Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5).
OBJECTIVE
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.
Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN, USA.
Z
Z
Skrivanek
B L
BL
Gaydos
J Y
JY
Chien
M J
MJ
Geiger
M A
MA
Heathman
S
S
Berry
J H
JH
Anderson
T
T
Forst
Z
Z
Milicevic
D
D
Berry
D000293:Adolescent; D000328:Adult; D000368:Aged; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000009:adverse effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000628:therapy; D003927:Diet, Diabetic; D004038:Diet, Reducing; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000009:adverse effects; D015444:Exercise; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D050177:Overweight / Q000150:complications / Q000188:drug therapy / Q000628:therapy; D018027:Receptors, Glucagon / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
D019440:Anti-Obesity Agents; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; D008687:Metformin; C555680:dulaglutide
AWARD-5; Bayesian adaptive; GLP-1; GLP-1 receptor agonist; dose finding; dulaglutide dose; metformin; type 2 diabetes