Background

Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.

Methods

We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18–45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L⁻¹ on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed).

Findings

Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI −0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events.

Interpretation

A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required.

Funding

Juvenile Research Diabetes Foundation.

中文翻译：

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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、安慰剂对照的 2 期试验

背景

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会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保护新发 1 型糖尿病患者 β 细胞功能方面的安全性和有效性。

方法

我们进行了一项多中心、随机、双盲、安慰剂对照的 2 期试验。新发 1 型糖尿病患者（诊断后 <100 天），年龄 18-45 岁，至少一种糖尿病相关自身抗体阳性，刺激 C 肽峰值大于 0·2 nmol·L ⁻¹在美国 (n=8) 和澳大利亚 (n=1) 的九个医疗中心参加了一项混合膳食耐受性测试 (MMTT)。参与者被随机分配 (2:1) 接受 400 mg 甲磺酸伊马替尼（每天 4 × 100 mg 薄膜包衣片剂）或匹配安慰剂 26 周，方法是通过计算机生成的按中心分层的区组随机化方案。除了每个临床地点的药剂师外，所有参与者和研究人员的治疗分配均被掩盖。主要终点是伊马替尼组与安慰剂组在 12 个月时 MMTT 的前 2 小时内 C 肽反应的平均曲线下面积 (AUC) 差异，使用针对性别进行调整的 ANCOVA 模型、基线年龄和基线 C 肽，进一步观察长达 24 个月。主要分析是通过意向治疗 (ITT)。在所有随机分配的参与者中评估了安全性。本研究已在 ClinicalTrials.gov 注册，NCT01781975（已完成）。

发现

患者在 2014 年 2 月 12 日至 2016 年 5 月 19 日期间接受筛选和入组。45 名患者被分配接受伊马替尼治疗，22 名患者接受安慰剂治疗。退出后，伊马替尼组的 43 名参与者和安慰剂组的 21 名参与者在 12 个月时被纳入主要 ITT 分析。该研究达到了其主要终点：伊马替尼与安慰剂治疗相比，12 个月时 2 小时 C 肽 AUC 的调整平均差异为 0·095（90% CI -0·003 至 0·191；p=0·048，单尾检验）。这种效果没有持续到 24 个月。在 24 个月的随访期间，接受伊马替尼治疗的 45 名参与者中有 32 名 (71%) 出现了严重程度为 2 级或更严重的不良事件，而接受安慰剂治疗的 22 名参与者中有 13 名 (59%) 出现了严重程度为 2 级或更严重的不良事件。最常见的不良事件（严重程度为 2 级或更严重）在各组之间存在差异，它们是胃肠道问题（伊马替尼组有 6 名 [13%] 参与者，主要是恶心，安慰剂组没有）和额外的实验室检查（10 [22 %] 参与者在伊马替尼组和两个 [9%] 在安慰剂组）。根据试验方案，伊马替尼组的 17 名 (38%) 参与者需要临时调整药物剂量，6 名 (13%) 参与者因不良事件永久停用伊马替尼；安慰剂组的五名 (23%) 参与者临时调整了剂量，没有人因不良事件而永久停药。和安慰剂组中没有）和额外的实验室检查（伊马替尼组中有 10 名 [22%] 参与者，安慰剂组中有 2 名 [9%] 参与者）。根据试验方案，伊马替尼组的 17 名 (38%) 参与者需要临时调整药物剂量，6 名 (13%) 参与者因不良事件永久停用伊马替尼；安慰剂组的五名 (23%) 参与者临时调整了剂量，没有人因不良事件而永久停药。和安慰剂组中没有）和额外的实验室检查（伊马替尼组中有 10 名 [22%] 参与者，安慰剂组中有 2 名 [9%] 参与者）。根据试验方案，伊马替尼组的 17 名 (38%) 参与者需要临时调整药物剂量，6 名 (13%) 参与者因不良事件永久停用伊马替尼；安慰剂组的五名 (23%) 参与者临时调整了剂量，没有人因不良事件而永久停药。

解释

伊马替尼 26 周疗程在 12 个月时对新发 1 型糖尿病成人患者的 β 细胞功能起到了保护作用。伊马替尼可能提供一种改变 1 型糖尿病病程的新方法。未来的考虑是确定治疗的理想剂量和持续时间、儿童的安全性和有效性、与补充药物的联合使用，以及伊马替尼延缓或预防高危人群进展为糖尿病的能力；然而，需要仔细监测可能的毒性。

资金

少年研究糖尿病基金会。