Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial.
Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial.
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DOI：
10.1016/s0140-6736(17)31585-4
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发表时间：
2017-10-07
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影响因子：
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通讯作者：
Foltynie T
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作者：
Athauda D;Maclagan K;Skene SS;Bajwa-Joseph M;Letchford D;Chowdhury K;Hibbert S;Budnik N;Zampedri L;Dickson J;Li Y;Aviles-Olmos I;Warner TT;Limousin P;Lees AJ;Greig NH;Tebbs S;Foltynie T
艾塞那肽是一种胰高血糖素样肽-1（GLP-1）受体激动剂，在帕金森病临床前模型中具有神经保护作用。我们研究了这些影响是否会在临床试验中表现出来。在这项单中心、随机、双盲、安慰剂对照试验中，中度帕金森病患者被随机分配（1：1）接受皮下注射exenlavin 2 mg或安慰剂，每周一次，持续48周，除常规药物外，随后是12周的洗脱期。符合条件的患者年龄在25-75岁之间，根据Queen Square Brain Bank标准测量患有特发性帕金森病，正在接受多巴胺能治疗，具有磨损效应，并且在治疗时处于Hoehn和Yahr 2.5级或更低。根据疾病严重程度采用两层区组设计，通过基于网络的随机化进行随机化。患者和研究者均对治疗分配设盲。主要结局是60周时实际定义的停药状态下运动障碍协会统一帕金森病评定量表（MDS-MRS）运动子量表（第3部分）的校正差异。所有疗效分析均基于改良的意向治疗原则，包括完成任何随机化后随访评估的所有患者。该研究在ClinicalTrials.gov（NCT 01971242）上注册并完成。在2014年6月18日至2015年3月13日期间，62名患者入组并随机分配，32名接受艾塞那肽治疗，30名接受安慰剂治疗。我们的主要分析包括艾塞那肽组31例患者和安慰剂组29例患者。60周时，艾塞那肽组MDS-SRS第3部分的停药评分改善了1.0分（95% CI-2.6至0.7），安慰剂组恶化了2.1分（-0.6至4.8），校正后的平均差异为-3.5分（-6.7至0.3; p= 0.0318）。注射部位反应和胃肠道症状是两组常见的不良事件。艾塞那肽组发生了6起严重不良事件，安慰剂组发生了2起，但两组均未被判定为与研究干预有关。艾塞那肽对帕金森病患者实际定义的停药运动评分有积极影响，这些评分持续超过暴露期。exenadine是否影响潜在的疾病病理生理学或只是引起长期持续的症状影响是不确定的。Exenglycine代表了帕金森病研究的一个主要新途径，对日常症状的影响应在长期试验中进行检查。Michael J Fox Foundation for Parkinson's Research（迈克尔·J·福克斯帕金森研究基金会）
Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson’s disease. We investigated whether these effects would be apparent in a clinical trial. In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson’s disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25–75 years, had idiopathic Parkinson’s disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI −2·6 to 0·7) in the exenatide group and worsened by 2·1 points (−0·6 to 4·8) in the placebo group, an adjusted mean difference of −3·5 points (−6·7 to −0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. Exenatide had positive effects on practically defined off-medication motor scores in Parkinson’s disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials. Michael J Fox Foundation for Parkinson’s Research.