This was a randomized, double-blind, parallel group, placebo-controlled, multicenter, phase 2b clinical study, consisting of a screening (up to 3 weeks), a treatment (8 weeks), and a follow-up period (4 weeks). The study was conducted in accordance with guidelines of all the institutional review boards, with the principles of the Declaration of Helsinki, and with the laws and regulations of the countries where the research was conducted.
The primary objectives of this study were to determine the efficacy, safety, and tolerability of multiple doses and regimens of taspoglutide, when added to metformin therapy. Secondary objectives were to compare the effects of taspoglutide versus placebo on body weight and additional parameters of glycemic and lipid control.
The study population comprised men and postmenopausal or surgically sterilized women with type 2 diabetes, treated with a daily dose of metformin (≥1,500 mg/day) monotherapy for at least 3 months before screening. Key inclusion criteria at screening were age 18–75 years, A1C between 7.0 and 9.5% (inclusive), fasting plasma glucose (FPG) >126 mg/dl (7.0 mmol/l) and ≤240 mg/dl (13.3 mmol/l), BMI >25 and ≤45 kg/m2, and stable weight (±10%) for at least 3 months before screening.
Key exclusion criteria were history of type 1 diabetes; treatment with any antihyperglycemic medication other than metformin during the prior 3 months (except insulin use in acute situations or during surgery for up to 7 days); previous exposure to GLP-1, GLP-1 analogs, or exenatide; weight-lowering medications in the prior 3 months; impaired liver or kidney function, clinically significant gastrointestinal disease, or uncontrolled hypertension at screening; or a stroke or myocardial infarction within 6 months before screening.
Patients were randomly assigned by a central randomization system (interactive voice response system) to either placebo once weekly or one of the following doses and regimens of taspoglutide: 5 mg once weekly; 10 mg once weekly; 20 mg once weekly; 10 mg once every 2 weeks; or 20 mg once every 2 weeks. Patients were asked to follow their prestudy diet and exercise plan and metformin regimen throughout the study. Patients reported to the study site for weekly visits. At each visit the lyophilized peptide was reconstituted at the study site with the diluent (zinc chloride solution). Patients in the placebo group received 0.9% NaCl. Study medication was administered by personnel not involved with the preparation of study drug to maintain the blinding and injected subcutaneously in the abdomen in a different site each time, according to a given scheme.
Patients measured their fasting blood glucose levels using a glucometer (ACCU-CHEK) while at home in the morning at least once weekly or more frequently if they felt unwell or had any symptoms of hypo- or hyperglycemia or if requested by local guidelines. A subset of patients (n = 118, ~20 per group) consumed a mixed-meal test with Ensure (350 kcal; 50 g carbohydrate, 13 g protein, and 11 g fat) at baseline and after 8 weeks of treatment. Central laboratories (Covance, Geneva, Switzerland; Harrogate, U.K.; Indianapolis, IN) were used to measure all laboratory parameters including drug concentrations of taspoglutide.
Study end points
The primary efficacy end point was the change from baseline in A1C (percent), assessed 1 week after 8 consecutive weeks of treatment. Secondary end points included the percentage of patients achieving the treatment goals of A1C <7% and <6.5% and the absolute changes from baseline in FPG, body weight, fructosamine, C-peptide, fasting insulin, proinsulin, proinsulin-to-insulin molar ratio, fasting glucagon, and lipid parameters. Safety assessments included vital signs, physical examination, clinical laboratory tests, electrocardiogram, local tolerance at the injection site, anti-taspoglutide antibodies, and adverse event reporting.
Randomization was stratified based on severity of disease (A1C <8% and ≥8%) and participation in the meal test. The sample size of 264 patients (44 patients per group) was calculated to provide 90% power to detect a 1% difference in the change of A1C from baseline in the individual comparison of all five active dose groups versus placebo, assuming a common SD of 1.2%, two-sided α = 0.05, and 20% dropout rate. ANCOVA with fixed-effect terms for region, treatment, and baseline A1C as covariates was used to assess possible differences in the changes in A1C among the treatment groups.
The intent-to-treat population consisted of all patients who were randomly assigned, received at least one dose of study medication, and had a baseline and at least one postbaseline A1C assessment. Missing data were handled using the last observation carried forward method. The safety population consisted of all patients who received at least one dose of study medication.