title: Testing non-inferiority of a new treatment in three-arm clinical trials with binary endpoints.
abstract: BACKGROUND
  A two-arm non-inferiority trial without a placebo is usually adopted to demonstrate that an experimental treatment is not worse than a reference treatment by a small pre-specified non-inferiority margin due to ethical concerns. Selection of the non-inferiority margin and establishment of assay sensitivity are two major issues in the design, analysis and interpretation for two-arm non-inferiority trials. Alternatively, a three-arm non-inferiority clinical trial including a placebo is usually conducted to assess the assay sensitivity and internal validity of a trial. Recently, some large-sample approaches have been developed to assess the non-inferiority of a new treatment based on the three-arm trial design. However, these methods behave badly with small sample sizes in the three arms. This manuscript aims to develop some reliable small-sample methods to test three-arm non-inferiority.
  
  
  METHODS
  Saddlepoint approximation, exact and approximate unconditional, and bootstrap-resampling methods are developed to calculate p-values of the Wald-type, score and likelihood ratio tests. Simulation studies are conducted to evaluate their performance in terms of type I error rate and power.
  
  
  RESULTS
  Our empirical results show that the saddlepoint approximation method generally behaves better than the asymptotic method based on the Wald-type test statistic. For small sample sizes, approximate unconditional and bootstrap-resampling methods based on the score test statistic perform better in the sense that their corresponding type I error rates are generally closer to the prespecified nominal level than those of other test procedures.
  
  
  CONCLUSIONS
  Both approximate unconditional and bootstrap-resampling test procedures based on the score test statistic are generally recommended for three-arm non-inferiority trials with binary outcomes.
authors.affiliation: Department of Statistics, Yunnan University, No,2 Cuihu North Road, 650091 Kunming, China. nstang@ynu.edu.cn.
authors.forename: Nian-Sheng
authors.initials: NS
authors.lastname: Tang
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.forename: Man-Lai
authors.initials: ML
authors.lastname: Tang
mesh_terms: D020117:Cisapride / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy; D012107:Research Design; D012841:Simethicone / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D012841:Simethicone; D020117:Cisapride