The RE-ENERGIZE Study: RandomizEd Trial of ENtERal Glutamine to minimIZE Thermal Injury (RE-ENERGIZE)

• ClinicalTrials.gov Identifier: NCT00985205
• Recruitment Status: Recruiting
• First Posted: September 28, 2009
• Last Update Posted: May 14, 2020
• Sponsor: Daren K. Heyland
• Collaborator: Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): Daren K. Heyland, Clinical Evaluation Research Unit at Kingston General Hospital

Tracking Information

• First Submitted Date: September 25, 2009
• First Posted Date: September 28, 2009
• Last Update Posted Date: May 14, 2020
• Actual Study Start Date: December 2010
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 3, 2019): Time to Discharge Alive [ Time Frame: 3 months ]
• Original Primary Outcome Measures (submitted: September 25, 2009): Hospital mortality recorded until complete healing, defined as 7 days after the last grafting procedure [ Time Frame: 3 years ]
• Current Secondary Outcome Measures (submitted: May 3, 2019): 6 Month Mortality [ Time Frame: 6 Months ]

Original Secondary Outcome Measures (submitted: September 25, 2009)

• 6 month mortality [ Time Frame: 6 months ]
• Incidence of infections [ Time Frame: 36 months ]
• Length of Care [ Time Frame: 36 months ]
• Length of mechanical ventilation [ Time Frame: 36 months ]
• APACHE & SOFA score [ Time Frame: 36 months ]
• Length of ICU stay [ Time Frame: 36 months ]

Current Other Pre-specified Outcome Measures (submitted: July 28, 2017)

• Health-Related Quality of Life - in particular the physical function domain of the SF-36, ADL, and IADL questionnaires. [ Time Frame: 6 Month ]
• Incidence of acquired bacteremia due to Gram negative organisms [ Time Frame: 3 Months ]
• Hospital Mortality [ Time Frame: 3 Months ]
• Duration of Mechanical Ventilation [ Time Frame: 3 months ]
• ICU Stay [ Time Frame: 3 Months ]
• Hospital Stay [ Time Frame: 3 Months ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Burns

Intervention

• Dietary Supplement: Enteral Glutamine
  0.5g/kg/day powdered glutamine to be mixed in with water and given via nasogastric or feeding tube q4 hrs or TID or QID if po.
  Other Name: Glutamine
• Dietary Supplement: Placebo
  Maltodextrin mixed with water given via NG or feeding tube Q 4 hours or TID or QID if po.
  Other Name: Maltodextrin

Study Arms

• Experimental: Enteral Glutamine
  0.5 g/kg/day mixed in water and given via nasogastric or feeding tube as boluses q 4 hrs or TID or QID if po
  Intervention: Dietary Supplement: Enteral Glutamine
• Placebo Comparator: Placebo
  Mixed in with water and given via nasogastric or feeding tube as boluses q 4hrs or TID or QID if po
  Intervention: Dietary Supplement: Placebo

Publications *

• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 3, 2019): 1200
• Original Estimated Enrollment (submitted: September 25, 2009): 200
• Estimated Study Completion Date: December 2021
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Maureen Dansereau; 613 549 6666 ext 6686; maureen.dansereau@kingstonhsc.ca

Contact: Daren Heyland, MD; dkh2@queensu.ca

• Listed Location Countries: Belgium, Canada, Dominican Republic, Germany, Mexico, Paraguay, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: Australia

Administrative Information

• NCT Number: NCT00985205
• Other Study ID Numbers: RE-ENERGIZE; CIHR # 190808 ( Other Grant/Funding Number: CIHR )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Daren K. Heyland, Clinical Evaluation Research Unit at Kingston General Hospital
• Study Sponsor: Daren K. Heyland
• Collaborators: Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: Daren Heyland, MD; Queen's University

• PRS Account: Clinical Evaluation Research Unit at Kingston General Hospital
• Verification Date: May 2019