title: Experiences with an adaptive design for a dose-finding study in patients with osteoarthritis.
abstract: Dose-finding studies in non-oncology areas are usually conducted in Phase II of the development process of a new potential medicine and it is key to choose a good design for such a study, as the results will decide if and how to proceed to Phase III. The present article has focus on the design of a dose-finding study for pain in osteoarthritis patients treated with the TRPV1 antagonist AZD1386. We describe different design alternatives in the planning of this study, the reasoning for choosing the adaptive design and experiences with conduct and interim analysis. Three alternatives were proposed: one single dose-finding study with parallel design, a programme with a smaller Phase IIa study followed by a Phase IIb dose-finding study, and an adaptive dose-finding study. We describe these alternatives in detail and explain why the adaptive design was chosen for the study. We give insights in design aspects of the adaptive study, which need to be pre-planned, like interim decision criteria, statistical analysis method and setup of a Data Monitoring Committee. Based on the interim analysis it was recommended to stop the study for futility since AZD1386 showed no significant pain decrease based on the primary variable. We discuss results and experiences from the conduct of the study with the novel design approach. Huge cost savings have been done compared to if the option with one dose-finding design for Phase II had been chosen. However, we point out several challenges with this approach.
authors.affiliation: AstraZeneca, Södertälje, Sweden. Electronic address: frank.miller@stat.su.se.
authors.forename: Frank
authors.initials: F
authors.lastname: Miller
authors.affiliation: AstraZeneca, Södertälje, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Björnsson
authors.affiliation: AstraZeneca, Södertälje, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Svensson
authors.affiliation: AstraZeneca, Södertälje, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Karlsten
mesh_terms: D001562:Benzimidazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D026661:Clinical Trials Data Monitoring Committees; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D010003:Osteoarthritis / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy*; D012107:Research Design; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: C574562:AZD1386; D001562:Benzimidazoles; D050916:TRPV Cation Channels; C494484:TRPV1 receptor
keywords: AZD1386; Adaptive design; Data Monitoring Committee; Dose-finding; Interim analysis; Osteoarthritis