-up
- 12-week open-label + up to 26-week double-blind
- Centers
- 91
- Countries
- USA
Primary Outcome
Definition: Time from randomization to relapse of psychosis
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 28/99 (28%) relapsed | 12/95 (13%) relapsed | 0.35 (0.17–0.73) | 0.005 |
Limitations & Criticisms
- Randomized discontinuation design enriches for responders
- trial stopped early possibly overestimating effect
- almost all patients White
- 15% had PD for which pimavanserin already approved
Citation
10.1056/NEJMoa2034634