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

Apr 26, 2014Diabetes, obesity & metabolism

Finding the best weekly dulaglutide dose with metformin for type 2 diabetes in a flexible randomized trial

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Abstract

Dulaglutide 1.5 mg was identified as the optimal dose for reducing HbA1c levels in patients with type 2 diabetes.

Dulaglutide 1.5 mg resulted in a mean HbA1c reduction of -0.63% compared to sitagliptin after 52 weeks.
Dulaglutide 0.75 mg met the criteria to be considered as a second effective dose.
Dulaglutide 2.0 mg showed a placebo-adjusted mean weight change of -1.99 kg.
Dulaglutide 2.0 mg was associated with a change in pulse rate of 0.78 beats per minute.
Dulaglutide 1.5 mg indicated a placebo-adjusted mean change in diastolic blood pressure of -0.62 mmHg.

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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 26 weeks and sitagliptin up to 104 weeks. 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 (100 mg), 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 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected.

RESULTS: Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0 mg 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 1.5 mg 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 0.75 mg for further investigation in this trial.

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

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