1. 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 European Partner: Dr. Michael Chourdakis European Project Leader: Eirini Kasapidou

2. Maureen Michael Eirini Daren Need photo of DKH here

4. www.criticalcarenutrition.com

5. Double blind treatment A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury R EN glutamine Maltodextran placebo Concealed Stratified by site 6 month mortality 2700 patients with TBSA ≥ 20%, if 18-59 yrs age ≥ 15%, if 18-59 yrs age with inhalation injury ≥ 10%, if ≥ 60 yrs age

6. Why are we doing this trial?

7. The Clinical Significance of Burn Injuries » Worldwide, burn injuries represent a significant public health problem. » Ranked the fourth most common injury. » Leading cause of disability adjusted life years in low and middle-income countries. » Mortality from burn injuries has plateaued and the leading cause of death from burn injuries continues to be sepsis and multiple organ failure. » Burn patients present with up to a 3-fold higher prevalence of sepsis than other trauma patients.

8. » The overall aim of the RE-ENERGIZE study is to reduce the burden of illness associated with significant burn injury using a naturally occurring substance, glutamine!

9. Canada: 8 United States: 32 UK: 4 Italy: 1 Serbia: 1 Greece: 3 Spain: 4 Switzerland: 1 Czech Republic: 2 Romania: 1 Netherlands: 1 Portugal: 1 Total Sites: 70 sites worldwide! r Sweden: 1 Austria: 2 Belgium: 2 Germany: 6

10. < 72 h (ACU admission to time of consent) ACU Admission Consent Obtained Randomization First Dose of IP 2 h < 74 hours Dosing until 7 d after last graft up to 3 m. 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 Study Overview 6 month

11. Presentation Outline Investigator Responsibilities Patient Eligibility Obtaining Consent Randomizing a Patient o Central Randomization System (CRS) Study Intervention Nutrition Management Outcomes REDCap (Electronic Data Capture System) o Data Collection and Data Entry

12. Role of the Site Investigator Delegation of Authority Burn Grafting Assessments SAEs Investigator Responsibilities

13. Ensure subject safety is protected & well-managed Full compliance with requirements of Good Clinical Practice (GCP) Conduct the study in compliance with the protocol Role of Site Investigator

14. Acknowledge and retain responsibility for study conduct Personally conduct or supervise the clinical study Ensure that all study staff are informed of their obligations (Delegation of Authority) Maintain records of staff qualifications Ensure that mechanisms are in place to ensure that site staff receive the appropriate information throughout the study Ensure that appropriate medical coverage is identified for any planned absences (holiday, attending a conference, etc.) Allow monitoring, auditing & regulatory inspections Notify CERU asap of any planned regulatory inspections Interact with the CERU monitor during monitoring visits Investigator Responsibilities

15. Site Investigator/sub-I delegate must make the following determinations and sign/date applicable documents, whether in the patient chart or on a study specific form, to indicate he/she made the assessment: 1)Confirmation of patient eligibility 2)SAE Identification & Assessment Ensure adherence to reporting requirements & timelines Provide causality assessment Determine relationship to investigational product 3)Severity of Burn and Grafting Assessments Highlighted Responsibilities

16. Delegation of Authority Logs “The Investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties” (ICH section 4.1.5) Complete log and send to CERU before start of trial. Each team member to must be trained on the study before performing any study related, delegated tasks.

17. Delegation of Authority Logs

18. Assessments to be done by the surgeon/physician using the Lund and Browder chart SI/sub-I must confirm all assessments. REMINDER: Area expected to require grafting cannot be zero – this is an inclusion criterion! Initial Grafting Assessment

19. Assessments to be done by the surgeon/physician and confirmed by the SI/sub-I Use the Lund and Browder Chart If Last Successful Graft was not achieved, indicate the reason Final Grafting Assessment

20. Initial Grafting Assessment Deep Partial/Full Thickness Burn expected to require grafting: __________%TBSA Record only the %TBSA you expect to graft. This may be a small percentage of the total burn size. There is no minimum, however this cannot be zero and should not be greater than the total burn size. Final Grafting Assessment Total Body Surface Area that actually required grafting: __________%TBSA Record the %TBSA you actually grafted. This may be zero if the patient healed without needing an expected graft. There is no minimum or maximum, however this should NOT be 100%. GRAFTING ASSESSMENTS: Important Note Grafting assessments are record as percent Total Body Surface Area (%TBSA).

