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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, On behalf of the NITRIC Study Group the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), and the ANZICS Paediatric Study Group (PSG)
Crit Care Resusc 2021; 23 (1): 47-58
- Kristen S Gibbons 1
- Luregn J Schlapbach 1, 2, 3
- Stephen B Horton 4, 5, 6
- Debbie A Long 1, 2
- John Beca 7
- Simon Erickson 8
- 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 Loon 19
- Brenda Gannon 20
- Jonas Fooken 20
- Antje Blumenthal 21
- Paul J Young 22
- Warwick Butt 6, 18
- Andreas Schibler 1, 2
- On behalf of the NITRIC Study Group the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), and the ANZICS Paediatric Study Group (PSG) 23
Yves d’Udekem receives consultancy fees from Actelion (Janssen) and travel fees from Berlin Heart.
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
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Author Contribution Statement
The statistical analysis plan first draft was designed by KG, LJS and AS. KG reviewed all sections on statistical analyses. SH, DL, JB, SE, MF, YdU, NA, DW, KJ, CD, KvL, BG, JF, PY, AB, MJ and WB reviewed the manuscript and approved the final version. KG prepared the final manuscript which was reviewed and approved by all authors.
Congenital heart disease affects approximately one in 100 infants, 1
The NITRIC trial design, which was informed by the encouraging pilot study data, 11, 12
Study design and participants
The primary hypothesis is to demonstrate that nitric oxide during CPB increases ventilator-free days compared with standard care in eligible infants. The full study protocol has been previously published 13
The study protocol has been approved by the Children’s Health Queensland Human Research Ethics Committee (HREC/17/QRCH/43; original submission approved on 6 March 2017). Minor modifications to the original study protocol were reviewed and approved by the HREC and are provided in the Online Appendix (table S1). This statistical analysis plan is based on version 1.4 of the study protocol.
- individual ventilator-free days components (ie, duration of mechanical ventilation, death within 28 days after CPB start);
- individual and components of composite measure of low cardiac output syndrome, and/or extracorporeal life support within 48 hours after CPB start and/or death within 28 days after CPB start;
- length of paediatric intensive care unit (PICU) stay after CPB start;
- length of hospital stay after CPB start;
- process of care measures:
- treatment with extracorporeal life support within 48 hours after CPB start;
- duration of postoperative time spent with open chest, including unplanned chest reopening after CPB start;
- treatment and duration of treatment using inhalational nitric oxide postoperatively after CPB start;
- treatment and duration of treatment of postoperative renal replacement therapy (includes peritoneal and continuous venous-venous haemodialysis) after CPB start;
- physiological descriptors:
- postoperative troponin levels during the first 24 hours after the operation;
- severity and duration of postoperative organ dysfunction; and
- postoperative acute kidney injury and serum creatinine levels measured during the first 24 hours.
- data verification on all screening data items (ie, inclusion and exclusion criteria) on a random sample of 20 ineligible patients (or all patients if < 20 ineligible patients) from each site;
- data verification on all screening data items (ie, inclusion and exclusion criteria) for every enrolled patient;
- data verification on the stratification used for randomisation and consent data items and data items related to calculation of the primary outcome and secondary outcomes for every enrolled patient; and
- data verification on key data items relating to cohort descriptors on a random sample of 10% of enrolled patients from each site.
Statistical analysis principles
- Analyses will be conducted based on the intention-to-treat principle. Specifically, patients who are eligible, who do not meet any exclusion criteria and who undergo randomisation will be analysed based on the treatment group they were allocated to, independent of the compliance with the treatment delivered.
- Participants who had more than one surgery before their second birthday will only have data analysed related to their first surgery for which study consent was available.
- Statistical tests will be two-sided applying a statistical significance level of 0.05. As we are not correcting for multiplicity when comparing secondary or other outcomes, such results will be considered exploratory and will be reported as point estimates with 95% confidence intervals (CIs).
- If there are missing data for the primary outcome measure for any participants, imputation methods will be used.
- Continuous variables will be assessed for normality; this will be undertaken using visual inspection of histograms and Q-Q plots.
- Standard descriptive statistics will be used when summarising variables; frequencies (percentages) for discrete variables, mean and SD for continuous variables, or, if continuous variables are non-normally distributed, median with interquartile range.
- This analysis plan and the primary manuscript will only include analyses up to 28 days. We will present analyses of postoperative delirium, health care costs, inflammatory markers and long term outcomes (12 months and later after procedure) separately.
- Pre-planned subgroup analyses will be performed including the pre-defined study strata; these will be executed regardless of any potential treatment effect on the primary or secondary outcomes in the main cohort.
- To ensure transparency and reproducibility, the Stata code that will be used to analyse the final study data is available on GitHub.
Gibbons KS. NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial: Statistical Analysis Code. GitHub, 2020. https://github.com/kgibbons44/NITRICAnalysis/ (viewed Dec 2020).
- The trial statistician will be blinded to the treatment group until the analyses outlined in this statistical analysis plan have been completed.
- Changes in the analysis plan by the investigators effective after publication of this statistical analysis plan will be declared as such.
Trial profile and overview
Patient baseline characteristics
Surgical procedure and intervention characteristics
We will report on the compliance with the study drug (nitric oxide) using a number of measures, reported for patients randomised to the intervention group only (Table 2). In addition, we will list protocol deviations relating to the administration of nitric oxide in supplementary material.
Outcome measures analysis
Primary outcome measure
Secondary outcome measures
Subgroup and sensitivity analyses
Subgroup analyses will be undertaken using the same analysis methods described for the primary and secondary outcome measures, with the addition of the subgroup variable and its related interaction term into the main regression model. For each subgroup, the relevant descriptive statistics will be presented for the primary and secondary outcomes, along with the appropriate measure of effect size (and 95% CI) and interaction effect (and 95% CI and P value). A Forest plot will be developed to present heterogeneity between the treatment group and subgroup variable, including the P value, and presented as a supplementary figure.
In addition, a sensitivity analysis for study outcomes will be undertaken including the variables treatment group, duration of CPB, surgical complexity (recorded using the Risk Adjustment for Congenital Heart Surgery [RACHS] score), blood prime use during surgery, sex, and strata variables as fixed effects and site as a random effect. Results will be presented in the same manner as primary analyses and included in the supplementary material.
Treatment of missing data
Yves d’Udekem and Luregn Schlapbach hold NHMRC Clinical Practitioner Fellowships and Andreas Schibler holds a Medical Research Future Fund Practitioner Fellowship. Simon Erickson is supported by a grant from the Perth Children’s Hospital Foundation. The Victorian Government’s Operational Infrastructure Support Program supported this research project. Paul Young holds a Clinical Practitioner Fellowship from the Health Research Council of New Zealand. The funding sources had no involvement in study design, analyses, or interpretation of the results.
Mallinckrodt Pharmaceuticals is providing nitric oxide delivery devices to Australian and New Zealand study sites, and The Netherlands site has a NO-A nitric oxide delivery system on loan from EKU Elektronik during the study period. Neither company have any involvement in study design, conduct or analyses.