Replacing Protein Via Enteral Nutrition in Critically Ill Patients (REPLENISH)

Replacing Protein Via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients: An International, Multicenter Randomized Controlled Trial

The investigator will investigate the effect of supplemental enteral protein (1.2 g/kg/day) added to standard formula to achieve high amount of enteral protein (range 2-2.4 g/kg/day) given from ICU day 5 until ICU discharge up to ICU day 90 as compared to no supplemental enteral protein to achieve moderate amount enteral protein (0.8-1.2 g/kg/day), given in conjunction with similar amounts of stepwise caloric administration in the two groups on all-cause 90-day mortality.

Study Overview

• Status: Recruiting
• Conditions: Critical Illness; Nutrition Disorders
• Intervention / Treatment: Other: Replenish protein group; Other: Standard protein group

Detailed Description

The REPLENISH is a multicentric, international, open label, randomized controlled trial which will enroll subjects in intensive care unit. Patients will be randomized on day 4 of ICU admission. Until ICU day 4, protein requirement will be provided according to the local practice as long as no intravenous amino acids are given and the average protein intake in the first 4 days does not exceed 0.8 g/kg/day. On ICU day 4, patients will be randomized to one of the two treatment groups: one with standard prescription without supplemental proteins (maximum1.2 g/kg/day) from the primary polymeric formula and another group will receive the standard amount of proteins (maximum 1.2 g/kg/day) from the primary polymeric formula AND supplemental protein at 1.2 g/kg/day.

Randomization will be stratified by suspected COVID-19 and then by site and the use of renal replacement therapy at the time of randomization (intermittent hemodialysis or continuous renal replacement therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 2502
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yaseen M Arabi, MD; Phone Number: 18855 0118011111; Email: arabi@ngha.med.sa
• Study Contact Backup: Name: Musharaf Sadat, MBBS; Phone Number: 10822 0118011111; Email: sadatmu@ngha.med.sa

Study Locations

• Saudi Arabia
  • Jeddah, Saudi Arabia, 21423
    • Recruiting
    • King Abdulaziz Medical City
    • Contact: Fahad M Al-Hameed, MD; Phone Number: 22771 00966 12 2266666; Email: HameedF@ngha.med.sa
    • Contact: Ohoud Al Orabi, MMedSC; Phone Number: 28864 0096612 2266666; Email: alorabioh@NGHA.MED.SA
    • Principal Investigator: Fahad Al-Hameed, MD
  • Riyadh,, Saudi Arabia, 11426
    • Recruiting
    • Intensive Care Unit, King Abdulaziz Medical City

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria(on ICU calendar day 4 or the morning of day 5)

1. Age ≥18-years old
2. Patient started on enteral nutrition (EN) via nasogastric/orogastric or duodenal or percutaneous endoscopic gastrostomy (PEG) or jejunostomy tubes.
3. The patient is on invasive mechanical ventilation and unlikely to be discharged from ICU next day.

Exclusion Criteria:

1. Lack of commitment to full life support or brain death. Patients with "Do Not Resuscitate" order but with commitment to ongoing life support can be enrolled.
2. Patients on any amount of parenteral nutrition (PN) in ICU at the time of screening, whether PN is used alone or in combination with enteral nutrition. Non-nutritional calories (dextrose, propofol, citrate) not considered as PN.
3. Patients who received an average protein of more than 0.8g/kg/day in the first 4 ICU days.
4. Patients being fed entirely through oral route - i.e. those who are eating.
5. Pregnancy.
6. Burn patients.
7. Prisoners or those undergoing forced treatment.
8. Patients with hepatic encephalopathy or Child C liver cirrhosis
9. Inherited defect of amino acid metabolism.
10. Allergies to protein supplement

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Replenish protein group; The subjects randomized to this group will receive the standard amount of proteins (maximum 1.2 g/kg/day) from the primary polymeric formula AND supplemental protein at 1.2 g/kg/day	Other: Replenish protein group; For patients with Body mass index(BMI) <30, use pre-ICU actual body weight(BW) for the calculation; if unavailable, use weight on ICU admission. For patients with BMI >=30, use adjusted body weight
Active Comparator: Standard protein group; The subjects randomized to this group will receive standard prescription without supplemental proteins (maximum1.2 g/kg/day) from the primary polymeric formula. No supplemental protein will be allowed	Other: Standard protein group; For patients with BMI <30, use pre-ICU actual BW for the calculation; if unavailable, use weight on ICU admission. For patients with BMI >=30, use adjusted body weight

