Clinical trial NCT00985205: The RE-ENERGIZE Study: RandomizEd Trial of ENtERal Glutamine to minimIZE Thermal Injury
Official title: Effects of Enteral Glutamine Supplementation on Mortality and Infectious Morbidity in Severely Burned Patients: a Multi-center Pilot Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Burns
Keywords: Randomized Clinical Trial
Glutamine
Themal Burn Injuries
Nutrition
Outcome Assessment
Critical Care
Total Body Surface Area
Lead sponsor: Clinical Evaluation Research Unit at Kingston General Hospital
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2009-09-28
Enrollment: 1201
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to test the following hypotheses:

1. Enteral glutamine administration decreases in-hospital mortality in adult patients with severe thermal burn injuries.
2. Enteral glutamine administration decreases hospital-acquired blood stream infections from Gram negative organisms and length of stay in ICU and hospital for adult patients with severe thermal burn injuries.
3. Enteral glutamine administration will improve the physical function of surviving burn injured patients and reduce their cost of care.

The objectives of this trial are to determine the overall treatment effect and safety of glutamine in burn patients. Specifically, the investigators want to assess the following outcomes in a sample of 1200 patients in 80 sites:

1. In patients with severe, life-threatening burn injury, what is the effect of enteral glutamine on time to discharge alive from hospital
2. In patients with severe, life-threatening burn injury, what is the effect of enteral glutamine on 6 month mortality, hospital-acquired blood stream infections from Gram negative organisms, hospital mortality, duration of stay in ICU and hospital, health-related quality of life, and health care resources?

Detailed description: Burn injuries represent a public health problem worldwide, ranked fourth in all injuries and are among the leading cause of disability adjusted life years in low and middle-income countries. More than in any other injury, the inflammation and catabolism associated with severe burns can exacerbate nutrient deficiencies, thereby predisposing patients to impaired immune function and increased risk of developing infectious complications, organ dysfunction, and death. Consequently, over the last few decades numerous trials have evaluated the impact of different nutrition/nutrient strategies in severe burns patients. Glutamine is of particular interest in this regard as it appears vital for a number of key stress-response pathways in serious illness. The existing randomized trials of glutamine supplementation in burns patients have suggested a significant reduction in mortality, infection, and hospital length of stay. However, in other critically ill patient populations, there is a signal of increased mortality associated with glutamine administration. Given this conflicting evidence, burn practitioners are either harming or saving lives with glutamine use. We hypothesize that the inexpensive therapeutic strategy tested in this multicenter randomized controlled clinical trial of supplemental enteral glutamine in 1200 severe burn injury patients will lead to lower morbidity and mortality and reduced health care costs in an otherwise very devastating and disabling injury worldwide.

In our pilot study (Critical Care Medicine, 2003, 31:2444) we found a protective effect of glutamine against blood infection in severely burned adult patients. In addition, a significant decrease in mortality was observed with glutamine. These results should be tested with a multi-center trial because our study was small and did not have mortality as an end point.

The specific aims of the study are to determine the overall treatment effect and safety of glutamine in burn patients. Clinical outcomes will be: mortality, time to discharge alive, incidence of acquired bacteremia due to Gram negative organisms, hospital mortality, duration of mechanical ventilation, ICU stay and hospital stay. The cost-effectiveness of glutamine administration will also be measured if the results show a decrease in length of care or a reduced incidence of acquired bacteremia due to Gram negative organisms with glutamine.

The study will be a large, multicenter, double-blind, pragmatic, randomized controlled trial of 1200 patients with severe burns randomly allocated to receive enteral glutamine or placebo. Randomization will be concealed and stratified by site allocating patients 1:1 to either glutamine or matching placebo by the method of permuted blocks of random undisclosed size within strata. Patients will be adults, a minimum of 18 years old, with deep 2nd and/or 3rd degree burns requiring grafting, and for patients age 18 - 39 years a (Total Body Surface Area) TBSA burn ≥ 20% or in the presence of an inhalation injury a minimum of 15% TBSA burn is required; for patients age 40 - 59 years a TBSA burn ≥ 15% is required; for patients aged 60 years or older a TBSA burn ≥ 10% is required. The study will include approximately 80 burn centers in Canada, the US, Europe and Latin America. Patients will receive glutamine or a placebo through their feeding tube, every 4 hours or TID or QID if taking things by mouth, for a total of 0.5 g/kg/day for patients with a BMI \<35. Patients with a BMI ≥35 will receive 0.5 g/kg/day based on an obesity-adjusted body weight. The study intervention will be administered until ≥7 days after the last successful grafting operation or until discharge from acute care unit or 3 months from admission, whichever comes first. Resuscitation, nutritional support, pain management, infection control and surgical care will be done according to standardized procedures.