21. Lund and Browder chart

22. Any untoward medical event that : Results in death, Is life-threatening, Requires hospitalization or prolongation of hospitalization, Results in disability/incapacity, Is a congenital anomaly/birth defect, A medically important event (e.g. one that may result in an intervention to prevent one of above outcomes) Serious Adverse Events (SAEs)

23. 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 Serious Adverse Events (SAEs)

24. Unexpected event - is NOT expected due to the progression of the underlying disease or co-morbid illnesses. Example: Seizure in the absence of seizure disorder Not all deaths – only unexpected. Related to the Study Intervention defined as: Possibly Related: suggests that the association of this SAE with the study supplement is unknown and the event is not reasonable supported by other conditions. Probably Related: suggests that a reasonable temporal sequence of this SAE with study supplement administration exists and the association of the event with the study supplement seems likely. Report SERIOUS Adverse Events that are: 1. Unexpected – regardless of relationship to intervention 2. Related to Intervention – regardless of expectedness SAE Identification

25. Do not report death as an SAE. Death – is an outcome not an event If a reportable SAE results in death, record death as the outcome and the underlying cause of death as the SAE. Not all deaths needed to be reported Do not report expected events that lead to death. Example: Patient with severe burns develops sepsis and dies. It is not unexpected and thus does not need to be reported to CERU. NOTE: please follow local ethics requirements for reporting death and adverse events SAEs: Death

26. The relationship of the study intervention to the SAE must be determined by SI Refer to the definitions below when determining relatedness: SAE RELATIONSHIP TO INTERVENTION

27. Worksheets are provided to assist with data collection. SAEs must be completed in REDCap™ within 24 hours of becoming aware of the event. SAE Worksheets

28. Remember to de-identify any supporting documentation that is scanned or faxed to the central study team. SAE Worksheets (cont.)

29. You may report up to 3 SAEs per day in REDCap. If you have more than 3 SAEs to report on any given day, contact the Project Leader. Click on the down error in the box on the grid on the specified day to reveal SAE forms. Record SAEs on the grid on the day the SAE occurred, not the day you are reporting it. SAEs in REDCap

30. Return to the same form to update data as it becomes available. Indicate the report status as updates are provided. SAEs in REDCap (cont.)

31. A subject may be withdrawn from IP at any time: at Substitute Decision Maker or her/his own request, or at the discretion of the investigator for safety, behavioral or administrative reasons. A subject may withdraw (or be withdrawn) from the study prematurely for the following reasons: Serious Adverse Event related to intervention Termination of the study by the sponsor Other (must be specified) Subject Withdrawal

32. Patient Eligibility Inclusion criteria Exclusion criteria Inhalation Injury Co-Enrollment Using your judgement

33. 1)Deep 2nd and/or 3rd degree burns requiring skin grafting*. *Note: there is no minimum area that requires grafting. As long as the total burn size meets the inclusion criteria and a graft is required, the patient is eligible. 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 Inclusion Criteria

34. Definitive Study: Exclusion Criteria 1. >72 hrs from admission to ACU (Acute Care Unit) to time of consent (>24 hrs from injury to admission also excluded – in SPM) 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. Changed to REDOXS criteria to address reviewer’s concerns

35. 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 2 10. 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 Also exclude patients you judge not able to follow up at 6 months (e.g. illegal aliens, homeless, etc.) Definitive Study: Exclusion Criteria

36. Obtaining Consent Informed Consent: ICH Definition Communication Location Time for Questions Signature and Date Documentation

37. 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.” What is Informed Consent?

38.  Treating physician/delegate provide update on patient’s condition to SDM (Substitute Decision Maker)  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 Consent Procedures for RE-ENERGIZE

39. Document patient participation in the medical chart, including: Study Name Eligibility was confirmed Physician who confirmed eligibility (must be on the Delegation Log) Date and Time consent was obtained Who provided consent (patient, spouse, child, etc.) Who obtained consent (PI, sub-I, nurse, etc.), signed & dated Documenting consent obtained

40. After obtaining consent, get the Contact Information Form completed. This will aid in obtaining 6 month follow-up data. Collect as much contact information as possible 6 Month mortality is the Primary Outcome Contact Information

41. Randomizing a Patient Central Randomization System (CRS) Access and Login CRS as a Screening Log Form Completion Eligible bit Not Consented Randomization Confirmation

42. CRS Access Log 1.Complete the CRS access Log 2.Send completed log to CERU (via email preferred) Each study team member needs her/his own login. Do not share.

