ADVANCE: Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients With Negative Symptoms of Schizophrenia

Pimavanserin is a selective, 5-hydroxytryptamine (5-HT)2A receptor inverse agonist/antagonist with lower activity at 5-HT2C receptors. Previous studies have shown beneficial effects of adjunctive pimavanserin in patients with schizophrenia, including improvement in negative symptoms. ADVANCE was a Phase 2, 26-week, randomized, double-blind, placebo-controlled study of stable outpatients with predominantly negative symptoms. Patients were randomized to either pimavanserin or placebo added to main antipsychotic therapy. Initial dose was 20mg once daily, with dose adjustments to 34mg or 10mg permitted until Week 8. The primary endpoint was change from baseline to Week 26 on the Negative Symptom Assessment-16 (NSA-16) total score. The efficacy analysis included 400 patients (201 placebo; 199 pimavanserin). The final pimavanserin dose was 34mg in 53.8% of patients, 20mg in 44.7%, and 10mg in 1.5%. Significant improvement versus placebo was observed for the NSA-16 total score at 26 weeks with pimavanserin (least squares [LS] mean: -10.4 versus -8.5; p=0.043; effect size: 0.21). Improvement versus placebo was greater in patients whose last dose was 34mg (n=107; LS mean: -11.6 versus -8.5; unadjusted p=0.0065; effect size: 0.34). Treatment-emergent adverse event (TEAE) incidence was 35.1% with placebo and 39.8% with pimavanserin. The most common TEAEs were headache (5.0% and 6.5%) and somnolence (5.0% and 5.5%) with placebo and pimavanserin, respectively. Negative symptoms improved significantly with pimavanserin versus placebo in stable patients with predominantly negative symptoms of schizophrenia. Greater improvement was observed at a 34mg dose. The tolerability profile of pimavanserin was comparable with placebo, with similar TEAE incidence rates.