Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
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伊马替尼治疗新发 1 型糖尿病患者：一项多中心、随机、双盲、安慰剂对照 2 期试验。
DOI：
10.1016/s2213-8587(21)00139-x
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Gleevec Trial Study Group
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文献类型：
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作者：
Gitelman SE;Bundy BN;Ferrannini E;Lim N;Blanchfield JL;DiMeglio LA;Felner EI;Gaglia JL;Gottlieb PA;Long SA;Mari A;Mirmira RG;Raskin P;Sanda S;Tsalikian E;Wentworth JM;Willi SM;Krischer JP;Bluestone JA;Gleevec Trial Study Group
1型糖尿病是由自身免疫介导的β细胞破坏引起的。酪氨酸激酶抑制剂伊马替尼可能影响相关的免疫和代谢途径，临床前研究表明它可以逆转和预防糖尿病。我们的目的是评估伊马替尼在新近发病的1型糖尿病患者中维持β细胞功能的安全性和有效性。我们进行了一项2期随机、安慰剂对照、双盲临床试验。新发1型糖尿病患者，年龄18-45岁，混合膳食耐受性试验（MMTT）中c肽峰值≥0.2 nmol /L，来自美国和澳大利亚的9个中心。参与者被随机分配为2:1，分别接受400 mg伊马替尼或匹配的安慰剂，为期26周，使用计算机生成的阻断随机方案按中心分层。主要终点是伊马替尼组与安慰剂组在12个月时对MMTT的2小时曲线下面积（AUC） c肽反应，使用ANCOVA模型调整性别、基线年龄和基线c肽，并进一步观察到24个月。分析的目的是治疗。本研究已在ClinicalTrials.gov注册，编号NCT01781975。患者在2014年2月12日至2016年5月19日期间被筛选并纳入试验。45名患者接受伊马替尼治疗，22名患者接受安慰剂治疗。该研究达到了其主要终点：伊马替尼组和安慰剂组在12个月时MMTT应答的2小时c肽AUC的调整平均差异为0.0946 (90% CI:−0.00279,0.191)（p= 0.048，单尾检验）。这种效果没有持续到24个月。在伊马替尼治疗的受试者中，71%的人经历了2级或更高的不良事件，而安慰剂治疗的受试者中这一比例为59%。根据方案指南，38%接受伊马替尼治疗的受试者需要暂时调整药物剂量，13%需要永久停药；23%的安慰剂组在剂量上有暂时的改变。26周的伊马替尼疗程可以保护新近发病的1型糖尿病成人患者12个月时的β细胞功能。伊马替尼可能提供一种改变1型糖尿病病程的新方法，但需要仔细监测可能的毒性。青少年研究糖尿病基金会
Type 1 diabetes results from autoimmune-mediated destruction of beta cells. The tyrosine kinase inhibitor imatinib may impact relevant immunologic and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our goal was to evaluate the safety and efficacy of imatinib in preserving beta cell function in subjects with recent-onset type 1 diabetes. We conducted a phase 2, randomised, placebo-controlled, double blind clinical trial. Patients with recent-onset type 1 diabetes, aged 18-45 years, and with peak C-peptide ≥ 0.2 nmoles/L on mixed meal tolerance test (MMTT) were enrolled from 9 centres in the USA and Australia. Participants were randomly assigned 2:1 to receive either 400 mg imatinib or matching placebo for 26 weeks, respectively, using a computer-generated blocked randomisation scheme stratified by centre. The primary endpoint was the 2-hour area under the curve (AUC) C-peptide response to MMTT in the imatinib versus placebo group at 12 months, using an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation out to 24 months. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01781975. Patients were screened and enrolled into the trial between February 12, 2014 and May 19, 2016. 45 patients were assigned to imatinib, 22 to placebo. The study met its primary endpoint: the adjusted mean difference between the imatinib and placebo-treated groups in 2-hour C-peptide AUC in response to an MMTT at 12 months was 0·0946 (90% CI: −0·00279, 0·191) (p=0·048, 1-tailed test). This effect was not sustained out to 24 months. Of the imatinib-treated subjects, 71% experienced a grade 2 or higher adverse event, compared to 59% of placebo-treated subjects. Per protocol guidelines, 38% of imatinib-treated subjects required a temporary modification in drug dosing and 13% permanently discontinued drug; 23% of the placebo group had temporary modifications in dosing. A 26-wk course of imatinib may preserve beta cell function at 12 months in adults with recent onset type 1 diabetes. Imatinib may offer a novel means to alter the course of type 1 diabetes, but requires careful monitoring for possible toxicities. Juvenile Research Diabetes Foundation