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

Research Coordinator Training Protocol Version: 31 August 2015

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

ICH Definition of Consent “A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.” Obtaining Informed Consent

Procedures when obtaining consent for RE-ENERGIZE patients  Physician/delegate provide update on patient’s condition to SDM  Physician/delegate introduce RC to SDM to discuss consent  RC find a quiet, private location to review study details with SDM  Fully inform SDM of all aspects of the study  Assess if language barriers – enlist a translator if necessary  Do Not coerce SDM to provide consent for patient to participate  Provide a copy of the ICF to SDM and allow time to read  Ask questions to ensure SDM understands  Sign and obtain SDM signature on ICF  Record date and time consent was obtained  Provide SDM with a copy of the signed ICF  Document consent & file copy of signed ICF in patient’s medical chart  File original signed ICF with the study-related documentation

After consent obtained

Enter all patients into Central Randomization System that: meet inclusion criteria –Even if they meet an exclusion criteria –Even if you did not get consent Screening Log - CRS

Research Coordinator to access CRS to enter Screening data at: One password per Research Coordinator (DO NOT SHARE!) CERU to assign access to Central Randomization System (CRS) after web access log signed CRS Login/Screening Log

After you Login, this is what you will see Click on “RE-ENERGIZE – Definitive” REENERGIZE - Definitive CRS Home Screen

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

To enter data for a new patient, select the Add patient link. “Q” = Screened “R” = Randomized R- 001 Site# Patient# CRS: Adding Patient

Click the Inclusion Criteria and complete the fields in the form as appropriate CRS Inclusion Criteria

Inclusion Criteria 1)Deep 2nd and/or 3rd degree burns requiring skin grafting. 2)One of the following:  Patients 18 – 59 years of age with a TBSA ≥ 20%  Patients 18 – 59 years of age with a TBSA > 15 % WITH an inhalation injury*  Patients > 60 years of age with a TBSA ≥ 10%. Diagnosis of *inhalation injury requires both of the following: 1) history of exposure to products of combustion 2) bronchoscopy revealing one of the following below the glottis  evidence of carbonaceous material  signs of edema or ulceration

Complete the exclusion criteria fields as appropriate CRS Exclusion Criteria

Exclusion Criteria 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.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.

Exclusion Criteria cont… 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

CRS Pre-Randomization Patient/SDM was NOT approached for Consent Indicate the primary reason the patient or SDM was not approached for consent

If consent is NOT obtained CRS Pre-Randomization

If consent IS obtained, YYYY-MM-DD format Times: 24-hour (military) clock, must use colon (:) to be saved CRS Pre-Randomization

CRS Randomization Contact Pharmacist and inform them of the following: Patient enrollment number (8 character I.D.) Pre-burn weight (in kg) Any other patient details requested by the pharmacist (patient medical ID#) Print a copy of the Randomization Web Form

Listing of all patients screened and randomized at your site Click on the pt # to review data Screening # : assigned to all patients entered in the CRS Enrollment #: only patients that are randomized Site Status Page

Indicates the status of each data entry form for the patient StatusSymbolDescription CompletedAll data has been completed and saved. Not CompletedData has not yet been entered on the fm. LockedThe patient has been randomized and the data is no longer able to be edited by the site user. Patient Status Page

Document in chart – make sure Investigator signs Study Orders

DATA COLLECTION REDCap is the data capture system for the study Worksheets are provided to assist in collecting the date to be entered.

PATIENTS AUTOMATICALLY POPULATED

electronic Case Report Form Worksheets  eCRF worksheets - are to assist you in collecting required data  Medical Chart - is the source document o Exception: 6 Month Follow-up Questionnaires worksheets are the source documents – need to keep  Instructions - are in the eCRF worksheets and must be reviewed  Data Entry - is done in REDCAP ™ and forms may look different

Contact Information Obtain as much contact information as possible. This will aid in obtaining 6 month follow-up data.

Rules: Data Collection Study days are defined as follows calendar days: Study Day 1 = ACU admit date/time (not randomization) until 23:59 the same day. Study Day 2 = the following day 00:00 to 23:59 Data must be collected according to study days Example: A patient is admitted to the ACU at 4:00 PM (16:00). Study Day 1 is from 16:00 to 23:59 that day

Inhalation Injury Diagnosis requires : 1) history of exposure to products of combustion 2) bronchoscopy revealing one of the following below the glottis Evidence of carbonaceous material Signs of edema or ulceration

High Dose Vitamin C as part of Resuscitation Common practice is: 66mg/kg/hr for the first 24 – 48 hours (above is a guide not a requirement) Do not report standard Vitamin C dosing

Select comorbidities from the list provided. If no comorbidities per the list, check the box titled “No Comorbidities”

Hx of Alcohol Abuse Record Alcohol Abuse as a comorbidity IF documented in the patient’s medical chart.

