Statistical analysis plan for the replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) randomized clinical trial
Authors: Arabi Yaseen M , Al-Dorzi Hasan M. , Aldibaasi Omar , Sadat Musharaf , Jose Jesna , Muharib Dina , Algethamy Haifa , Al-Fares Abdulrahman A. , Al-Hameed Fahad , Mady Ahmed , Kharaba Ayman , Al Bshabshe Ali , Maghrabi Khalid , AlGhamdi Khalid , Rasool Ghulam , AlGhamdi Adnan , Almekhlafi Ghaleb. A , Chalabi Jamal , AlHumedi Haifaa Ibrahim , Sakkijha Maram Hasan , Alamrey Norah Khalid , Alaskar Amjad Sami , Alhutail Rabeah Hamad , Sifaoui Kaouthar , 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 , Elghannam Madiha Fawazy , Almaani Mohammed , Buabbas Sarah Fadel , Alfilfil Wadiah Alawi M. , Alshahrani Mohammed S. , Starkopf Joel , Preiser Jean-Charles , Perner Anders , AlMubarak Jumana Hani , Hazem Wafa Mansoor , Albrahim Talal , Al-Dawood Abdulaziz ,   and the Saudi Critical Care Trials Group, Almatroud Amal , Naidu Brintha , Burrow Vicki , Al Zayer Salha , Khan Haseena Banu , Varela Afonso , Arishi Hatim , Hejazi Mohammed Moneer , Alodat Mohamed Ali , Alshayeh Rayan , AlHarthi AbdulRehman , Al Qahtani Naif , AlHejiely Yasmeen Ayed , AlZahrani Mada Muzhir , Lhmdi Mohammed Haddad , AlBakhiet Nouf , Baguisa Katrina , Mhawisg Huda , Alghethamy Haifa , Khan Liyakat , Gabr Moataz , Nuzhat Shehla , AlOrabi Ohoud , Malabari Raghad , Shobragi Kholoud , Asaas Shaymaa , Elghannam Madiha Fawazy , Bcuizon Beverly , AlAnezi Bander , Anaud Christine Joy , AlDammad Munir , Otaif Yahia , Hakami Osama , AlHusseini Arwa , Bashir Shahinaz , Hefni Lama , Alamoudi Samahar , Ansing Milyn L. , Albalawi Sawsan , Alahmadi Manar , AlHumaid Mohammed , Nouri Samar Talal , Huma Rozeena , Farhan Khawla , Hussein Mohamed , Baji Olfa , Alerw Abdulrehman , Johani Khloud , AlEnezi Monera , Boudrar Ismail , Atiq Rabiah , Junid Maali , Yusef Maram , Quadri Ahmed , Idrees Khalid , Bin Mabkoot Mona , Alfilfil Wadiah Alawi , Alkraidees AbdulRehman Fahad , Asonto Laila Perlas 
Published: May 2024

Abstract
Background
The optimal amount and timing of protein intake in critically ill patients are unknown. REPLENISH (Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial evaluates whether supplemental enteral protein added to standard enteral nutrition to achieve a high amount of enteral protein given from ICU day five until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve a moderate amount of enteral protein would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients.

Methods
In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2–2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8–1.2 g/kg/day). The primary outcome is 90-day all-cause mortality; other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30 to 25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data.

Conclusion
Ethics approval was obtained from the institutional review board, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings.

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