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Randomized clinical trials with run-in periods: frequency, characteristics and reporting

Authors Laursen DRT, Paludan-Müller AS, Hróbjartsson A

Received 30 September 2018

Accepted for publication 7 December 2018

Published 11 February 2019 Volume 2019:11 Pages 169—184


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Henrik Toft Sørensen

David Ruben Teindl Laursen,1–4 Asger Sand Paludan-Müller,2 Asbjørn Hróbjartsson1,3,4

1Centre for Evidence-Based Medicine Odense (CEBMO), Odense University Hospital, Odense, Denmark; 2Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 4Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark

Background: Run-in periods are occasionally used in randomized clinical trials to exclude patients after inclusion, but before randomization. In theory, run-in periods increase the probability of detecting a potential treatment effect, at the cost of possibly affecting external and internal validity. Adequate reporting of exclusions during the run-in period is a prerequisite for judging the risk of compromised validity. Our study aims were to assess the proportion of randomized clinical trials with run-in periods, to characterize such trials and the types of run-in periods and to assess their reporting.
Materials and methods: This was an observational study of 470 PubMed-indexed randomized controlled trial publications from 2014. We compared trials with and without run-in periods, described the types of run-in periods and evaluated the completeness of their reporting by noting whether publications stated the number of excluded patients, reasons for exclusion and baseline characteristics of the excluded patients.
Results: Twenty-five trials reported a run-in period (5%). These were larger than other trials (median number of randomized patients 217 vs 90, P=0.01) and more commonly industry trials (11% vs 3%, P<0.01). The run-in procedures varied in design and purpose. In 23 out of 25 trials (88%), the run-in period was incompletely reported, mostly due to missing baseline characteristics.
Conclusion: Approximately 1 in 20 trials used run-in periods, though much more frequently in industry trials. Reporting of the run-in period was often incomplete, precluding a meaningful assessment of the impact of the run-in period on the validity of trial results. We suggest that current trials with run-in periods are interpreted with caution and that updates of reporting guidelines for randomized trials address the issue.

Keywords: run-in periods, lead-in periods, enrichment design, single-blind placebo, washout periods, research methodology

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