Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5)

Abstract

Aims: AWARD-5 was an adaptive, seamless, double-blind study comparing dulaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, with placebo at 26weeks and sitagliptin up to 104weeks. The study also included a dose-finding portion whose results are presented here. Methods: Type 2 diabetes (T2D) patients on metformin were randomized 3:1:1 to seven dulaglutide doses, sitagliptin (100mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26weeks. The algorithm randomly assigned patients until two doses were selected. Results: Dulaglutide 1.5mg was determined to be the optimal dose. Dulaglutide 0.75mg met criteria for the second dose. Dulaglutide 1.5mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0mg showed the greatest placebo-adjusted mean change in weight [-1.99 (-2.88 to -1.20)kg] and in PR [0.78 (-2.10 to 3.80)bpm]. Dulaglutide 1.5mg showed the greatest placebo-adjusted mean change in DBP [-0.62 (-3.40 to 2.30)mmHg]. Conclusions: The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75mg for further investigation in this trial. © 2014 John Wiley & Sons Ltd.