HARMONY
(2021)Objective
To evaluate whether pimavanserin, a selective 5-HT2A inverse agonist/antagonist, reduces relapse of psychosis in patients with dementia-related psychosis from multiple etiologies (Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, vascular dementia)
Study Summary
• Trial stopped early for efficacy at interim analysis
• No worsening of cognition (MMSE) or motor function (ESRS-A) observed with pimavanserin
Intervention
Pimavanserin 34 mg (or 20 mg if tolerability issues) once daily orally
Inclusion Criteria
Age 50-90, dementia diagnosis (AD, PDD, DLB, FTD, or vascular), MMSE 6-24, psychotic symptoms ≥2 months, SAPS-H+D score ≥10 with global subscore ≥4, CGI-S ≥4
Study Design
Arms: Open-label phase: All received pimavanserin 12 weeks; Double-blind phase: Responders randomized to continue pimavanserin vs switch to placebo for up to 26 weeks
Patients per Arm: Open-label: 392; Double-blind: 105 pimavanserin, 112 placebo
Outcome
• Secondary: Discontinuation for any reason 22% vs 38% (HR 0.45, 95% CI 0.26-0.79, P=0.005)
• Common AEs: headache (9.5% vs 4.5%), UTI (6.7% vs 3.6%), QT prolongation (asymptomatic, 1.3%)
Bottom Line
In patients with dementia-related psychosis who responded to open-label pimavanserin, continuation of treatment significantly reduced relapse of psychosis compared with discontinuation (13% vs 28%, HR 0.35). The trial was stopped early for efficacy. Pimavanserin did not worsen cognition or motor function.
Major Points
- Randomized discontinuation design: 12-week open-label phase followed by double-blind randomization of responders to continue pimavanserin or switch to placebo
- 61.8% of eligible patients (217/351) met sustained response criteria at weeks 8 and 12 and were randomized
- Relapse occurred in 13% of pimavanserin group vs 28% of placebo group (HR 0.35, P=0.005)
- Trial stopped early at interim analysis when P<0.0066 threshold was met
- 66.3% had Alzheimer's disease, 15.1% Parkinson's disease dementia, 9.7% vascular dementia, 7.1% DLB, 1.8% FTD
- Mean MMSE score improved by 1.0 point during open-label phase and was maintained with continued pimavanserin
- No worsening of extrapyramidal symptoms (ESRS-A score improved with pimavanserin)
- Pimavanserin acts via selective 5-HT2A inverse agonism without D2 dopamine receptor binding
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled discontinuation trial
- Randomization
- Yes
- Blinding
- Double-blind after randomization; investigators, site staff, adjudication committee, and sponsor personnel unaware of assignments
- Sample Size
- 392
- Follow-up
- Up to 26 weeks double-blind phase (plus 4-week safety follow-up)
- Centers
- 101
- Countries
- United States, Canada, Eastern Europe, Western Europe, Latin America
Primary Outcome
Definition: Time from randomization to relapse of psychosis (defined as: ≥30% increase in SAPS-H+D and CGI-I 6 or 7, OR hospitalization for dementia-related psychosis, OR stopping trial/withdrawal for lack of efficacy, OR use of other antipsychotics)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 28 of 99 (28%) | 12 of 95 (13%) | 0.35 (0.17-0.73) | 0.005 |
Limitations & Criticisms
- Randomized discontinuation design selects for responders, limiting ability to assess response in initial non-responders
- Trial stopped early for efficacy, limiting assessment of clinical predictors of relapse and long-term safety
- ~15% of patients had Parkinson's disease (for which pimavanserin is already approved), potentially biasing results
- Almost all patients were White (96.6%), limiting generalizability
- Median double-blind exposure was only ~18 weeks (pimavanserin) and ~11 weeks (placebo) due to early stopping
- Response criteria required sustained response at both weeks 8 and 12, excluding late responders
- QT prolongation is a known class concern; mean 5.4 msec increase observed
- Brief psychosocial therapy during screening may have contributed to improvement
Citation
N Engl J Med 2021;385:309-19