Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial

Kristen S Gibbons; Luregn J Schlapbach; Stephen B Horton; Debbie A Long; John Beca; Simon Erickson; Marino Festa; Yves d'Udekem; Nelson Alphonso; David Winlaw; Kerry Johnson; Carmel Delzoppo; Kim van Loon; Brenda Gannon; Jonas Fooken; Antje Blumenthal; Paul J Young; Warwick Butt; Andreas Schibler; NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), and the ANZICS Paediatric Study Group (PSG)

doi:10.51893/2021.1.OA4

Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial

Crit Care Resusc. 2023 Oct 18;23(1):47-58. doi: 10.51893/2021.1.OA4. eCollection 2021 Mar.

Authors

Kristen S Gibbons¹, Luregn J Schlapbach^{1

2

3}, Stephen B Horton^{4

5

6}, Debbie A Long^{1

2}, John Beca⁷, Simon Erickson⁸, Marino Festa^{9

10}, Yves d'Udekem^{11

12

13}, Nelson Alphonso^{14

15}, David Winlaw^{16

17}, Kerry Johnson^{1

2}, Carmel Delzoppo^{6

18}, Kim van Loon¹⁹, Brenda Gannon²⁰, Jonas Fooken²⁰, Antje Blumenthal²¹, Paul J Young²², Warwick Butt^{6

18}, Andreas Schibler^{1

2}; NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), and the ANZICS Paediatric Study Group (PSG)

Affiliations

¹ Paediatric Critical Care Research Group, Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Queensland, Australia.
³ Department of Intensive Care Medicine and Neonatology, and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁴ Cardiac Surgical Unit, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁵ Faculty of Medicine, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
⁶ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁷ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
⁸ Paediatric Critical Care, Perth Children's Hospital, Western Australia and The University of Western Australia, Crawley, Western Australia, Australia.
⁹ Kids Critical Care Research, Paediatric Intensive Care Unit, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁰ Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
¹¹ Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Victoria, Australia.
¹² Heart Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
¹³ Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁴ Cardiac Surgery, Queensland Children's Hospital, Brisbane, Queensland, Australia.
¹⁵ School of Medicine, Children's Health Clinical Unit, University of Queensland, Brisbane, Queensland, Australia.
¹⁶ Heart Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁷ Sydney Children's Hospital Network and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁸ Paediatric Intensive Care Unit, Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.
¹⁹ Division of Anaesthetics, University Medical Center Utrecht, Utrecht, The Netherlands.
²⁰ Centre for the Business and Economics of Health, The University of Queensland, Brisbane, Queensland, Australia.
²¹ The University of Queensland, Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
²² The Intensive Care Research Programme, Medical Research Institute of New Zealand, Wellington, New Zealand.

Abstract

Background: The NITric oxide during cardiopulmonary bypass (CPB) to improve Recovery in Infants with Congenital heart defects (NITRIC) trial, a 1320-patient, multicentre, randomised controlled trial, is aiming to improve survival free of ventilation after CPB by using nitric oxide delivered into the oxygenator of the CPB. Objective: To provide a statistical analysis plan before completion of patient recruitment and data monitoring. Final analyses for this study will adhere to this statistical analysis plan, which details all key pre-planned analyses. Stata scripts for analyses have been prepared alongside this statistical analysis plan. Methods: The statistical analysis plan was designed collaboratively by the chief investigators and trial statistician and builds on the previously published study protocol. All authors remain blinded to treatment allocation. Detail is provided on statistical analyses including cohort description, analysis of primary and secondary outcomes and adverse events. Statistical methods to compare outcomes are planned in detail to ensure methods are verifiable and reproducible. Results: The statistical analysis plan developed provides the trial outline, list of mock tables, and analysis scripts. The plan describes statistical analyses on cohort and baseline description, primary and secondary outcome analyses, process of care measures, physiological descriptors, and safety and adverse event reporting. We define the pre-specified subgroup analyses and the respective statistical tests used to compare subgroups. Conclusion: The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field of neonatal and paediatric heart surgery. The plan ensures standards for trial analysis validity aiming to minimise bias of analyses. Trial registration: ACTRN12617000821392.