Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials.

The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease.

Evoke和Evoke+试验旨在研究早期阿尔茨海默病患者中口服司美格鲁肽的疗效和安全性。

Methods

evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlledphase 3 trials conducted across 566 sites in 40 countries.

evoke 和 evoke+ 是在40个国家的566个地点进行的多中心、随机、双盲、安慰剂对照的3期临床试验。

The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease.

这些试验评估了每日一次口服司美格鲁肽（semaglutide）高达14毫克在确认有淀粉样蛋白沉积的阿尔茨海默病患者中的疗效和安全性，这些患者年龄在55至85岁之间，患有轻度认知障碍或因阿尔茨海默病引起的轻度痴呆。

In evoke+, participants with significant small vessel pathology were included.

在Evoke+研究中，纳入了具有显著小血管病变的参与者。

Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks.

参与者被随机分配（1:1），每天一次接受14毫克的semaglutide（灵活剂量）或安慰剂，最长治疗周期为156周。

The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants.

主要终点是从基线到第104周临床痴呆评分-总分（CDR-SB）的变化，评估所有随机参与者。

Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug.

所有随机参与者均进行了安全性评估，并报告了至少接受一次研究药物剂量的参与者。

These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome.

这些试验已在ClinicalTrials.gov上注册（NCT04777396和NCT04777409）；由于临床结果不佳，两项试验均已终止。

Results

Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977).

在2021年5月18日至2023年9月8日期间，共有9981名参与者接受了筛查，其中3808名被随机分配；在evoke试验中（司美格鲁肽，n=928；安慰剂，n=927），以及在evoke+试验中（司美格鲁肽，n=976；安慰剂，n=977）。

Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline.

基线时，平均年龄为72.2岁（标准差7.1），平均CDR-SB评分为3.7（标准差1.6）。

In evoke+, 54 (2·8%) participants had small vessel pathology.

在evoke+研究中，有54名（2.8%）参与者存在小血管病变。

In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+).

在evoke和evoke+研究中，从基线到第104周，接受semaglutide治疗的患者的CDR-SB评分平均变化为2.3（标准误0.1）和2.2（0.1），而接受安慰剂治疗的患者为2.3（0.1）和2.1（0.1）（估计差异为-0.08 [95% 置信区间-0.35至0.20]，p=0.57在evoke研究中，以及0.10 [-0.17至0.38]，p=0.46在evoke+研究中）。

Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo.

在1896名接受semaglutide治疗的参与者中，有1729名（91.2%）报告了治疗后出现的不良事件，而在1902名接受安慰剂治疗的参与者中，有1613名（84.8%）报告了不良事件。

There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group).

调查人员认为有五例死亡与治疗相关（semaglutide组一例，安慰剂组四例）。

interpretation

Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease.

口服semaglutide在减缓早期阿尔茨海默病参与者的临床进展方面没有效果。

Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications.

在早期阿尔茨海默病中使用司美格鲁肽的安全性和耐受性与其他适应症的研究结果一致。

funding

Novo Nordisk.

诺和诺德。