Non-inferiority trial design for recurrent events.
We describe methods for designing non-inferiority trials with recurrent event responses arising from mixed-Poisson models. Sample size formulae are derived for trials in which treatment effects are expressed as relative rates and as absolute differences in cumulative mean functions at a particular time. Simulation studies are conducted to provide empirical validation of the frequency properties of the design and testing procedures under the null and alternative hypotheses using both mixed-Poisson models and robust marginal methods. The robustness of the design to mis-specification of the random effect distribution is also studied empirically. Sample size requirements based on the proposed method are contrasted with those from a design based on the time to the first event for a motivating study of patients with bone metastases at risk of skeletal complications. When the between-patient heterogeneity in the event rate is small, there may be a considerable reduction in sample size with recurrent event outcomes.
Cook
Richard J
RJ
Department of Statistics and Actuarial Science, University of Waterloo, 200 University Avenue West, Waterloo, ON, Canada N2L 3G1.
Lee
Ker-Ai
KA
Li
Hongdan
H
D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D002986:Clinical Trials as Topic / Q000379:methods*; D003198:Computer Simulation; D004164:Diphosphonates / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D015233:Models, Statistical; D012107:Research Design; D018401:Sample Size; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid