title: Application of adaptive design methodology in development of a long-acting glucagon-like peptide-1 analog (dulaglutide): statistical design and simulations.
abstract: BACKGROUND
  Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus.
  
  
  METHODS
  To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies.
  
  
  RESULTS
  Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design).
  
  
  CONCLUSIONS
  This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm-including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design.
authors.affiliation: Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN 46285, USA. skrivanek_zachary@lilly.com
authors.forename: Zachary
authors.initials: Z
authors.lastname: Skrivanek
authors.forename: Scott
authors.initials: S
authors.lastname: Berry
authors.forename: Don
authors.initials: D
authors.lastname: Berry
authors.forename: Jenny
authors.initials: J
authors.lastname: Chien
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Geiger
authors.forename: James H
authors.initials: JH
authors.lastname: Anderson
authors.forename: Brenda
authors.initials: B
authors.lastname: Gaydos
mesh_terms: D000465:Algorithms; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D004763:Glucagon-Like Peptides / Q000031:analogs & derivatives; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D012107:Research Design
chemical_list: D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; C555680:dulaglutide