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Sequential co-enrolment in randomised trials in neonatal intensive care medicine
  1. Whitney Yoder1,
  2. Floris Groenendaal2,
  3. Wes Onland3,
  4. Anna van Oploo4,
  5. Charlotte Rietbergen5,
  6. Rolf Groenwold6
  1. 1Departmentof Clinical, Neuro and Developmental Psychology, Faculty of Behavioural andMovement Sciences, Free University, Amtersdam, the Netherlands
  2. 2Department of Neonatology, Wilhelmina Children’sHospital, University Medical Center Utrecht, Utrecht, the Netherlands
  3. 3Department of Neonatology, Emma Children’s Hospital/AMC, Amsterdam, The Netherlands
  4. 4Department of Intensive Care Medicine, Leiden University Medical Centre, Leiden, The Netherlands
  5. 5Department of Methodology and Statistics, Faculty of Social and Behavioural Science, Utrecht University, Utrecht, the Netherlands
  6. 6Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands
  1. Correspondence to Professor Rolf Groenwold, Department of Clinical Epidemiology, Leids Universitair Medisch Centrum, Leiden 2333ZA, The Netherlands; r.h.h.groenwold{at}lumc.nl

Abstract

In many medical research settings, such as the neonatal intensive care unit, the number of patients who are eligible for a randomised clinical trial is relatively small and recruiting a sufficient number of patients into trials is often difficult. Furthermore, some infants may have already been enrolled into a trial as a fetus. Sequential co-enrolment of patients into more than one trial may offer a solution, yet runs the risk of contaminated results. We consider the situation of two sequential trials and describe requirements for different possible treatments effects (‘estimands’) to be estimated in such situations. These estimands differ regarding the extent to which participation status and treatment status in the previous trial is accounted for. Because of differences in available information about previous trials, analyses may result in estimated effects which differ in terms of interpretation and generalisability, except when in the absence of an interaction between the studied treatments. If co-enrolment cannot be ruled out, researchers should collect information about co-enrolment and treatment status in a previous or concurrent trial and mitigate the trial analysis plan in order to estimate meaningful effects.

  • randomized clinical trials
  • co-enrolment
  • neonatal intensive care unit
  • statistics
  • preterm birth
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Footnotes

  • Contributors WY, RG, CR, WO and FG contributed to the design of the study. WY, WO, FG and AvO contributed to the collection of information about co-enrolment in two neonatal intensive care units in the Netherlands. WY and RG wrote the first version of the manuscript. All authors contributed to the writing of the final version of the manuscript.

  • Funding RG received financial support from the Netherlands Organisation for Scientific Research (ZonMW, project 917.16.430).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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