During the placebo run-in period, participants received single-blind placebo capsules matching study drug once daily. Participants were randomised to receive canagliflozin 100 mg or 300 mg, sitagliptin 100 mg or placebo (2:2:2:1) once daily for 26 weeks. The canagliflozin 100 mg and 300 mg once-daily doses were selected based on findings from a dose-ranging, Phase 2 study in patients with type 2 diabetes on background metformin [5 (link)]; a 300 mg twice-daily regimen provided only incremental benefits vs the once-daily regimen and was therefore not selected for further development. The use of placebo as a control for the 26 week core treatment period was done in accordance with US Food and Drug Administration and European Medicines Agency regulatory guidelines [15 , 16 ]. The computer-generated randomisation schedule was prepared by the sponsor before the study. Randomisation was balanced using permuted blocks of seven and stratified by whether a participant was on metformin monotherapy or metformin plus sulfonylurea at screening. After randomisation, HbA1c and FPG values were masked to the study centres unless they met glycaemic rescue criteria. After completion of period I, the database was locked and the study was unblinded by the sponsor for regulatory filing; the participants and the study centre and local sponsor personnel remained blinded throughout period II.
Participants who completed period I then entered period II, during which those randomised to canagliflozin (100 or 300 mg) or sitagliptin 100 mg continued on those treatments while those randomised to placebo switched to sitagliptin 100 mg in a blinded fashion. During the double-blind treatment period, glycaemic rescue therapy with glimepiride (added to study drug and background metformin) was initiated if FPG >15.0 mmol/l after day 1 to week 6, >13.3 mmol/l after week 6 to week 12, and >11.1 mmol/l after week 12 to week 26. Glimepiride therapy was also started if HbA1c >8.0% (64 mmol/mol) after week 26.
Participants who completed period I then entered period II, during which those randomised to canagliflozin (100 or 300 mg) or sitagliptin 100 mg continued on those treatments while those randomised to placebo switched to sitagliptin 100 mg in a blinded fashion. During the double-blind treatment period, glycaemic rescue therapy with glimepiride (added to study drug and background metformin) was initiated if FPG >15.0 mmol/l after day 1 to week 6, >13.3 mmol/l after week 6 to week 12, and >11.1 mmol/l after week 12 to week 26. Glimepiride therapy was also started if HbA1c >8.0% (64 mmol/mol) after week 26.