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90 day-all cause mortality	Mortality 90 days post randomization	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive at day 90 without life support	use of vasopressor/inotropic support, invasive mechanical ventilation and/or renal replacement therapy	90 days
Days alive and out of hospital at day 90	90 day survival after randomization	90 days
Bacteremia until 2 days of ICU stay	Any symptoms of bacteremia	until 2 days post ICU.
New or progression of Skin Pressure Ulcers	anytime during ICU stay	ICU stay
Functional assessment at day 90	SARC-F screen for sarcopenia and EuroQoL	Day 90

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcomes during ICU stay	New episode of stage 2 or higher AKI by KDIGO criteria; 2. Pneumonia defined as episodes of newly confirmed pneumonia according to the modified CDC criteria; 3. Grade IV Acute Gastrointestinal injury (AGI)	ICU stay
Minor safety outcomes during ICU stay	Feeding tolerance; Diarrhoea; Refeeding syndrome	ICU stay

Collaborators and Investigators

• Sponsor: King Abdullah International Medical Research Center
• Investigators: Principal Investigator: Yaseen M Arabi, MD, King Saud Bin Abdulaziz University for Health Sciences

Publications and helpful links

General Publications

• Weijs PJ, Looijaard WG, Beishuizen A, Girbes AR, Oudemans-van Straaten HM. Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients. Crit Care. 2014 Dec 14;18(6):701. doi: 10.1186/s13054-014-0701-z.
• McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts PR, Compher C; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863. No abstract available. Erratum In: JPEN J Parenter Enteral Nutr. 2016 Nov;40(8):1200.
• Liebau F, Wernerman J, van Loon LJ, Rooyackers O. Effect of initiating enteral protein feeding on whole-body protein turnover in critically ill patients. Am J Clin Nutr. 2015 Mar;101(3):549-57. doi: 10.3945/ajcn.114.091934. Epub 2015 Feb 4.
• Compher C, Chittams J, Sammarco T, Nicolo M, Heyland DK. Greater Protein and Energy Intake May Be Associated With Improved Mortality in Higher Risk Critically Ill Patients: A Multicenter, Multinational Observational Study. Crit Care Med. 2017 Feb;45(2):156-163. doi: 10.1097/CCM.0000000000002083.
• Koekkoek WACK, van Setten CHC, Olthof LE, Kars JCNH, van Zanten ARH. Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation: The PROTINVENT retrospective study. Clin Nutr. 2019 Apr;38(2):883-890. doi: 10.1016/j.clnu.2018.02.012. Epub 2018 Feb 17.
• Arabi YM, Aldawood AS, Al-Dorzi HM, Tamim HM, Haddad SH, Jones G, McIntyre L, Solaiman O, Sakkijha MH, Sadat M, Mundekkadan S, Kumar A, Bagshaw SM, Mehta S; PermiT trial group. Permissive Underfeeding or Standard Enteral Feeding in High- and Low-Nutritional-Risk Critically Ill Adults. Post Hoc Analysis of the PermiT Trial. Am J Respir Crit Care Med. 2017 Mar 1;195(5):652-662. doi: 10.1164/rccm.201605-1012OC.
• Heyland DK, Patel J, Bear D, Sacks G, Nixdorf H, Dolan J, Aloupis M, Licastro K, Jovanovic V, Rice TW, Compher C. The Effect of Higher Protein Dosing in Critically Ill Patients: A Multicenter Registry-Based Randomized Trial: The EFFORT Trial. JPEN J Parenter Enteral Nutr. 2019 Mar;43(3):326-334. doi: 10.1002/jpen.1449. Epub 2018 Sep 27.
• Arabi YM, Casaer MP, Chapman M, Heyland DK, Ichai C, Marik PE, Martindale RG, McClave SA, Preiser JC, Reignier J, Rice TW, Van den Berghe G, van Zanten ARH, Weijs PJM. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med. 2017 Sep;43(9):1239-1256. doi: 10.1007/s00134-017-4711-6. Epub 2017 Apr 3.
• Al-Dorzi HM, Stapleton RD, Arabi YM. Nutrition priorities in obese critically ill patients. Curr Opin Clin Nutr Metab Care. 2022 Mar 1;25(2):99-109. doi: 10.1097/MCO.0000000000000803.

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2020
• Primary Completion (Anticipated): June 30, 2025
• Study Completion (Anticipated): December 30, 2025

Study Registration Dates

• First Submitted: June 7, 2020
• First Submitted That Met QC Criteria: July 14, 2020
• First Posted (Actual): July 17, 2020

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: January 8, 2023
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Nutrition Disorders
• Other Study ID Numbers: RC19/414/R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No