title: A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.
abstract: The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.
authors.affiliation: Department of Biometrics and Data Management, Boehringer Ingelheim Pharmaceuticals, P.O. Box 368, Ridgefield, CT 06877, USA. dhall@rdg.boehringer-ingelheim.com
authors.forename: David B
authors.initials: DB
authors.lastname: Hall
authors.forename: Ulrich
authors.initials: U
authors.lastname: Meier
authors.forename: Hans-Cristoph
authors.initials: HC
authors.lastname: Diener
mesh_terms: D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D003198:Computer Simulation; D018849:Controlled Clinical Trials as Topic / Q000379:methods*; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy*; D018579:Patient Selection; D012107:Research Design; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage* / Q000627:therapeutic use; D018170:Sumatriptan / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D017366:Serotonin Receptor Agonists; D018170:Sumatriptan