Testing non-inferiority of a new treatment in three-arm clinical trials with binary endpoints

Nian Sheng Tang*, Bin Yu, Man Lai TANG

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

12 Citations (Scopus)


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.

Original languageEnglish
Article number134
JournalBMC Medical Research Methodology
Issue number1
Publication statusPublished - 2014

Scopus Subject Areas

  • Epidemiology
  • Health Informatics

User-Defined Keywords

  • Approximate unconditional test
  • Bootstrap-resampling test
  • Non-inferiority trial
  • Rate difference
  • Saddlepoint approximation
  • Three-arm design


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