The Data will be collected and managed by a professional and centralized organization for multi centres clinical research (Clinical Evaluation Research Unit, Kingston, Ontario, Canada).

Eligibility criteria: Inclusion Criteria:

1. Deep 2nd and/or 3rd degree burns requiring grafting
2. Patient meets one of the following 4 criteria:

   1. Patients 18 - 39 years of age with ≥ 20% TBSA\* burn
   2. Patients 18 - 39 years of age with ≥ 15% TBSA\* burn and with inhalation injury
   3. Patients 40 - 59 years of age with ≥ 15% TBSA\* burn
   4. Patients ≥ 60 years of age ≥ 10% TBSA\* \*TBSA - Total Body Surface Area

Exclusion Criteria:

1. \> 72 hrs from admission to ICU to time of consent.
2. Patients younger than 18 years of age.
3. a) Patients without known renal disease and renal dysfunction defined as a serum creatinine \>171 µmol/L or a urine output of less than 500 mL/last 24 hours (or 80 mL/last 4 hours if a 24 hour period of observation is not available).

   b) Patients with acute on chronic renal failure (pre-dialysis) with an absolute increase of \>80 µmol/L from baseline or pre-admission creatinine or a urine output of \<500 mL/last 24 hours (or 80 mL/last 4 hours).

   c) Patients with chronic renal failure on dialysis will be excluded.
4. Liver cirrhosis - Child-Pugh class C liver disease
5. Pregnant or lactating females.
6. Contra-indication for EN: intestinal occlusion or perforation, intra-abdominal injury.
7. Patients with injuries from high voltage electrical contact.
8. Patients who are moribund (not expected to survive the next 72 hours).
9. Patients with extreme body sizes: BMI \< 18 or \> 50
10. Enrollment in another industry sponsored ICU intervention study.
11. Received glutamine supplement for \> 24 hrs prior to randomization
12. Known allergy to maltodextrin, corn starch, corn, corn products or glutamine.

