VOGLIBOSE IN TYPE II DIABETES

目的：本研究的目的是比较口服伏格列波糖(AO-128)2 mg，每天3次或3 mg，每天2次与安慰剂的安全性和有效性。II型糖尿病以空腹高血糖和糖耐量异常为特征，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，通常是通过饮食和运动疗法或口服药物，如磺脲类药物(如格列吡嗪)、双胍类药物(二甲双胍)，以及最近的α-葡萄糖苷酶抑制剂(阿卡波糖)。伏格列波糖是伐洛拉明的N-取代衍生物，也是一种α-葡萄糖苷酶抑制剂。这类化合物通过可逆地抑制小肠刷状边缘的α-葡萄糖苷酶来延迟二糖和复杂碳水化合物的消化。伏格列波糖的抑制活性大约是阿卡波糖的190-270倍，阿卡波糖已经获得FDA的批准。由于伏格列波糖对麦芽糖酶和蔗糖酶有抑制作用，因此被认为是一种选择性的二糖酶抑制剂。方法：这是一项为期36周的III期双盲对照安慰剂对照试验。总共324名II型糖尿病患者将被随机抽查，以便在美国获得276名可评估的患者。一半的受试者将被随机接受伏格列波糖(2 mg，tid或3 mg，bid)或安慰剂，为期26周。成功完成这项试验的患者可能有资格获得为期一年的开放标签方案延期(D-103)。在筛查访问期间，患者将接受病史和身体、血液和尿液测试、EKG和视网膜照片。患者将在6-8周的单盲引导期内给予安慰剂，届时研究前口服药物(S)将停止使用，并将确定基线值。在引导期结束时，符合条件的患者将被随机分配到26周的双盲治疗中，服用伏格列波糖或安慰剂。第1组口服伏格列波糖1 mg，每日1次，早餐1 mg，每日1次，疗程2周，早餐2 mg，晚餐1 mg，疗程2周，其余22周，早餐、晚餐各3 mg。第2组患者每天早餐1 mg，疗程2周，早餐、午餐、晚餐各服用1 mg，疗程2周，其余22周，早餐、午餐、晚餐各服用2 mg。第三组患者将在整个26周的早餐、午餐和晚餐中服用安慰剂。治疗结束后1-2周将进行随访。患者将每隔2周至2个月返回诊所就诊，在此期间将采集血液和尿液样本，并进行身体检查。在治疗之前和治疗结束时，将进行葡萄糖耐量测试，在此期间，患者将被要求喝一种“葡萄糖”饮料，并将采集测量血糖和胰岛素反应的定时样本。眼底照片和EKG将在研究结束时重复。结果与结论：本研究于1998年2月在本站完成。这是一项由药物赞助的多中心研究，到目前为止还没有向我们提供结果。这项研究的意义和未来的计划：如前所述，动物研究表明，伏格列波糖的抑制活性是阿卡波糖(一种目前上市的α-葡萄糖苷酶抑制剂)的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的方式显著降低餐后血糖和胰岛素曲线下的峰值和面积。对259名II型糖尿病患者进行的一项欧洲安慰剂对照研究的中期分析表明，糖化HbA1c呈剂量依赖性下降。本研究和D-103的研究结果将为今后的研究提供基础。

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.