43. Access the CRS (Central Randomization System) at: https://ceru.hpcvl.queensu.ca/CRS/. You will receive an email with your username and temporary password after the completed CRS Access Log is received CRS Login Login to enter screening data and randomize patients.

44. Enter all screened patients, who meet the inclusion criteria into the CRS: Even if they meet an exclusion criteria Even if you did not get consent CRS Screening: who to enter

45. After you Login, you will see a list of studies you are participating in with CERU using the CRS: Click on “RE-ENERGIZE – Definitive” CRS Home Screen How to Randomize your patient

46. To enter data for a new patient, select “Add patient” Hid e CRS: Adding a Patient

47. Click Inclusion Criteria and complete the fields in the form When you click the ‘Save’ button you will be taken to the next form CRS: Inclusion Criteria

48. Complete the exclusion criteria form CRS: Exclusion Criteria

49. CRS: Pre-Randomization If the patient is eligible and Patient/SDM was not approached for Consent Indicate the primary reason you did not approach for consent

50. If you approach for consent and consent is NOT obtained Indicate the primary reason consent was not obtained CRS Pre-Randomization

51. When consent IS obtained, complete the Pre-Randomization form Enter Times per 24-hour clock. If time is before 10:00, you must enter a leading zero. Enter dates in YYYY-MM-DD format, or click in the date box to open the calendar CRS Pre-Randomization Indicate if height and weight were ‘measured’, ‘estimated’, or you don’t know how they were obtained

52. After clicking ‘Save’ on the bottom of the Pre-Randomization form, you will receive a Randomization Confirmation Print the page File it with your study records Contact your pharmacy CRS Randomization Confirmation

53. Randomization and Screening Numbers Every patient entered into the CRS will have a Screening Number Each patient randomized will also have a Randomization Number Number format: First 4 digits = your site number 5 th alpha character indicates Screened or Randomized Last 3 digits = ascends sequentially starting with 001 Screening and randomization numbers advance independently Example in the table above: Screening #: 1002Q006 Randomization #: 1002R003 This is the 6 th patient screened and 3 rd randomized “Q” = Screened “R” = Randomized 1002 - R- 001 Site# Patient#

54. This page lists all patients screened and randomized at your site. Site Status Page To view any patient in the list, click on the corresponding: Screening ID or Status

55. 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 form. LockedThe patient has been randomized and the data is locked (no longer able to be edited by the site user). Patient Status Page

56. Investigational Product (IP) Supply and package appearance Dosing Study Orders – sample documentation Mixing and Administration Making up Missed Doses Changing the Prescription

57. Investigational Product The glutamine and maltodextrin will be shipped to you in 5g packets with blinding labels applied. You will need an unblinded team member (pharmacy/delegate) for IP accountability and dispensing. OR MALTRIN® Maltodextrin

58. cool, dry area, below 32  C (90  F) Storage and Temperature Logs The temperature in the IP storage area should be documented everyday. If IP is stored in an area where temperature is monitored, duplicate documentation is not required. Sample Temperature log available Product must be stored at controlled room temperature cool, dry area, 25  C (77  F) excursions allowed 15-30  C (59-86  F)

59. Temperature recorded in (circle one) Celsius Fahrenheit DateTemperatureInitialsComments DateTemperatureInitialsComments 16 1 17 2 18 3 19 4 20 5 21 6 22 7 23 8 24 9 25 10 26 11 27 12 28 13 29 14 30 15 31 Site Name ___________________________________________________Site # _____________ Investigational Product is to be stored in a cool dry area 15°- 30° Celsius / 59°- 86° Fahrenheit. Record temperature daily. Provide comment for days temperature is not recorded. Keep this log with study IP documents. To be provided to Central Pharmacy Manager/Unblinded Monitor upon request. Month _____________________Year ______________ sample Temperature Log

