HOE901 VERSUS NPH HUMAN INSULIN WITH TYPE I DIABETES MELLITUS

目的：比较HOE 901和NPH对糖化血红蛋白的影响，并比较HOE 901和NPH治疗I型糖尿病的安全性。还将在血糖变异性、低血糖、代谢控制的其他指标、生活质量和药物经济学方面对这两种治疗方法进行比较。方法：这是一项III期、随机、多中心、开放、NPH人胰岛素对照、随机(1：1)、为期28周的平行分组研究，包括两个治疗组(HOE901和NPH人胰岛素)。这项研究将对520名患者(所有地点的患者总数)进行评估。这项研究包括1至4周的筛选阶段和28周的治疗阶段，其中包括初始有效剂量滴定阶段。被随机分配到NPH胰岛素组的受试者将继续他们以前的每日注射方案。被随机分配到HOE901的受试者将在睡前接受一次HOE 901注射。除了HOE901或NPH人胰岛素外，两个治疗组还将接受常规胰岛素治疗。受试者将根据他们是否接受基础胰岛素治疗一次或每天两次进行分层。这项研究将包括5次门诊和3次住院。在屏幕访问期间，受试者将接受病史和体检、血液测试、孕期筛查、扩眼检查和眼底摄影。受试者将被指导进行家庭血糖监测，发放血糖仪和用品，并被要求每天监测4次血糖。在接下来的访问中，符合条件的患者将被允许进入GCRC约36小时，在此期间将采集24小时血糖样本。患者还将进行EKG和血液测试。患者在这次访问中是随机的。门诊随访包括验血将在第1周和第4周进行。患者将在第8周重新住院，包括24小时抽样。门诊随访包括血液测试将在第12周和第20周进行，可选的眼科检查和眼底照片将在第12周进行。最后入院将在第28周进行。除24小时抽样外，还将进行EKG、眼科检查、眼底照片和血液测试。在这次访问中，患者将重新开始他们的研究前胰岛素方案。结果与结论：本研究于1998年6月完成。这是一项由药物赞助的多中心研究，到目前为止还没有提供结果。意义：I型糖尿病的特征是由于胰岛β细胞丢失而导致的全身性胰岛素缺乏，需要胰岛素替代治疗。正常的胰岛β细胞分泌大约50%的胰岛素，作为对食物的反应，其余的作为持续的基础分泌。在I型糖尿病的治疗中，长效胰岛素，如NPH或Ultraalente，经常被用来模拟内源性基础胰岛素。然而，NPH和Ultraalente都没有提供稳定的24小时基础胰岛素供应，因为要么作用持续时间太短(NPH)，要么从部位吸收不稳定(Ultraalente)。NPH还经常导致夜间低血糖，因为夜间的血浆胰岛素峰值。因此，不能安全地适当增加睡前NPH的剂量，导致早晨血糖升高，这是总体正常血糖的主要障碍。糖尿病控制和并发症试验表明，严格的血糖控制极大地降低了糖尿病并发症的风险，如视网膜病变、神经病变和肾病。人类胰岛素类似物HOE901是一种长效胰岛素，如果被证明是安全有效的，可以每天单次注射，以提供接近正常的血糖控制，并比以前使用现有药物时更平稳的24小时基础胰岛素谱。未来计划：这项研究的结果将为今后对HOE901的调查提供依据。

PURPOSE: The purpose of this study is to compare the effects of HOE 901 and NPH on glycated hemoglobin and to compare the safety of HOE 901 with NPH in subjects with type I diabetes mellitus. A comparison between the two treatments will also be made in terms of blood glucose variability, hypoglycemia, other indicators of metabolic control, quality-of-life, and pharmacoeconomics. METHODS: This is a phase III, randomized, multicenter, open, NPH human insulin controlled, randomized (1:1), 28-week parallel-group study with two treatment groups (HOE901 and NPH human insulin). A total of 520 patients ( a total for all sites) will be evaluated in this study. The study consists of a 1 to 4-week screening phase and a 28-week treatment phase which includes an initial active dose titration phase. Subjects randomized to the NPH insulin group will continue their previous regimen of injections per day. Subjects randomized to HOE901 will receive a single injection of HOE 901 at bedtime. Both treatment groups will also receive regular insulin in addition to either HOE901 or NPH human insulin. The subjects will be stratified by whether they were being treated with a basal insulin once versus twice daily. This study will involve 5 outpatient visits and 3 inpatient visits. During the screen visit, subjects will undergo a history and physical examination, blood tests, pregnancy screen, dilated eye exam, and fundus photography. Subjects will be instructed in home blood glucose monitoring, issued a glucose meter and supplies, and will be asked to monitor their blood glucose 4x/day. At the following visit, patients who qualify will be admitted to the GCRC for approximately 36 hours, during which 24 hr blood glucose samples will be taken. Patients will also have an EKG and blood tests. Patients are randomized at this visit. Outpatient follow-up visits including blood tests will occur at Weeks 1 & 4. Patients will be readmitted for an inpatient stay, including 24 hr sampling, at Week 8. Outpatient follow-up visits including blood tests will occur at Weeks 12 & 20, with optional eye exam and fundus photos at Week 12. The final admission will occur at Week 28. In addition to 24 hr sampling, an EKG, eye exam, fundus photos, and blood tests will be performed. Patients will restart their prestudy insulin regimen at this visit. RESULTS AND CONCLUSIONS: The study was completed in June 1998. This is a pharmaceutical-sponsored, multicenter study, and results have not been provided to date. SIGNIFICANCE: Type I diabetes mellitus is characterized by general insulin deficiency due islet beta-cell loss and requires insulin replacement therapy. Normal pancreatic beta-cells secrete approximately 50% of insulin as boluses in response to food and the rest as a continuous basal secretion. Longer-acting insulins such as NPH or Ultralente are often used to simulate endogenous basal insulin in the treatment of type I diabetes. However, neither NPH nor Ultralente provides a stable 24 hr basal insulin supply because either the duration of action is too short (NPH) or absorption from the site is erratic (Ultralente). NPH also often results in nocturnal hypoglycemia due to plasma insulin peaks during the night. Consequently, the bedtime NPH dose cannot be safely increased as appropriate, resulting in elevated blood glucose in the morning, a major obstacle to overall euglycemia. The Diabetes Control and Complications Trial has shown that tight blood glucose control greatly reduces the risk of diabetic complications such as retinopathy, neuropathy, and nephropathy. Human insulin analogue HOE901 is a long-acting insulin that, if proven safe and effective, can be given as a single daily injection to provide near normal blood glucose control and a smoother 24 hr basal insulin profile than previously possible with available medications. FUTURE PLANS:The results of this study will provide the basis for future investigation of HOE901.