Background

Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT_2A inverse agonist and antagonist, on negative symptoms of schizophrenia.

Methods

The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18–55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete.

Findings

Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean −10·4 [SE 0·67]) versus placebo (least squares mean −8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]).

Interpretation

Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect.

Funding

Acadia Pharmaceuticals.

中文翻译：

---

Pimavanserin 治疗精神分裂症阴性症状：北美和欧洲 ADVANCE 2 期随机安慰剂对照试验的结果

背景

精神分裂症的阴性症状与不良的临床结果相关，但有效的治疗方法很少。我们旨在评估匹马万色林（一种选择性 5-HT _2A反向激动剂和拮抗剂）对精神分裂症阴性症状的影响。

方法

ADVANCE 研究是一项为期 26 周、随机、双盲、安慰剂对照的 Pimavanserin 2 期研究，用于治疗 18-55 岁以阴性症状为主的稳定门诊精神分裂症患者。根据计算机生成的时间表（按地理区域分层），患者被随机分配 (1:1) 跨越 83 个地点（北美 18 个和欧洲 65 个）每天接受匹马万色林或安慰剂，添加到正在进行的抗精神病药物治疗中。符合条件的患者在七个阳性和阴性综合征量表 (PANSS) Marder 阴性因素项目的总和上得分至少为 20（至少三个阴性症状项目得分≥4 或至少两个阴性症状项目得分≥5）。在研究的前 8 周内，可将 20 mg pimavanserin 或安慰剂的起始剂量调整为 34 mg 或 10 mg，之后剂量保持稳定直到研究结束。pimavanserin 和安慰剂均作为两片单独的片剂每天口服给药一次（pimavanserin 片剂为 10 mg 或 17 mg）。主要终点是使用 16 项阴性症状评估 (NSA-16) 从基线到第 26 周的总分变化。主要结果在接受至少一剂研究药物并在基线和至少一次基线后（完整分析集）。在已接受至少一剂研究药物的患者中分析安全性结果。该试验已在 ClinicalTrials.gov 注册，NCT02970305，并且已经完成。主要终点是使用 16 项阴性症状评估 (NSA-16) 从基线到第 26 周的总分变化。主要结果在接受至少一剂研究药物并在基线和至少一次基线后（完整分析集）。在已接受至少一剂研究药物的患者中分析安全性结果。该试验已在 ClinicalTrials.gov 注册，NCT02970305，并且已经完成。主要终点是使用 16 项阴性症状评估 (NSA-16) 从基线到第 26 周的总分变化。主要结果在接受至少一剂研究药物并在基线和至少一次基线后（完整分析集）。在已接受至少一剂研究药物的患者中分析安全性结果。该试验已在 ClinicalTrials.gov 注册，NCT02970305，并且已经完成。在已接受至少一剂研究药物的患者中分析安全性结果。该试验已在 ClinicalTrials.gov 注册，NCT02970305，并且已经完成。在已接受至少一剂研究药物的患者中分析安全性结果。该试验已在 ClinicalTrials.gov 注册，NCT02970305，并且已经完成。

发现

2016 年 11 月 4 日至 2019 年 4 月 16 日期间，我们将 403 名患者随机分配至匹马万色林（n=201；131 [65%] 男性；187 [93%] 白人）或安慰剂（n=202；137 [68%]）男性，186 名 (92%) 白人），其中 400 名被纳入疗效分析（匹马万色林组 199 名，安慰剂组 201 名）。pimavanserin 组的平均年龄为 37·7 岁 (SD 9·4)，安慰剂组为 36·7 (9·2) 岁。使用匹马文色林（最小二乘均值 -10·4 [SE 0·67]）与安慰剂（最小二乘均值 -8·5 [0·67]; p =0·043；效果大小：0·211）。组间出现治疗出现的不良事件 (TEAE) 的患者数量相似：匹马万色林组 80 (40%) 名患者和安慰剂组 71 (35%) 名患者出现 TEAE。大多数 TEAE 是头痛（6% [n=13]vs 5% [n=10]）和嗜睡（5% [n=11] vs 5% [n=10]）。安慰剂组的一名患者报告严重头痛 (0·5%)、流鼻涕 (0·5%)、咳嗽 (0·5%) 和流感 (0·5%)。在匹马万色林组中，1 名患者报告严重牙痛 (0·5%)，2 名患者精神分裂症恶化 (1%)。Pimavanerin (4·5 ms [SD 18·0]) 的 QTcF 间期平均变化高于安慰剂 (0·0 ms [16·0])。

解释

精神分裂症主要阴性症状的稳定患者在用匹马万色林治疗后阴性症状有所减少。然而，鉴于效应量较小，需要进一步研究优化剂量，以确定这种效应的临床意义。

资金

阿卡迪亚制药公司。