Run-in periods

Run-in periods

A run-in period is a phase that occurs before randomization in a randomized controlled trial (RCT), during which all participants receive a specified intervention—this could be an active treatment, a placebo, or no intervention at all. This pre-randomization period is used strategically to improve the quality and efficiency of the trial. By observing participants during the run-in, researchers can exclude those who are unlikely to comply with study procedures, do not tolerate the intervention, or fail to meet key inclusion criteria based on early response.

Purpose and Objectives

One of the main purposes of a run-in period is to assess adherence. Participants who fail to follow the prescribed regimen during the run-in can be excluded from randomization, thereby increasing the likelihood that those who remain will complete the trial as planned. This reduces dropout rates and increases the statistical power of the study.

Another important function is to confirm eligibility. Some trials require more than static baseline characteristics to determine eligibility; a participant’s response to an intervention may also be considered. For instance, a trial might use a short course of treatment during the run-in to ensure only those who demonstrate a certain physiological response are randomized.

Run-in periods can also help reduce baseline variability, particularly in studies of chronic conditions. Allowing participants’ health status to stabilize before randomization ensures that outcome measurements are more consistent, improving the reliability of treatment comparisons.

In trials evaluating treatments for subjective symptoms, a run-in period may be used to identify placebo responders. These participants can be excluded prior to randomization to minimize placebo effects, which could otherwise mask the true efficacy of the intervention.

Types of Run-in Periods

There are several types of run-in periods, each with distinct methodological implications:

• Single-blind run-in: Participants are unaware of whether they are receiving an active treatment or placebo, but investigators know. This allows for early identification of non-adherent participants or those experiencing adverse events.

• Double-blind run-in: Neither participants nor investigators know the treatment allocation. This design minimizes bias in participant retention decisions and maintains methodological integrity.

• Active treatment run-in: All participants receive the study drug before randomization to identify those who cannot tolerate it or are unlikely to adhere.

• Placebo run-in: A placebo is used to identify placebo responders and assess general adherence.

Limitations and Ethical Considerations

Despite their advantages, run-in periods also come with limitations.

• Selection bias: Excluding non-adherent or intolerant participants can limit the generalizability of results to real-world settings.
• Ethical concerns: Participants may invest time and effort during the run-in without being randomized, raising issues around fairness and informed consent.
• Prolonged study duration: Including a run-in phase can extend the timeline and increase study costs.
• Loss of information: Participants excluded during run-in may differ systematically from those who are randomized, introducing bias.

Examples from Major Trials

Several major trials have used run-in periods effectively:

• The ALLHAT trial (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) included a run-in to assess medication adherence prior to randomization.
• The HOPE trial (Heart Outcomes Prevention Evaluation) used a run-in phase to exclude participants who were non-adherent or experienced adverse events early on.

Conclusion

Run-in periods can be a valuable methodological tool in RCTs, enhancing adherence, reducing variability, and ensuring that only suitable participants are randomized. However, their design and implementation require careful consideration to avoid introducing bias, undermining generalizability, or compromising ethical standards. When used thoughtfully, run-in periods can contribute meaningfully to the internal validity and overall success of a clinical trial.

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Bibliography

1. Pocock SJ. Clinical Trials: A Practical Approach. Wiley; 1983. Chapter 9: Run-in periods and pre-randomization screening.
2. Meinert CL. Clinical Trials: Design, Conduct, and Analysis. Oxford University Press; 2012. Section on run-in and lead-in phases.
3. Prentice RL, Freedman LS. The use of screening examinations in randomized trials. Statistics in Medicine. 1988;7(1–2):31–39. Discusses methodological concerns related to run-in phases.
4. Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. The Lancet. 2002;359(9307):696–700. Includes discussion of run-in phases in the context of maintaining blinding.
5. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Statistics in Medicine. 1984;3(4):409–422. Discusses the use of run-in periods in trial efficiency and participant selection.

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Adapted for educational use. Please cite relevant trial methodology sources when using this material in research or teaching.