Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients: A Multicenter Randomized Controlled Trial: The REPLENISH Trial Protocol

Background Protein intake is recommended in critically ill patients to mitigate the negative effects of critical illness-induced catabolism and muscle wasting. However, the optimal dose of enteral protein remains unknown. We hypothesize that supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition formula to achieve high amount of enteral protein (range 2-2.4 g/kg/day) given from ICU day 5 until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve moderate amount enteral protein (0.8-1.2 g/kg/day) would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. Methods The REPLENISH (Replacing Protein Via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial is an open-label, multicenter randomized clinical trial. Patients will be randomized to the Supplemental protein group or the Control group. Patients in both groups will receive the primary enteral formula as per the treating team, which includes a maximum protein 1.2 g/kg/day. The Supplemental protein group will receive, in addition, supplemental protein at 1.2 g/kg/day starting the fifth ICU day. The Control group will receive the primary formula without supplemental protein. The primary outcome is 90-day all-cause mortality. Other outcomes include functional and quality of life assessments at 90 days. The trial will enroll 2502 patients. Discussion The study has been initiated in September 2021. Interim analysis is planned at one third and two thirds of the target sample size. The study is expected to be completed by the end of 2024 Trial Registration [ClinicalTrials.gov][1] Identifier: [NCT04475666][2]. Registered on July 17, 2020 ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04475666 ### Funding Statement The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. ### Author Declarations 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: Institutional Review Board of Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia gave ethical approval for this work 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that will support the findings of this study are available from the corresponding author upon reasonable request as per the regulations of King Abdullah International Medical Research Center (KAIMRC) * APACHE : Acute Physiology and Chronic Health Evaluation DSMB : Data Safety Monitoring Board ESPEN : European Society for Clinical Nutrition and Metabolism ICU : Intensive Care Unit KDIGO : Kidney Disease: Improving Global Outcomes PN : Parenteral Nutrition RCT : Randomized Controlled Trial SOFA : Sequential Organ Failure Assessment [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04475666&atom=%2Fmedrxiv%2Fearly%2F2022%2F11%2F11%2F2022.11.10.22282161.atom