MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study
MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study
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DOI：
10.1016/s0140-6736(18)30726-8
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发表时间：
2018-06-30
期刊：
影响因子：
168.9
通讯作者：
Jermutus, Lutz
中科院分区：
文献类型：
--
作者：
Ambery, Philip;Parker, Victoria E.;Jermutus, Lutz
减肥通常是肥胖或超重2型糖尿病患者管理的关键，但很少有糖尿病治疗能达到临床意义的减肥。我们的目的是评估MEDI 0382治疗2型糖尿病患者的疗效、耐受性和安全性，MEDI 0382是一种平衡的胰高血糖素样肽-1和胰高血糖素受体双重激动剂，旨在提供血糖控制和体重减轻。在德国的11个研究中心（医院和合同研究组织）进行了多次给药剂量递增（MAD）和2a期联合研究。我们招募了年龄在18-65岁之间的2型糖尿病患者（筛选时糖化血红蛋白A（1c）[HbA（1c）]水平为6中心点5-8中心点5%），体重指数在27 kg/m2和40 kg/m2之间。使用交互式网络应答系统随机分配患者接受MEDI 0382或安慰剂。在研究的MAD部分，患者以2：1的比例随机分配至队列A-C，以3：1的比例随机分配至队列D和E，以1：1的比例随机分配至IIa期部分。随机化由未参与研究临床操作的签约第三方操作员完成。参与治疗和评估受试者的药剂师、受试者和研究中心工作人员对治疗分配设盲。在研究的MAD部分，患者接受每日一次皮下注射研究药物，剂量不超过300 μ g，持续22天或更短时间，在IIa期部分，剂量不超过200 μ g，持续41天或更短时间。IIa期部分的两个主要终点是0-4 h葡萄糖曲线下面积从基线至第41天的变化混合餐耐受试验（MMTT）后的AUC（0- 4 h），在接受至少一剂研究药物的所有受试者中进行评估，并在基线和第41天进行测量，以及体重较基线的变化，在意向治疗（ITT）人群中进行评估。根据接受的治疗，对接受任何研究药物的所有受试者进行了安全性分析。本研究已在ClinicalTrials注册。结果患者在2015年12月9日至2017年2月24日期间招募。61名患者被随机分配到研究的MAD部分（42名分配到MEDI 0382，19名分配到安慰剂）。51名患者被随机分配到2a期部分，其中25名被随机分配到MEDI 0382，26名被随机分配到安慰剂。在2a期研究中，MEDI 0382组中的三名患者和安慰剂组中的一名患者停止治疗，全部是由于不良事件。MEDI 0382组中的22名（88%）患者和安慰剂组中的25名（96%）患者接受至少一个剂量，并在基线和第41天进行测量。MEDI 0382与安慰剂相比，MMTT后葡萄糖AUC（0- 4 h）显著降低（最小二乘[LS]平均值-32中心点78% [90%CI-36中心点98至-28中心点57] vs-10中心点16% [-14中心点10至-6中心点21]，平均差异为-22中心点62% [-28中心点40至-16中心点85]; p
Background Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes.Methods This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A(1c) [HbA(1c)] levels of 6 center dot 5-8 center dot 5% at screening) and a body-mass index between 27 kg/m(2) and 40 kg/m(2). An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2: 1 in cohorts A-C and 3: 1 in cohorts D and E in the MAD portion of the study, and 1: 1 in the phase 2a portion. Randomisation was done by a contracted third- party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 mu g for 22 days or less in the MAD portion of the study, and a dose of no more than 200 mu g for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC(0-4h)) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials. gov, number NCT02548585.Findings Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC(0-4h) post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32 center dot 78% [90% CI-36 center dot 98 to-28 center dot 57] vs-10 center dot 16% [-14 center dot 10 to -6 center dot 21], and the mean difference was -22 center dot 62% [-28 center dot 40 to -16 center dot 85]; p