Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol
Authors: Arabi Yaseen M. , Al-Dorzi Hasan M. , Sadat Musharaf , Muharib Dina , Algethamy Haifa , Al-Hameed Fahad , Mady Ahmed , AlGhamdi Adnan , Almekhlafi Ghaleb. A. , Al-Fares Abdulrahman A. , Kharaba Ayman , Al Bshabshe Ali , Maghrabi Khalid , Al Ghamdi Khalid , Rasool Ghulam , Chalabi Jamal , AlHumedi Haifaa Ibrahim , Sakkijha Maram Hasan , Alamrey Norah Khalid , Alhutail Rabeah Hamad , Sifaoui Kaouthar , Almaani Mohammed , Alqahtani Rakan , Qureshi Ahmad S. , Hejazi Mohammed Moneer , Arishi Hatim , AlQahtani Samah , Ghazi Amro Mohamed , Baaziz Saleh T. , Azhar Abeer Othman , Alabbas Sara Fahad , AlAqeely Mohammed , AlOrabi Ohoud , Al-Mutawa Aliaa , AlOtaibi Maha , Aldibaasi Omar , Jose Jesna , Starkopf Joel , Preiser Jean-Charles , Perner Anders , Al-Dawood Abdulaziz ,   the Saudi Critical Care Trials Group, Almatroud Amal , Naidu Brintha , Burrow Vicki , Al Zayer Salha , Khan Haseena Banu , Varela Afonso , Alodat Mohamed Ali , Alshayeh Rayan , AlHarthi AbdulRehman , Al Qahtani Naif , AlHejiely Yasmeen Ayed , AlZahrani Mada Muzhir , Lhmdi Mohammed Haddad , Baguisa Katrina , Mhawisg Huda , Khan Liyakat , Gabr Moataz , Nuzhat Shehla , ElGhannam Madiha , Bcuizon Beverly , AlAnezi Bander , Anaud Christine Joy , Albalawi Sawsan , Alahmadi Manar , AlHumaid Mohammed , Nouri Samar Talal , Huma Rozeena , Farhan Khawla , Alamoudi Samahar , Ansing Milyn L. , Malabari Raghad , Shobragi Kholoud , Asaas Shaymaa , Quadri Ahmed , Idrees Khalid , AlHusseini Arwa , Bashir Shahinaz , Hussein Mohamed , Baji Olfa , Alerw Abdulrehman , Johani Khloud , AlEnezi Monera , Boudrar Ismail , Atiq Rabiah , Junid Maali , Yusef Maram , Mabkoot Mona Bin , AlDammad Munir , Otaif Yahia , Hakami Osama , Kenawy Mariam Ehab , Alkhamees Dalal Ali , Behbehani Tasneem Abdullah 
Published: July 2023

Abstract
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 2025.

Trial registration
ClinicalTrials.gov Identifier: NCT04475666. Registered on July 17, 2020.