VOGLIBOSE IN TYPE II DIABETES

目得：本研究的目的是比较口服伏格列波糖（AO-128）2 mg每日3次或3 mg每日2次与安慰剂的安全性和疗效。II型糖尿病的特征是空腹高血糖和葡萄糖耐受不良，表现为餐后血糖浓度和胰岛素分泌急剧增加。治疗II型糖尿病的目标是达到血糖正常，通常通过使用饮食和运动疗法或口服药物如磺脲类（例如，格列吡嗪）、双胍（二甲双胍）和最近的α-葡糖苷酶抑制剂（阿卡波糖）。伏格列波糖是井冈霉醇胺的N-取代衍生物，也是α-葡糖苷酶抑制剂。该类化合物通过可逆抑制小肠刷状缘中的α-葡糖苷酶来延迟二糖和复合碳水化合物的消化。伏格列波糖的抑制活性比阿卡波糖强约190-270倍，阿卡波糖已经获得FDA批准。由于伏格列波糖有利于抑制麦芽糖酶和蔗糖酶，因此被认为是一种选择性的双磷酸酶抑制剂。方法：这是一项为期36周的III期、安慰剂对照、双盲比较试验。将对共计324例II型糖尿病患者进行随机化，以便在美国获得276例可评价患者。一半受试者将随机接受伏格列波糖（2 mg tid或3 mg bid）或安慰剂治疗，持续26周。成功完成本试验的患者可能有资格参加为期一年的开放标签方案扩展（D-103）。在筛选访视期间，患者将接受病史和体格检查、血液和尿液检查、EKG和视网膜照片。患者将在6-8周单盲导入期接受安慰剂给药，此时将停用研究前口服药物并确定基线值。在导入期结束时，合格的患者将被随机分配到26周的伏格列波糖或安慰剂双盲治疗。第1组患者将接受伏格列波糖1 mg qd早餐给药，持续2周，然后早餐2 mg+晚餐1 mg给药，持续2周，然后早餐和晚餐3 mg给药，持续22周。第2组患者将在早餐时接受1 mg治疗，持续2周，然后在早餐、午餐和晚餐时接受1 mg治疗，持续2周，最后在早餐、午餐和晚餐时接受2 mg治疗，持续22周。第3组患者将在整个26周内接受安慰剂与早餐、午餐和晚餐。随访访视将在治疗期后1-2周进行。患者将每隔2周至2个月返回诊所进行访视，在此期间将采集血液和尿液样本并进行体格检查。将在治疗期之前和结束时进行葡萄糖耐量试验，在此期间，将要求患者饮用“glucola”饮料，并采集测量血糖和胰岛素反应的定时样本。在研究参与结束时重复眼底照片和EKG。结果和结论：本研究于1998年2月在我们的研究中心完成。这是一项制药申办的多中心研究，迄今为止尚未向我们提供结果。研究意义和未来计划：如前所述，动物研究表明伏格列波糖的抑制活性比阿卡波糖（目前市售的α葡萄糖苷酶抑制剂）强190 - 270倍。此外，迄今为止的人体研究（368名志愿者和1635名接受伏格列波糖治疗的患者）表明，伏格列波糖以剂量依赖性方式显著降低餐后血糖和胰岛素的峰值和曲线下面积。一项在259例II型糖尿病患者中进行的安慰剂对照欧洲研究的中期分析表明，糖化HbA 1c呈剂量依赖性降低。本研究结果和D-103的研究结果将为今后的研究提供依据。

PURPOSE: The purpose of this study is to compare the safety and efficacy of orally administered voglibose (AO-128) 2 mg three times daily or 3 mg twice daily with placebo. Type II diabetes is characterized by fasting hyperglycemia and glucose intolerance, manifested by a steep increase in post-prandial blood glucose concentration and insulin secretion. The goal in treatment of type II diabetes is to achieve normoglycemia, usually through use of diet and exercise therapy or with oral agents such as sulfonylureas (e.g., glipizide), biguanides (metformin), and, most recently, alpha-glucosidase inhibitors (acarbose). Voglibose, an N- substituted derivative of valiolamine, is also an alpha-glucosidase inhibitor. The compounds in this class delay digestion of disaccharides and complex carbohydrates by reversible inhibition of alpha-glucosidases in the brush border of the small intestine. The inhibitory activity of voglibose is about 190-270 times more potent than acarbose, which has already received FDA approval. Because it favors inhibition of maltase and sucrase, voglibose is considered to be a selective disaccharidase inhibitor. METHODS: This is a phase III, 36 week, placebo- controlled, double-blind comparative trial. A total of 324 patients with type II diabetes will be randomized in order to obtain 276 evalable patients in the USA. Half of the subjects will be randomized to receive either voglibose (2mg tid or 3mg bid) or placebo for a period of 26 weeks. Patients who successfully complete this trial may be eligible for a one-year, open-label protocol extension (D-103). During the screening visit, patients will undergo a history and physical, blood and urine tests, an EKG, and retinal photos. Patients will be given placebo during a 6-8 week single-blind lead-in period when the pre-study oral agent(s) will be discontinued and baseline values will be determined. At the end of the lead-in period, eligible patients will be randomly assigned to 26 weeks of double-blind treatment with either voglibose or placebo. Group 1 patients will receive voglibose 1mg qd with breakfast for 2 weeks, then 2mg with breakfast plus 1mg with dinner for 2 weeks, then 3mg with breakfast and dinner for the remaining 22 weeks. Group 2 patients will receive 1mg with breakfast for 2 weeks, then 1mg with breakfast, lunch, and dinner for 2 weeks, and finally 2mg with breakfast, lunch, and dinner for the remaining 22 weeks. Group 3 patients will receive placebo with breakfast, lunch, and dinner for the entire 26 weeks. A follow-up visit will occur 1-2 weeks following the treatment period. Patients will return for clinic visits at 2 week to 2 month intervals, during which blood and urine samples will be collected and physical exams will be performed. A glucose tolerance test will be conducted prior to and at the end of the treatment period, during which patients will be asked to drink a "glucola" beverage and timed samples measuring glycemic and insulin response will be taken. The fundus photos and EKG will be repeated at the end of study participation. RESULTS AND CONCLUSIONS: The study was completed at our site in February 1998. This was a pharmaceutical-sponsored multicenter study and results have not been provided for us to date. SIGNIFICANCE OF THE STUDY AND FUTURE PLANS: As mentioned previously, animal studies have indicated that the inhibitory activity of voglibose is 190 - 270 times more potent than acarbose (a currently marketed alpha glucosidase inhibitor). Also, human studies (368 volunteers and 1635 patients treated with voglibose) to date have indicated that voglibose significantly reduces the postprandial peak and area under the curve of blood glucose and insulin in a dose-dependent manner. Interim analysis of a placebo-controlled European study in 259 patients with type II diabetes indicates a dose-dependent decrease in glycated HbA1c. The results of this study and D-103 will provide the basis for future studies.