Collected once at baseline MAP (if not available) Calculation: 1/3 lowest systolic BP + 2/3 corresponding diastolic BP Web link:

Note: Do not record episodes of temporary ventilation (defined as < 48 hrs)

Using the Lund and Browder Chart Burn Grafting Assessments Assessments to be done by the surgeon/physician and confirmed by the SI/sub-I

Lund and Browder chart

Timing of Study Intervention

From Randomization to: a)7 days post last graft b) or ACU discharge c) or 3 months from ACU admission, whichever comes first. Date: yyyy-mm-dd 1) # grams given Route  EN  PO  EN  PO  EN  PO  EN  PO  EN  PO 2) # grams given Route  EN  PO  EN  PO  EN  PO  EN  PO  EN  PO 3) # grams given Route  EN  PO  EN  PO  EN  PO  EN  PO  EN  PO 4) # grams given Route  EN  PO  EN  PO  EN  PO  EN  PO  EN  PO 5) # grams given Route  EN  PO  EN  PO  EN  PO  EN  PO  EN  PO 6) # grams given Route  EN  PO  EN  PO  EN  PO  EN  PO  EN  PO X) # grams given Route  EN  PO  EN  PO  EN  PO  EN  PO  EN  PO TOTAL grams received today Percentage of prescribed grams received today Protocol Violation  Yes  No  Yes  No  Yes  No  Yes  No  Yes  No Daily Monitoring Prescribed # _______ gm/day

Dose Related Protocol Violation

Daily: Study Days 1 – 14 Weekly: Study Days 15 – 90 From ACU admit to: a)10 days post last graft b) or ACU discharge c) or 3 months from ACU admission, whichever comes first. Daily/Weekly Laboratory Data WBCs – if only one for the day record as both highest and lowest Highest or lowest as indicated Glucose: closest to 8:00 A.M.

Obtain from dietitian Or team member responsible for prescribing and monitoring patients’ energy and protein needs/adequacy

Obtain from dietitian

EN Formulas List Protein Supplements List

Recorded each day a Burn Related Operative Procedure occurs From ACU admit to: a)10 days post last graft b) or ACU discharge c) or 3 months from ACU admission, whatever comes first.

Record only the medications (or type of medications) listed here. Daily from ACU admission to: a)10 days post last graft b) or ACU discharge c) or 3 months from ACU admission, whatever comes first. Do NOT record stool softeners

Record ONLY Gram negative bacteremias… …from venous or arterial blood collected > 72 hours after ACU admission Do not record results from catheter line tip specimens

Gram Negative bacteria Do NOT record Gram Positive bacteria

When any of the following occur: Investigational Product (IP) Daily dose delivered is < 80% prescribed over a 3 day average. o Report a dose related protocol violation when both of the following are true:  Dose received on the indicated day is < 80% prescribed  Dose received over a 3 day average is < 80% prescribed IP dispensing/dosing error Accidental unblinding Enrollment of a patient that does not fulfill inclusion/exclusion criteria Unapproved procedures performed Protocol Violations

Must be entered into REDCap within 24 hrs of becoming aware

 Last Successful Graft achieved & date or Reason not achieved  ACU discharge info  Hospital discharge info  If deceased – patient death date, time, & cause

6 Month Survival Primary Outcome of this Study It is vital that you use EVERY resource possible to obtain the 6 Month Survival Status of each study Patient

Record all attempts to contact the patient and document completion of the 6 Month Follow-up Questionnaires Contact Log

6-Month Follow-up Assessments  SF-36  ADL (Activities of Daily Living)  IADL (Instrumental Activities of Daily Living)  Employment Status Assessment Completed 6 months after ACU admission +/- 2 weeks

Highest functional level: What is the patient able to do? Example: If patient does not do the laundry, but is able, indicate level of ability.

SAEs Given the high acuity of diseases and morbidity related to burns, adverse events are NOT to be reported to CERU, only report Serious Adverse Events (SAEs). SAE: Adverse and Serious Life threatening Prolongs Hospital Stay Results in persistent or significant disability/incapacity Requires medical or surgical intervention Congenital anomaly/birth defect Other serious medical event Death – outcome not event Record death as an outcome Report the underlying cause of death as the SAE.

What to report REPORT All SAEs that are: 1.Unexpected (whether related to treatment or not) 2.Related to treatment (whether unexpected or not) Unexpected: Seizure is the absence of hx of seizure disorder Related: Caused by the study intervention

RELATIONSHIP TO INTERVENTION Must be determined by SI

Resources online