在英国，每周一次注射艾塞那肽与安慰剂作为帕金森病患者潜在疾病修饰治疗的比较：一项3期、多中心、双盲、平行组、随机、安慰剂对照试验。

Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson's disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial.

作者信息

Vijiaratnam Nirosen, Girges Christine, Auld Grace, McComish Rachel, King Alexa, Skene Simon S, Hibbert Steve, Wong Alan, Melander Sabina, Gibson Rachel, Matthews Helen, Dickson John, Carroll Camille, Patrick Abigail, Inches Jemma, Silverdale Monty, Blackledge Bethan, Whiston Jessica, Hu Michele, Welch Jessica, Duncan Gordon, Power Katie, Gallen Sarah, Kerr Jacqueline, Chaudhuri K Ray, Batzu Lucia, Rota Silvia, Jabbari Edwin, Morris Huw, Limousin Patricia, Greig Nigel, Li Yazhou, Libri Vincenzo, Gandhi Sonia, Athauda Dilan, Chowdhury Kashfia, Foltynie Tom

机构信息

Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, University College London, London, UK.

Comprehensive Clinical Trials Unit, University College London, London, UK.

出版信息

Lancet. 2025 Feb 22;405(10479):627-636. doi: 10.1016/S0140-6736(24)02808-3. Epub 2025 Feb 4.

DOI:10.1016/S0140-6736(24)02808-3

PMID:39919773

Abstract

BACKGROUND

GLP-1 receptor agonists have neurotrophic properties in in-vitro and in-vivo models of Parkinson's disease and results of epidemiological studies and small randomised trials have suggested possible benefits for risk and progression of Parkinson's disease. We aimed to establish whether the GLP-1 receptor agonist, exenatide, could slow the rate of progression of Parkinson's disease.

METHODS

We did a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial at six research hospitals in the UK. Participants were aged 25-80 years with a diagnosis of Parkinson's disease, were at Hoehn and Yahr stage 2·5 or less when on dopaminergic treatment, and were on dopaminergic treatment for at least 4 weeks before enrolment. Participants were randomly assigned (1:1) using a web-based system with minimisation according to Hoehn and Yahr stage and study site to receive extended-release exenatide 2 mg by subcutaneous pen injection once per week over 96 weeks, or visually identical placebo. All participants and all research team members at study sites were masked to randomisation allocation. The primary outcome was the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, off dopaminergic medication at 96 weeks, analysed in the intention-to-treat population using a linear mixed modelling approach. This study is registered with ISRCTN (14552789), EudraCT (2018-003028-35), and ClinicalTrials.gov (NCT04232969).

FINDINGS

Between Jan 23, 2020, and April 23, 2022, 215 participants were screened for eligibility, of whom 194 were randomly assigned to exenatide (n=97) or placebo (n=97). 56 (29%) participants were female and 138 (71%) were male. 92 participants in the exenatide group and 96 in the placebo group had at least one follow-up visit and were included in analyses. At 96 weeks, MDS-UPDRS III OFF-medication scores had increased (worsened) by a mean of 5·7 points (SD 11·2) in the exenatide group, and by 4·5 points (SD 11·4) points in the placebo group (adjusted coefficient for the effect of exenatide 0·92 [95% CI -1·56 to 3·39]; p=0·47). Nine (9%) participants in the exenatide group had at least one serious adverse event compared with 11 (11%) in the placebo group.

INTERPRETATION

Our findings suggest that exenatide is safe and well tolerated. We found no evidence to support exenatide as a disease-modifying treatment for people with Parkinson's disease. Studies with agents that show better target engagement or in specific subgroups of patients are needed to establish whether there is any support for the use of GLP-1 receptor agonists for Parkinson's disease.

FUNDING

National Institute for Health and Care Research and Cure Parkinson's.

摘要

背景

在帕金森病的体外和体内模型中，胰高血糖素样肽-1（GLP-1）受体激动剂具有神经营养特性，流行病学研究和小型随机试验的结果表明其对帕金森病的风险和进展可能有益。我们旨在确定GLP-1受体激动剂艾塞那肽是否能减缓帕金森病的进展速度。

方法

我们在英国的六家研究医院进行了一项3期、多中心、双盲、平行组、随机、安慰剂对照试验。参与者年龄在25至80岁之间，诊断为帕金森病，在接受多巴胺能治疗时处于霍恩和雅尔分期2.5期或更低，且在入组前接受多巴胺能治疗至少4周。参与者使用基于网络的系统按1:1随机分配，并根据霍恩和雅尔分期及研究地点进行最小化处理，以接受每周一次皮下笔注射2mg缓释艾塞那肽，共96周，或外观相同的安慰剂。研究地点的所有参与者和所有研究团队成员均对随机分配不知情。主要结局是96周时停用多巴胺能药物后的运动障碍协会赞助的统一帕金森病评定量表（MDS-UPDRS）第三部分评分，使用线性混合模型方法在意向性治疗人群中进行分析。本研究已在国际标准随机对照试验编号注册库（ISRCTN，编号14552789）、欧盟临床试验注册库（EudraCT，编号2018-003028-35）和美国国立医学图书馆临床试验注册库（ClinicalTrials.gov，编号NCT04232969）注册。

结果

在2020年1月23日至2022年4月23日期间，215名参与者接受了资格筛查，其中194名被随机分配至艾塞那肽组（n = 97）或安慰剂组（n = 97）。56名（占29%）参与者为女性，138名（占71%）为男性。艾塞那肽组92名参与者和安慰剂组96名参与者至少有一次随访并纳入分析。96周时，艾塞那肽组停用药物后的MDS-UPDRS第三部分评分平均增加（恶化）5.7分（标准差11.2），安慰剂组增加4.5分（标准差11.4）（艾塞那肽效应的校正系数为0.92 [95%置信区间 -1.56至3.39]；p = 0.47）。艾塞那肽组9名（占9%）参与者至少发生一次严重不良事件，安慰剂组为11名（占11%）。