Primary outcomes:
measure: Time to Discharge Alive
timeFrame: 3 months
Secondary outcomes:
measure: 6 Month Mortality
timeFrame: 6 Months
Other outcomes:
measure: Health-Related Quality of Life - in particular the physical function domain of the SF-36, ADL, and IADL questionnaires.
timeFrame: 6 Month
measure: Incidence of acquired bacteremia due to Gram negative organisms
timeFrame: 3 Months
measure: Hospital Mortality
timeFrame: 3 Months
measure: Duration of Mechanical Ventilation
timeFrame: 3 months
measure: ICU Stay
timeFrame: 3 Months
measure: Hospital Stay
timeFrame: 3 Months
Locations:
city: Mobile
country: United States
facility: University of South Alabama Medical Center
state: Alabama
city: Phoenix
country: United States
facility: Arizona Burn Center at Maricopa Medical Center
state: Arizona
city: Los Angeles
country: United States
facility: Southern California Regional Burn Ctr at LAC & USC Med. Ctr.
state: California
city: Sacramento
country: United States
facility: Shriners Hospitals for Children Northern California
state: California
city: Aurora
country: United States
facility: Department of Anesthesiology, University of Colorado
state: Colorado
city: Greeley
country: United States
facility: North Colorado Medical Center - Banner Health
state: Colorado
city: Bridgeport
country: United States
facility: Connecticut Burn Center
state: Connecticut
city: Washington
country: United States
facility: The Burn Center at Washington Hospital Center
state: District of Columbia
city: Gainesville
country: United States
facility: Shands Burn Center at the University of Florida
state: Florida
city: Tampa
country: United States
facility: University of South Florida/Tampa Gen. Hosp. Reg. Burn Center, FL
state: Florida
city: Augusta
country: United States
facility: Joseph M Still Burn Center
state: Georgia
city: Iowa City
country: United States
facility: Department of Surgery University of Iowa Hospitals & Clinics
state: Iowa
city: Saint Louis
country: United States
facility: Mercy Hospital St. Louis
state: Missouri
city: Lincoln
country: United States
facility: CHI St.Elizabeth Regional Burn Center
state: Nebraska
city: Omaha
country: United States
facility: The Nebraska Medical Center
state: Nebraska
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Akron
country: United States
facility: Akron's Children's Hospital, Paul & Carol David Foundation
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexnar Medical Center
state: Ohio
city: Portland
country: United States
facility: Legacy Emmanuel Hospital & Health Center
state: Oregon
city: Pittsburgh
country: United States
facility: The Western Pennsylvania Hospital Burn Center
state: Pennsylvania
city: Memphis
country: United States
facility: Firefighters' Regional Burn Center TN, University of Tennesse Health & Sciences Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Fort Sam Houston
country: United States
facility: JBSA Fort Sam Houston
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: Memorial Hermann/UTHSC
state: Texas
city: Seattle
country: United States
facility: Harbourview Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Columbia-St. Mary's, Milwaukee, Wi
state: Wisconsin
city: Graz
country: Austria
facility: Medical University of Graz
state: Styria
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Liège
country: Belgium
facility: University Hospital of Liège
city: São Paulo
country: Brazil
facility: The Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Hamilton
country: Canada
facility: HHS/Hamilton Firefighters Burn Unit
state: Ontario
city: Toronto
country: Canada
facility: Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: CHUM/Centre des Grands Brules
state: Quebec
city: Quebec
country: Canada
facility: HEJ/Centre des Grands Brules
city: Santo Domingo
country: Dominican Republic
facility: Instituto Tecnologico de Santo Domingo
city: Aachen
country: Germany
facility: RWTH Aachen University
state: North Rhine-Westphalia
city: Ludwigshafen
country: Germany
facility: Berufsgenossenschaftliche Unfallklinik Ludwigshafen
state: Rhein
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino
state: TO
city: Asunción
country: Paraguay
facility: Centro Nacional de Quemaduras y Cirugia Reconstructiva
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital, Divison of Trauma Surgery, Mahidol University
state: NOI
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital Chulalongkorn University
state: Pathumwan
city: Mueang Nonthaburi
country: Thailand
facility: Khon Kaen University
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
state: Edgbaston
city: Liverpool
country: United Kingdom
facility: St Helens & Knowsley Teaching Hospitals
state: England
city: London
country: United Kingdom
facility: Chelsea and Westminster Hospital
state: England
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals
state: England
city: Manchester
country: United Kingdom
facility: Manchester University NHSFT
state: London
city: London
country: United Kingdom
facility: Pinderfields Hospital, Mid Yorkshire NHS Trust
state: West Yorkshire
Study officials:
affiliation: Queen's University
name: Daren Heyland, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Garrel D, Patenaude J, Nedelec B, Samson L, Dorais J, Champoux J, D'Elia M, Bernier J. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med. 2003 Oct;31(10):2444-9. doi: 10.1097/01.CCM.0000084848.63691.1E.
citation: Zhou YP, Jiang ZM, Sun YH, Wang XR, Ma EL, Wilmore D. The effect of supplemental enteral glutamine on plasma levels, gut function, and outcome in severe burns: a randomized, double-blind, controlled clinical trial. JPEN J Parenter Enteral Nutr. 2003 Jul-Aug;27(4):241-5. doi: 10.1177/0148607103027004241.
citation: Peng X, Yan H, You Z, Wang P, Wang S. Effects of enteral supplementation with glutamine granules on intestinal mucosal barrier function in severe burned patients. Burns. 2004 Mar;30(2):135-9. doi: 10.1016/j.burns.2003.09.032.
citation: Heyland DK, Wibbenmeyer L, Pollack J, Friedman B, Turgeon AF, Eshraghi N, Jeschke MG, Belisle S, Grau D, Mandell S, Velamuri SR, Hundeshagen G, Moiemen N, Shokrollahi K, Foster K, Huss F, Collins D, Savetamal A, Gurney JM, Depetris N, Stoppe C, Ortiz-Reyes L, Garrel D, Day AG; RE-ENERGIZE Trial Team. A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries. N Engl J Med. 2022 Sep 15;387(11):1001-1010. doi: 10.1056/NEJMoa2203364. Epub 2022 Sep 9.
citation: Heyland DK, Wischmeyer P, Jeschke MG, Wibbenmeyer L, Turgeon AF, Stelfox HT, Day AG, Garrel D. A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury (The RE-ENERGIZE Trial): a clinical trial protocol. Scars Burn Heal. 2017 Dec 12;3:2059513117745241. doi: 10.1177/2059513117745241. eCollection 2017 Jan-Dec.