Comparison of intention-to-treat and per-protocol results in non-inferiority trials: a methodological review protocol

Non-inferiority (NI) trial designs, which assess whether an experimental intervention is no worse than the standard of care, have become increasingly prevalent in recent years. Current thinking suggests that the intention-to-treat (ITT) analysis is considered anti-conservative in the presence of protocol violations when compared with the per-protocol (PP) analysis.

We aim to conduct a methodological review of NI trials to compare the results from ITT and PP analysis in NI trials. A comprehensive electronic search strategy will be used to identify studies indexed in MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases. We will include 390 NI trials published prior to 31 December 2024. The primary outcomes are the treatment effect estimates from ITT and PP analyses. Secondary outcomes are the CI widths and the bounds of the CIs from the ITT and PP analyses. Analysis will calculate the relative difference in the point estimates, CI widths and CI bounds between the two approaches. Linear models will be used to investigate the relationship between the outcomes and the proportion of patients excluded from the PP analysis.

This is a methodological review that has been registered on the International Prospective Register for Systematic Reviews (PROSPERO, CRD420251125360). Research ethics is not required as the project is a methodological review of previously published trials. Study findings will be shared via peer-reviewed publications and presentations at academic conferences.