Study Design
This 14-week, multicenter, double-blind, parallel-group, placebo-controlled, randomized study was conducted across 30 centers in Japan from May 2013 to February 2014. Patients with T2DM inadequately controlled (HbA1c 7.0–10.0%) with diet, exercise and vildagliptin monotherapy were eligible for inclusion. Following the screening visit (visit 1), eligible patients on vildagliptin 50 mg bid monotherapy for at least 10 weeks proceeded directly to randomization (baseline, visit 2). Whereas patients taking other OADs were switched to vildagliptin 50 mg bid and were asked to complete a 12-week run-in period (visit 101) before randomization (Fig. 1).
Eligible patients were randomized (2:1) to receive either vildagliptin/metformin SPC (hereafter called the vilda/met group) or vildagliptin/placebo SPC (hereafter called the vilda/placebo group). In the vilda/met treatment group, patients were randomized (1:1) to receive either vilda/met 50/250 or 50/500 mg bid (Fig. 1). In the vilda/met group, all patients started double-blind treatment with vilda/met 50/250 mg bid, and patients randomized to the subgroup vilda/met 50/500 mg bid were up-titrated after 2 weeks. Efficacy and safety were assessed at baseline and at weeks 2, 6, 10, and 14. No rescue medication was allowed, and patients with unsatisfactory therapeutic effect [fasting plasma glucose (FPG) ≥15.0 mmol/L] were discontinued from the study.
Study Population
The study included patients with T2DM aged ≥20 to <75 years, BMI ≥20 to ≤35 kg/m2, and who were inadequately controlled (HbA1c ≥7.0% to ≤10.0%) by diet and vildagliptin 50 mg bid monotherapy. The key exclusion criteria were: FPG ≥15.0 mmol/L; history of type 1 diabetes, acute metabolic conditions such as ketoacidosis, lactic acidosis; patients with congestive heart failure (New York Heart Association Class III or IV); myocardial infarction, or coronary artery bypass surgery in the past 6 months, unstable angina in the past 3 months; acute or chronic liver disease; or impaired renal function.
Study Endpoints and Assessments
Change in HbA1c from baseline to study end in all vilda/met groups was the primary efficacy endpoint. The secondary endpoints included: HbA1c change from baseline to study end in the subgroups of patients by metformin dose, percentage of patients achieving HbA1c target (<7.0%)/reduction of ≥0.5% and change in FPG from baseline to study end. HbA1c values are reported in National Glycohemoglobin Standardization Program units (NGSP, %).
Safety assessments included collecting all adverse events (AEs), serious AEs (SAEs) data with their severity and suspected relationship to the study drug, regular assessments of hematology, biochemistry, vital signs and body weight. All the laboratory assessments were performed at a central laboratory (Mitsubishi Chemical Medience Corporation, Tokyo, Japan). Patients were asked to record hypoglycemic events in a study diary. Hypoglycemia was defined as symptoms suggestive of hypoglycemia, further confirmed by self-monitored blood glucose measurement of <3.1 mmol/L. The event was considered severe if the patient required assistance of another person or hospitalization.
Statistical Analysis
Assuming a dropout rate of 5%, 171 patients were to be randomized in a ratio of 2:1 (vilda/met 114; vilda/placebo: 57) to achieve the target sample size of 162. This sample size would ensure 90% power to detect a between-group difference of 0.6 absolute units in HbA1c at a one-sided significance level of 0.025 and a standard deviation of 1.1%. The sample size of 57 patients in each vilda/met subgroup would ensure 90% power with a one-sided significance level of 0.025 to detect a reduction of 0.5 absolute units in HbA1c from baseline at a standard deviation of 1.0%. Statistical analysis was performed using SAS 9.2 (SAS Institute Inc., Cary NC, USA).
All randomized patients who received at least one dose of the study drug and had at least one post-randomization efficacy parameter (HbA1c, FPG) assessment constituted the full analysis set (FAS). The primary and secondary efficacy analyses were based on FAS. The changes in HbA1c and FPG from baseline to study endpoint [final available assessment value at any visit up to the final visit (week 14)] reported as mean ± SE were analyzed using the analysis of covariance model, with treatment as a classification variable and baseline value as a covariate. The last observation carried forward method was used for imputing missing data.
Chi-squared test was used to assess and compare the proportion of responders in the two groups. Safety data were summarized descriptively by treatment for the safety analysis set which included all the patients who received at least one dose of the study drug.
Ethics and Good Clinical Practice
The independent Ethics Committee/Institutional Review Board at each center reviewed and approved the study protocol. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. Informed consent was obtained from all patients for being included in the study. The study is registered with ClinicalTrials.gov, identifier: NCT01811485.