Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia
Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia
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DOI：
10.2337/dc15-1988
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发表时间：
2016-07-01
期刊：
影响因子：
16.2
通讯作者：
Turgeon, Nicole A.
中科院分区：
文献类型：
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作者：
Hering, Bernhard J.;Clarke, William R.;Turgeon, Nicole A.
目的低血糖意识受损 (IAH) 和严重低血糖事件 (SHE) 会导致 1 型糖尿病 (T1D) 患者显着发病率和死亡率。目前的疗法可有效预防 50-80% 的 IAH 和 SHE 患者发生 SHE，但仍有大量患者面临风险。我们评估了标准化人胰岛产品在接受药物治疗后 IAH 和 SHE 持续存在的受试者中的有效性和安全性。 研究设计和方法 这项针对研究产品纯化人胰岛 (PHPI) 的多中心、单臂、3 期研究在北美的八个中心进行。纳入了 48 名患有 T1D 超过 5 年、缺乏刺激 C 肽、尽管经过专家护理但仍记录有 IAH 和 SHE 的成人。每例均接受免疫抑制和一次或多次 PHPI 移植，并在良好生产实践条件下使用通用批次记录和标准化批次放行标准和测试方法在现场生产。主要终点是达到 HbA(1c) 0.0001)。没有发生与研究相关的死亡或残疾。其中 5 名参与者 (10.4%) 经历过需要输血的出血（相当于 75 例手术中的 5 例），两名参与者 (4.1%) 因免疫抑制而出现感染。免疫抑制后肾小球滤过率显着下降，两名患者出现了供体特异性抗体。结论移植的 PHPI 为患有顽固性 IAH 和 SHE 的受试者提供了血糖控制、低血糖意识恢复以及免受 SHE 的保护。发生与输注程序和免疫抑制相关的安全事件，包括出血和肾功能下降。对于 T1D 和 IAH 患者，目前其他侵入性较小的治疗方法对于预防 SHE 无效，应考虑胰岛移植。
OBJECTIVEImpaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment.RESEARCH DESIGN AND METHODSThis multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA(1c) 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients.CONCLUSIONSTransplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.