Multicentre, randomised controlled trial of physiological-based cord clamping versus immediate cord clamping in infants with a congenital diaphragmatic hernia (PinC): statistical analysis plan

Trials, vol. 25, pp. 198

Abstract

BACKGROUND: Infants born with congenital diaphragmatic hernia (CDH) are at high risk of respiratory insufficiency and pulmonary hypertension. Routine practice includes immediate clamping of the umbilical cord and endotracheal intubation. Experimental animal studies suggest that clamping the umbilical cord guided by physiological changes and after the lungs have been aerated, named physiological-based cord clamping (PBCC), could enhance the fetal-to-neonatal transition in CDH. We describe the statistical analysis plan for the clinical trial evaluating the effects of PBCC versus immediate cord clamping on pulmonary hypertension in infants with CDH (PinC trial). DESIGN: The PinC trial is a multicentre, randomised controlled trial in infants with isolated left-sided CDH, born ≥ 35.0 weeks of gestation. The primary outcome is the incidence of pulmonary hypertension in the first 24 h after birth. Maternal outcomes include estimated maternal blood loss. Neonatal secondary outcomes include mortality before discharge, extracorporeal membrane oxygenation therapy, and number of days of mechanical ventilation. Infants are 1:1 randomised to either PBCC or immediate cord clamping using variable random permutated block sizes (4-8), stratified by treatment centre and estimated severity of pulmonary hypoplasia (i.e. mild/moderate/severe). At least 140 infants are needed to detect a relative reduction in pulmonary hypertension by one third, with 80% power and 0.05 significance level. A chi-square test will be used to evaluate the hypothesis that PBCC decreases the occurrence of pulmonary hypertension. This plan is written and submitted without knowledge of the collected data. The trial has been ethically approved. TRIAL REGISTRATION: ClinicalTrials.gov NCT04373902 (registered April 2020).

Authors 21

1. Emily J.J. Horn-Oudshoorn

   Erasmus MC

   Affiliation as printed

   Division of Neonatology, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands

2. Marijn J. Vermeulen

   Erasmus MC

   Affiliation as printed

   Division of Neonatology, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands

3. Ronny Knol

   Erasmus MC

   Affiliation as printed

   Division of Neonatology, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands

4. Rebekka Bout-Rebel

   Erasmus MC

   Affiliation as printed

   Division of Neonatology, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands

5. Arjan B. te Pas Aachen Division of Neonatology Department of Paediatrics, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Division of Neonatology, Department of Paediatrics, Leiden University Medical Center, Leiden, the Netherlands

6. Stuart B. Hooper

   Hudson Institute of Medical Research · Monash University

   Affiliation as printed

   The Ritchie Centre, Hudson Institute for Medical Research, Monash University, Melbourne, Victory, Australia

7. Suzan C.M. Cochius-den Otter

   Erasmus MC

   Affiliation as printed

   Division of Paediatric Intensive Care, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands

8. Rene M. H. Wijnen

   Erasmus MC

   Affiliation as printed

   Division of Paediatric Intensive Care, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands

9. Kelly J. Crossley

   Hudson Institute of Medical Research · Monash University

   Affiliation as printed

   The Ritchie Centre, Hudson Institute for Medical Research, Monash University, Melbourne, Victory, Australia

10. Neysan Rafat

    University Medical Centre Mannheim

    Affiliation as printed

    Department of Neonatology, University Medical Center Mannheim, Mannheim, Germany

11. Thomas Schaible

    University Medical Centre Mannheim

    Affiliation as printed

    Department of Neonatology, University Medical Center Mannheim, Mannheim, Germany

12. Willem Pieter de Boode

    Radboud University Nijmegen · Radboud University Medical Center · Amalia Kinderziekenhuis · Radboud Institute for Health Sciences

    Affiliation as printed

    Division of Neonatology, Department of Paediatrics, Radboudumc University Medical Center, Radboud Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, The Netherlands

13. Anne Debeer

    Universitair Ziekenhuis Leuven

    Affiliation as printed

    Department of Neonatology, University Hospitals Leuven, Leuven, Belgium

14. Berndt Urlesberger

    Medical University of Graz

    Affiliation as printed

    Division of Neonatology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria

15. Calum T. Roberts

    Monash University

    Affiliation as printed

    Department of Paediatrics, Monash University, Melbourne, Victoria, Australia

16. Florian Kipfmueller

    University of Bonn

    Affiliation as printed

    Department of Neonatology and Paediatric Intensive Care Medicine, University of Bonn Children's Hospital, Bonn, Germany

17. Irma Capolupo

    Bambino Gesù Children's Hospital · Istituti di Ricovero e Cura a Carattere Scientifico

    Affiliation as printed

    Department of Medical and Surgical Neonatology, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy

18. Carmen Mesas Burgos

    Karolinska University Hospital · Karolinska Institutet

    Affiliation as printed

    Department of Paediatric Surgery, Karolinska University Hospital, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden

19. Bettina E. Hansen

    University Health Network · University of Toronto · Erasmus MC

    Affiliation as printed

    Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands

    Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada

    Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

20. Irwin K. M. Reiss

    Erasmus MC

    Affiliation as printed

    Division of Neonatology, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands

21. Philip L J DeKoninck corresponding

    Erasmus MC · Hudson Institute of Medical Research · Monash University

    Affiliation as printed

    Department of Obstetrics and Gynaecology, Erasmus MC University Medical Center, Rotterdam, the Netherlands. p.dekoninck@erasmusmc.nl

    Division of Neonatology, Department of Neonatal and Paediatric Intensive Care, Erasmus MC University Medical Center, Rotterdam, the Netherlands. p.dekoninck@erasmusmc.nl

    The Ritchie Centre, Hudson Institute for Medical Research, Monash University, Melbourne, Victory, Australia. p.dekoninck@erasmusmc.nl

    Department of Obstetrics and Gynaecology, Erasmus MC University Medical Center, Rotterdam, the Netherlands