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.
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