Background: The Identification and Treatment of Hypoxemic Respiratory Failure (HRF) and ARDS with Protection, Paralysis, and Proning (TheraPPP) study is a type-1 hybrid stepped-wedge cluster randomized effectiveness-implementation study involving 17 adult Intensive Care Units (ICUs). This study will evaluate the effectiveness and implementation of an evidence-based, stakeholder-informed, multidisciplinary care pathway called Venting Wisely that standardizes the diagnosis and delivery of life-saving therapies for critically ill patients with Hypoxemic Respiratory Failure (HRF) and acute respiratory distress syndrome (ARDS). Objective: To describe a pre-specified statistical analysis plan (SAP) for the TheraPPP study prior to completion of recruitment, electronic data retrieval, and before any analysis has been conducted. Methods and analysis: The Statistical Analysis Plan (SAP) was designed by the principal investigators and senior biostatistician and reviewed in detail by the Venting Wisely Scientific Steering Group before being approved. This statistical analysis plan is reported in accordance with Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. A study specific CONSORT diagram and baseline characteristics table were developed. We estimate a total of 18816 mechanically ventilated patients will be included in this study with 11424 patients pre-implementation and 7392 patients post implementation. Given that ARDS patients are an important subgroup within this study, we estimate that this will generate a sample size of 2688 sustained ARDS patients within our TheraPPP study cohort. The primary clinical outcome is 28-day ventilator free days (VFDs). For the primary analysis, we will compare the mean 28-day VFDs pre-implementation and post-implementation using a mixed effects linear regression model to account for clustering of patients within site. Secondary clinical outcomes will be similarly compared pre-implementation and post-implementation using mixed effects linear or logistic regression models, as appropriate. All models will be adjusted for age, sex, severity of illness (sequential organ failure assessment score on admission) and severity of hypoxemia on admission based on PF ratio, as well as type and size of ICU. Pre-specified subgroups will include patient sex, age, HRF, ARDS, Covid-19 and cardiac surgical status, body mass index (BMI), height, illness acuity, and ICU volume. Ethics and Trial Registration: The study has received ethics approval from the University of Calgary (20-0646) and the University of Alberta (pro00112232). The trial was registered with ClinicalTrials.gov (NCT04744298) prior to the enrollment of any patients on Feb 8, 2021.

The authors have declared no competing interest.

NCT04744298

This work was supported by a project grant from Canadian Institutes of Health Research (2020) and a Health Innovation Implementation and Spread (HIIS 2) grant from Alberta Health Services (2020). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Conjoint Health Research Ethics Board of University of Calgary gave ethical approval for this work (20-0646)

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

This is a statistical analysis plan. At the time of this dissemination no retrieval of electronic data or analyses has been conducted.