Abstract
Background: A run-in period is often employed in randomised controlled trials to increase adherence to the intervention and reduce participant loss to follow-up in the trial population. However, it is uncertain whether use of a run-in period affects the magnitude of treatment effect. Methods: We will conduct a sensitive search for systematic reviews of cardiovascular preventative trials and a complete meta-analysis of treatment effects comparing cardiovascular prevention trials using a run-in period (“run-in trials”) with matched cardiovascular prevention trials that did not use a run-in period (“non-run-in trials”). We describe a comprehensive matching process which will match run-in trials with non-run-in trials by patient populations, interventions, and outcomes. For each pair of run-in trial and matched non-run-in trial(s), we will estimate the ratio of relative risks and 95% confidence interval. We will evaluate differences in treatment effect between run-in and non-run-in trials and our and our priamry outcome will be the ratio of relative risks for matched run-in and non-run-in trials for their reported cardiovascular composite outcome. Our secondary outcomes are comparisons of mortality, loss to follow up, frequency of adverse events and methodological quality of trials. Conclusions: This study will answer a key question about what influence a run-in period has on the magnitude of treatment effects in randomised controlled trials for cardiovascular prevention therapies.
Highlights
A pre-randomisation run-in period is used widely in randomised controlled trials evaluating cardiovascular preventative therapies, with intended advantages including exclusion of non-adherent subjects, placebo responders, non-responders, or those who experience early side effects or could not tolerate the intervention[1,2,3,4,5]
Data sources We have identified high quality previous systematic reviews of cardiovascular preventative therapies and will extract data these reviews assessing the treatment effect of anti-hypertensive[8,9,10,11,12], lipid lowering[13,14,15,16], and glucose lowering drugs[17,18] in primary and secondary prevention trials
To allow a consistent comparison of treatment effects trials in the individual systematic reviews will be eligible for inclusion in the matched meta-analysis of treatment effects if an active agent is compared with a placebo control, or if an active agent in addition to standard therapy is compared with standard therapy
Summary
Keywords Run-in, clinical trial design, clinical trial methodology, treatment effect. Author roles: Murphy R: Conceptualization, Methodology, Writing – Original Draft Preparation; McGrath E: Conceptualization, Methodology; Nolan A: Conceptualization, Methodology, Writing – Original Draft Preparation; Smyth A: Methodology, Supervision; Canavan M: Supervision, Writing – Review & Editing; O'Donnell M: Conceptualization, Methodology, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing; Judge C: Conceptualization, Methodology, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing.
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