Institute of Health Research, University of Exeter Medical School, Exeter, UK.
Wolfson Centre for Age-related Diseases, King's College London, London, UK.
Lancet Neurol. 2018 Mar;17(3):213-222. doi: 10.1016/S1474-4422(18)30039-5.
Pimavanserin is a selective 5-HT receptor inverse agonist and antagonist approved in the USA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. No safe or effective pharmacological treatment is approved for psychosis in patients with Alzheimer's disease. Therefore, we aimed to evaluate the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis.
We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (<6 or ≥6) and Neuropsychiatric Inventory-Nursing Home version (NPI-NH) psychosis score (<12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI-NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553.
Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI-NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI-NH psychosis score at week 6 was -3·76 points (SE 0·65) for pimavanserin and -1·93 points (0·63) for placebo (mean difference -1·84 [95% CI -3·64 to -0·04], Cohen's d=-0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference -0·51 [95% CI -2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group.
Pimavanserin showed efficacy in patients with Alzheimer's disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo.
ACADIA Pharmaceuticals.
匹莫范色林是一种选择性 5-HT 受体反向激动剂和拮抗剂，已获美国批准用于治疗帕金森病精神病相关的幻觉和妄想。目前尚无安全有效的药物治疗可用于治疗阿尔茨海默病患者的精神病。因此，我们旨在评估匹莫范色林与安慰剂在阿尔茨海默病精神病患者中的安全性、耐受性和疗效。
我们进行了一项 2 期、随机、双盲、安慰剂对照、单中心（英国有多个附属疗养院）研究。我们纳入了年龄在 50 岁及以上、可能或可能患有阿尔茨海默病且有幻觉、妄想或两者兼有的精神病症状的男女患者。参与者被随机分配（1:1）接受 12 周的口服治疗，分别为匹莫范色林（每天两片 17mg 片剂）或安慰剂，使用 4 个和按基线 Mini-Mental State Examination（MMSE）总分（<6 或≥6）和神经精神疾病住院患者护理版（NPI-NH）精神病评分（<12 或≥12）分层的置换块大小。参与者、护理人员、研究赞助商和诊所的研究人员对治疗分配进行了掩蔽。主要终点是在修改后的意向治疗人群中，匹莫范色林与安慰剂相比，在基线至第 6 周的 NPI-NH 精神病评分的平均变化。通过第 12 周评估匹莫范色林的持续获益和安全性。该研究在 ClinicalTrials.gov 上注册，编号为 NCT02035553。
2014 年 1 月 16 日至 2016 年 10 月 27 日，在 133 家疗养院中有 345 名患者接受了筛查，其中 181 名患者被随机分配治疗（匹莫范色林组 90 名，安慰剂组 91 名）。178 名参与者纳入修改后的意向治疗人群。匹莫范色林组的总基线 NPI-NH 精神病评分平均为 9.5（标准差 4.8），安慰剂组为 10.0（5.6）。匹莫范色林组第 6 周的 NPI-NH 精神病评分平均变化为-3.76 分（SE 0.65），安慰剂组为-1.93 分（0.63）（平均差异-1.84[95%CI-3.64 至-0.04]，Cohen's d=-0.32;p=0.045）。在第 12 周时，匹莫范色林与安慰剂相比，对整个研究人群没有明显的优势（治疗差异-0.51[95%CI-2.23 至 1.21];p=0.561）。常见的不良反应有跌倒（匹莫范色林组 90 名参与者中有 21 名[23%]，安慰剂组 91 名中有 21 名[23%]）、尿路感染（匹莫范色林组 20 名[22%]，安慰剂组 25 名[28%]）和激越（匹莫范色林组 19 名[21%]，安慰剂组 13 名[14%]）。有 8 名（9%）服用匹莫范色林的参与者和 11 名（12%）服用安慰剂的参与者因不良反应而停止治疗。在任何一组中均未观察到认知或运动功能的不良影响。
匹莫范色林在阿尔茨海默病精神病患者的主要终点（第 6 周）显示出疗效，具有可接受的耐受性特征，并且对认知功能没有负面影响。进一步随访至第 12 周，匹莫范色林与安慰剂相比没有显著优势。
ACADIA 制药公司。
