title: On the three-arm non-inferiority trial including a placebo with a prespecified margin.
abstract: Three-arm trials including the experimental treatment, an active reference treatment and a placebo are recommended in the guidelines of the ICH and EMEA/CPMP as a useful approach to the assessment of assay sensitivity. Generally, the acceptable non-inferiority margin Δ has been defined as the maximum clinically irrelevant difference between treatments in many two-arm non-inferiority trials. However, many recent articles discussing three-arm trials have considered a design with unknown Δ which is the prespecified fraction f of unknown effect size of the reference drug, where the prespecified fraction f is treated as if it were a revised margin. Therefore, these methods cannot be applied to the case where the acceptable non-inferiority margin must be a prespecified difference between treatments. In this paper, we propose a statistical test procedure for three-arm non-inferiority trials with the margin Δ defined as a prespecified difference between treatments under the situation that the primary endpoints are normally distributed with a common, but unknown, variance. In addition, we derive the optimal allocation that minimizes the total sample size. The proposed method is illustrated with data on a randomized controlled trial on major depressive disorder.
authors.affiliation: Department of Technology Assessment and Biostatistics, National Institute of Public Health, Japan. e-hida@niph.go.jp
authors.forename: Eisuke
authors.initials: E
authors.lastname: Hida
authors.forename: Toshiro
authors.initials: T
authors.lastname: Tango
mesh_terms: D000465:Algorithms; D000928:Antidepressive Agents / Q000627:therapeutic use; D003198:Computer Simulation; D016001:Confidence Intervals; D003865:Major Depressive Disorder / Q000188:drug therapy; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride; D006801:Humans; D015233:Models, Statistical; D009010:Monte Carlo Method; D015337:Multicenter Studies as Topic / Q000379:methods; D016011:Normal Distribution; D017374:Paroxetine / Q000627:therapeutic use; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D018401:Sample Size; D013876:Thiophenes / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D010919:Placebos; D013876:Thiophenes; D017374:Paroxetine; D000068736:Duloxetine Hydrochloride