Early in-bed cycle ergometry with critically ill, mechanically ventilated patients - Statistical Analysis Plan for CYCLE (Critical care cycling to improve lower extremity strength), an international, multi-centre, randomized clinical trial (Preprint)

BACKGROUND Survivors of critical illness are at risk of developing physical dysfunction following intensive care unit (ICU) discharge. ICU-based rehabilitation interventions, such as early-in bed cycle ergometry, may improve patients’ short-term physical function. CYCLE (Critical care cycling to improve lower extremity strength) is a 360-patient, international, multi-center, open-label, parallel group randomized control trial (1:1 ratio) with blinded primary outcome assessment at 3 days post-ICU discharge. OBJECTIVE Before unblinding and trial database lock, we describe a prespecified statistical analysis plan (SAP) for the CYCLE RCT. METHODS The CYCLE principal investigator and statisticians prepared this SAP with approval by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes (including adverse events), and describes the planned, primary, secondary, and subgroup analyses. RESULTS The primary outcome for the CYCLE trial is the Physical Function Intensive Care Unit Test-scored (PFIT-s) at 3 days post-ICU discharge. The PFIT-s is a reliable and valid performance-based measure. We plan to use a frequentist statistical framework for all analyses. We will conduct a linear regression to analyze the primary outcome, including randomization as an independent variable, adjusting for age ( 65 years versus <65 years) and center. We will report the regression results as mean difference in PFIT-s with corresponding 95% confidence intervals (CIs) and p-values. We consider a 1-point difference in PFIT-s score as clinically important. We plan 3 subgroup analyses including age (≥65 versus <65 years), frailty (Baseline Clinical Frailty Scale ≥5 versus <5) and sex (male versus female). CONCLUSIONS We developed and present an SAP for the CYCLE RCT and will adhere to it for all analyses. This study will add to the growing body of evidence evaluating the efficacy and safety of ICU-based rehabilitation interventions. CLINICALTRIAL NCT03471247 (Full RCT); NCT02377830 (CYCLE Vanguard 46 patient internal pilot)