A RandomizEd Trial of ENtERal Glutamine to MinimIZE Thermal Injury: A multicenter Pragmatic RCT (definitive study) Study Sponsor Dr. Daren Heyland Clinical Evaluation Research Unit Project Leader: Maureen Dansereau

Protocol: Version 31 August 2015 Site Investigators re-Training for Definitive Study

R EN glutamine Maltodextran placebo Concealed Stratified by site Double blind treatment A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury 6 month mortality 2700 patients with TBSA ≥ 20% if yrs age ≥ 15% if yrs age with inhalation injury ≥ 10% if ≥ 60 yrs age

Canada: 8 United States: 38 Australia: 2 Israel: 1 Sweden: 1 Italy: 1 Serbia: 1 Greece: 2 Spain: 3 France: 1 Germany: 1 Total Sites: 59 sites worldwide!

Major Changes from Pilot to Definitive Renal Dysfunction added as an exclusion criteria Dosing when BMI >35 kg/m 2 based on an adjusted body weight Maximum treatment duration reduced to 3 months Quality of life assessments added at 6 months Microbiology – only collecting data on Gram negative bacteremias No Infection Adjudication to be completed New Term: ACU (Acute Care Unit) One term to include both Burn Unit and ICU

Study Flow Overview 72 hours from ACU admission to time of consent 2 hours from randomization to start of IP 3 month maximum treatment period –Dosing from randomization to: 7 days post last successful grafting or ACU discharge or 3 months from ACU admission, whichever comes first 6 month survival and quality of life follow-up

6 month < 72 h (ACU admission to time of consent) ACU Admission Consent Obtained Randomization First Dose of IP 2 h < 74 hours Dosing until 7 days after last graft up to 3 mos. Mortality assessment Data collection from ACU admission to 10 days after last graft up to 3 mos. 3 mos. Maintain regular contact SF-36 Quality of Life Assessment Activities of Daily Living Instrumental Activities of Daily Living Employment Status Assessment 6 month follow-up Study Overview

Inclusion Criteria - Definitive Study Deep 2nd and/or 3rd degree burns requiring skin grafting. One of the following: –Patients age 18 – 59 years with a burn of ≥ 20% TBSA (Total Body Surface Area) –Patients age 18 – 59 years with a burn of ≥ 15 % TBSA when concomitant inhalation injury is present. –For patients aged 60 years or older we require a burn of ≥10% TBSA. No Change Inhalation Injury – diagnosis requires both of the following: 1)History of exposure to products of combustion 2)Bronchoscopy revealing one of the following below the glottis: a)evidence of carbonaceous material b)signs of edema or ulceration

Exclusion Criteria - Definitive Study 1. >72 hrs from admission to ACU (Acute Care Unit) to time of consent 2. Patients younger than 18 years of age (age of maturity for an eligible patient to obtain consent is 18 years in Canada and in the US) 3.Renal Dysfunction as defined below:  In patients without known renal disease, renal dysfunction defined as a serum creatinine >171 μmol/L or >1.93 mg/dL or 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).  In patients with acute on chronic renal failure (pre-dialysis), an absolute increase of >80 μmol/L or >0.9 mg/dL from baseline or pre-admission creatinine or a urine output of <500 ml/last 24 hours (or 80 ml/last 4 hours) will be required.  Patients with chronic renal failure on dialysis will be excluded. Changed to REDOXS criteria to address reviewer’s concerns NEW

Exclusion Criteria cont. – Definitive Study 4. Liver cirrhosis -Child’s class C liver disease 5. Pregnancy (urine/blood tests for pregnancy will be done on all women of childbearing age by each site as part of standard ACU practice) 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 50 kg/m Enrolment in another industry sponsored ACU intervention study (co- enrollment in academic studies will be considered on a case by case basis) 11. Received glutamine supplement for > 24 hrs prior to randomization 12. Known allergy to maltodextrin, corn starch, corn, corn products or glutamine Removed 6. Patients admitted > 48 hours post burn (removed)

Investigational Product and Dosing Glutamine or Maltodextrin  Patient’s with BMI > 35 kg/m 2 will be dosed on an adjusted body weight based on a BMI of 25 kg/m 2.  Calculation used to obtain obesity adjusted body weight is: Adjusted Body Weight (ABW) = Ideal Body Weight (IBW ) + [(pre-burn dry weight – IBW) x 0.25] 0.5g/kg/day based on pre-Burn Dry Weight If BMI > 35 kg/m 2 patient is dosed on *Adjusted Body Weight

Primary Outcome: 6 month mortality Secondary Outcome: Time to discharge alive Teritiary Outcomes: Health-related quality of life 6 months) Incidence of acquired bacteremias due to Gram negative organisms Hospital Mortality Duration of mechanical ventilation ACU stay and hospital stay Outcomes

6 Month Follow-up Assessments SF-36 – Short Form 36 quality of life survey ADL – Activities of Daily Living IADL – Instrumental Activities of Daily Living Employment Status

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