A RandomizEd Trial of ENtERal Glutamine to MinimIZE Thermal Injury Study Sponsors Dr. Paul Wischmeyer (US) Dr. Dominique Garrel (Canada) Clinical Evaluation Research Unit Director: Dr. Daren Heyland Project Leader: Rupinder Dhaliwal Project Assistant: Maureen Dansereau

Why are we doing this trial? Look at the literature on glutamine in burn injury

META ANALYSIS Effect of glutamine on INFECTIONS

META ANALYSIS: Effect of glutamine on LOS

META ANALYSIS: Effect of glutamine on mortality The effects of glutamine on infectious morbidity and mortality in burn patients have not been determined in a large study

Hypotheses In adult subjects with severe thermal burn injuries enteral glutamine : 1) decreases in-hospital mortality 2) decreases infectious morbidity and shortens length of care in adult subjects with severe thermal burn injuries 3) decreases the cost of care of adult subjects with severe thermal burn injuries

1. Recruitment rate 2.Compliance with experimental procedure 3. Compliance with data collection and transfer to the Coordinating Centre (CERU) Objectives (Pilot Study)

200 patients with TBSA ≥ 20% Randomized within 48 hrs of admission L- glutamine enteral Placebo (maltodextrin) Study Design

Pharmacist Checking allocation Dispensing Logs RE-ENERGIZE Teamwork Study Coordinator Regulatory Screening/Randomization Pharmacy communication Data collection Study intervention monitoring Collaboration with SI SAE reporting Protocol Violation reporting Dietitian Optimizing nutrition Monitoring Adequacy Site Investigator Regulatory Inclusion/exclusion criteria Burn outcome assessment ICU infection adjudication SAE reporting

Study Intervention MALTRIN® Maltodextrin OR Enteral glutamine (0.5 gm/kg/day) or maltodextrin will be given through the feeding tube, qx4h until 7 days post last successful graft Imp Manual p 14

Study Overview Imp Manual p 8

Inclusion Criteria Imp Manual p 12 Study Tools/CRF Inclusion criteria: all criteria 1, 2 and 3 must be met for patient to be eligible Assessed by the burn surgeon (clinical judgment, Lund Browder) soon before randomization

Exclusion Criteria Imp Manual p 13 Tools/CRFs Exclusion criteria: patient is ineligible if any one of the following is met product to be given soon after injury urine tests as standard of care 96 hrs if resuscitation before ICU admission (per Site Investigator) Consent 24 hrs from admit NPO not an exclusion

To minimize any potential contamination, patients that have received glutamine supplements for >24 hrs before randomization, should NOT be included Imp Manual p 13

Investigational Product Dosing of Glutamine Pharmacy Procedures

Study Intervention MALTRIN® Maltodextrin Imp Manual p OR

Intervention to start ASAP –within 48 hrs-50 of admission to ICU –within 2 hrs of randomization To be administered by RN as a bolus infusion via: –NG/feeding tube q 4 hrs –If po TID or QID (mixed in apple juice, oatmeal, pudding, etc) –NOT to be mixed with orange juice, grapefruit juice or lemonade  Product is to given regardless of whether the attending MD wants to start enteral nutrition Imp Manual p 15 supplement vs. nutrition

Delivery of Supplement  Powder is to be mixed in 50 mls water q 4 hrs by RN (sterile/tap as per standard practice for enteral nutrition) and given as a bolus. Followed by flushes  Avoid any interruptions to the daily dose. Do not hold for surgery/procedures.  Missed doses can be made up by doubling the dose at the next scheduled interval. EXCEPTION: weight < 54 kgm, upto q 8 hrs. See Dosing Chart Imp Manual p 15

Duration of Study Intervention ICU admission 7 days post last successful graft Study Intervention Randomization Imp Manual p 16 even if d/c to another unit in your facility

Missed Doses Imp Manual p 15

Pharmacy Procedures

Training and Delegation Log Imp Manual, appendix E

Ordering of Product Before trial starts, CERU will arrange for intial product to be delivered from Colorado For subsequent orders, complete Product Order/Shipment Form Imp Manual p 18

Dispensing Procedures After randomization, Research Coordinator will immediately notify the pharmacy and provide: 1.the 8 digit randomization # (automatically generated ) 2.the patient’s pre-burn weight 3.and other details required by the pharmacist i.e. patient medical record ID# Imp Manual p 19

CRS Pharmacy Login CERU to assign access to Central Randomization System (CRS) after web access log signed Pharmacist to access Central Randomization System (CRS) at: One password per pharmacy (shared amongst other pharmacy staff) Imp Manual p 19

CRS Home Screen After you Login, this is what you will see Click on RE-ENERGIZE Imp Manual p 19

CRS: Your Site On the next screen, your site name will be displayed RE-ENERGIZE your site name will be displayed here Imp Manual p 20

CRS Treatment Assignment Treatment assignment for the patient will be displayed as below: Will be displayed as Glutamine (Nutrestore) OR Placebo (Maltrin) Check the patient ID #  print off the treatment assignment  must be signed by 2 pharmacists/delegates  file in the Pharmacy Study files Imp Manual p 20

Dosing Imp Manual, appendix F

Dosing Weight Chart Imp Manual, Study Tools

Labelling Need to create a blinded label for every package Send up enough packs to last a week Repeat weekly Imp Manual p 23

Dispensing Log Imp Manual, appendix G

Accountability Logs Imp Manual, appendix H, I

Storage and Temperature Logs cool, dry area, 25  C (77  F) excursions allowed  C (59-86  F) cool, dry area, below 32  C (90  F) MALTRIN® Maltodextrin Will be asked to send logs/documentation to CERU Imp Manual p 24

Role of Dietitian Assessment of energy and protein needs Start and stop times of nutrition Standardization of nutrition Avoidance of glutamine supplements Monitoring of nutritional adequacy

Standardization of Nutrition: Dietitian Prescribed calorie ranges Prescribed protein ranges Vitamin/mineral prescription Optimization of the Delivery of Enteral Nutrition Glycemic control Arginine enriched formulas (> 6 gms arginine/L) i.e. Pivot, Perative Glutamine supplements or formulas containing any additional glutamine Imp Manual Appendix C

Feeding Intolerance/high GRVs? Imp Manual p 16

Energy and Protein Needs Timing of start and stop of EN and PN Case Report Forms p Give RD a copy

RD to calculate daily Closer to real time preferred so that action can be taken Need to refer to appendix 3 Case Report Forms p Give RD a copy at least for 1 week after EN stopped

Case Report Forms appendix p 3 Give RD a copy R Coordinator to enter in CRFs

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