The NOTACS (Nasal Oxygen Therapy After Cardiac Surgery) trial, a multicenter adaptive randomized controlled trial, has updated its statistical analysis plan (SAP) to reflect changes following an interim sample size re-estimation (SSR). The trial compares the use of High-Flow Nasal Therapy (HFNT) to Standard Oxygen Therapy (SOT) for a minimum of 16 hours after tracheal extubation in patients at high risk of respiratory complications following cardiac surgery.
The study, conducted across the UK, Australia, and New Zealand, aims to determine if HFNT improves patient-centered outcomes compared to SOT. The primary outcome is Days Alive and at Home within 90 days post-surgery (DAH90), a metric chosen with patient input to reflect recovery and quality of life post-discharge.
Interim Analysis and Sample Size Re-estimation
An interim SSR was conducted in December 2022 after a soft database lock. The initial plan was to perform the SSR after 300 patients completed 90-day follow-up. At the time of the interim analysis, 241 of the 300 patients included had complete 90-day follow-up data. The purpose of this analysis was to re-estimate the sample size and assess safety, recruitment, compliance, and data completeness.
Based on the interim SSR, the Data Monitoring and Ethics Committee (DMEC) recommended increasing the maximum sample size to 1280 patients. This adjustment, approved by the NIHR HTA in June 2023, aims to maintain the trial's power at 90% and ensure more robust results. The original minimum sample size was 850 patients.
Statistical Analysis
The primary analysis will use the Mann-Whitney-Wilcoxon test to compare DAH90 between the HFNT and SOT groups, with a significance level of 5%. The analysis will follow an intention-to-treat (ITT) principle. Secondary outcomes include DAH30 (days alive and at home in the first 30 days), incidence of adverse events, ICU readmission rates, total length of hospital stay, and patient-reported outcomes measured by EQ-5D-5L.
Handling of Missing Data
The trial is powered on the basis of a 5% loss to follow-up rate. Provided there is no more than 5% missing data in DAH90 and no obvious cause for concern over the pattern of missing data, then we will run complete-case analysis. If the missingness rate in DAH90 exceeds 5%, we will take further steps to investigate the type of missingness for the subset of variables included in the primary and secondary analyses. If the missing data is found not to be MCAR in any instance, we will assume the missing data is MAR and perform multiple imputation as a sensitivity analysis to evaluate the robustness of the primary analysis.
Sensitivity Analyses
Several sensitivity analyses are planned to assess the robustness of the primary analysis, including using a per-protocol population, time-on-treatment populations, alternative definitions of DAH90 for patients who die during follow-up, and multiple imputation for missing data.
Safety Assessments
Safety will be assessed by monitoring adverse events (AEs) and serious adverse events (SAEs) from tracheal extubation to discharge, with SAEs tracked up to 90 days post-surgery. Specific SAEs of interest include death, stroke, sepsis, myocardial infarction, and acute kidney injury.
The NOTACS trial aims to provide robust evidence on the efficacy of HFNT compared to SOT in preventing respiratory complications after cardiac surgery. The adaptive design and updated statistical analysis plan are intended to ensure the reliability and validity of the trial's findings.