60. Dosage = 0.5g/kg/day of Dosing Weight Based on pre-burn dry weight Adjusted for patient’s with BMI > 35 kg/m 2 Rounded to the nearest 5g (for dispensing) IP Dosing and Administration  BMI > 35 weight will be adjusted based on a BMI of 25 using the following formula: Adjusted Body Weight (ABW) = IBW (Ideal Body Weight) + [(pre-burn dry weight – IBW) x 0.25] Administration schedule: q4h as a bolus via small bore feeding tube (preferred) or a larger bore gastric/Levine tube TID or QID via the oral route

61. Quick Reference Dosing Chart Dose # 123456q4h Body weight (kg) Number of 5g doses Total dosesg/day 35-44101011 420 45-54111011 525 55-64111111 630 65-74211111 735 75-84211211 840 85-94211212945 95-1042122121050 105-1142222121155 115-1242222221260 125-134322222 13 65 135-144323222 14 70

62. Sample Study Order Ensure the order is signed by the Site Investigator or sub-I Document Study Orders in the Chart

63. IP: Dispensing and Initiation Contact the Pharmacy delegate as soon as the patient is randomized Provide the patient Randomization number Pharmacy staff will access the CRS to view treatment allocation and dispense initial dose IP is dispensed in 5g packets IP is reconstituted and administered bedside by the clinical staff IP should be initiated even if enteral nutrition has not been started Administer IP within 2 hours after randomization

64. Each 5g packet should be mixed with a minimum 50 mL of *water or other non-heated liquid or food, such as: Chocolate Milk Yogurt Applesauce Cereal Mashed Potatoes Do NOT mix IP with soda or highly acidic juices (grapefruit juice, orange juice, lemonade). The IP degrades or becomes unstable in an acidic medium *When mixing in water, use either sterile or tap water, per your standard procedure for mixing enteral formulas. IP Mixing and Administration

65. Interrupted or Missed Does of IP IP should be treated as a medication If at all possible, IP should continue as ordered through procedures or surgery In the event of an interruption or missed doses, you should make up the missed doses on the same calendar: Give additional doses – at least one hour apart (There must be at least one hour between dose administration) Double scheduled doses (Do not give more than double the prescribed dose at one time) Do Not stop IP for procedures or surgery

66. Step by Step IP administration procedures Place a copy at each study patients bedside Administration Procedures

67. Administration Procedures (cont.)

68. Glutamine may contribute to elevated urea levels in patients with renal dysfunction who are not on dialysis. If patient is on dialysis, study intervention should NOT be held or discontinued, regardless of Urea or Cr levels. The clinical team may choose to hold the study intervention if: o the team is uncomfortable with the urea level AND o the patient is not to be dialyzed on the same calendar day Recommended Guideline for holding intervention: o Urea/BUN >21.5 mmol/L or >60 mg/dL Restart study intervention when urea is below the threshold for holding intervention (above), at the discretion of the clinical team. IP Adjustments: Renal Dysfunction

69. IP Dosing Changes IP is based on the patient’s pre-burn dry weight Patients will remain on the initially calculated dose of IP for the duration of the study, with one exception: EXCEPTION: If the patient has a change in body weight sufficient for the clinical team to alter dosage of clinical treatments, the study treatment dose should be adjusted as well. IP does change is triggered by the clinical team changing the weight used to dose clinical treatments. Examples of events that may trigger a change in IP dosing weight: o Amputation o Greater than 10% weight loss Notify the pharmacy of any changes in IP dosing weight Document changes in the patient chart

70. The following tasks are all a part of managing the nutrition received by each of your patients: Utilizing the Standardization of Nutrition Practices Assessing Energy needs upon admission to Acute Care Unit (ACU) Assessing Protein needs upon admission to ACU Prescribing daily Calories and Protein goals Assessing Vitamin and Mineral intake and supplementation Ensuring Glutamine and Arginine supplements are not given Optimizing Enteral Nutrition Delivery Monitoring & Recording Daily Nutritional Adequacy Nutrition Management

71. To reduce the effect of varying nutritional practices as confounding factors on the outcomes of The RE- ENERGIZE study, it is important to standardize (as much as possible) the following: Prescription of Enteral and Parenteral Nutrition Micronutrient delivery Withholding Feeds for High Gastric Residual Volumes We recommend compliance with the following nutritional practices. This will allow for most current practices to continue. Standardization of Nutrition Practices

72. Calculated by using : Indirect Calorimetry, a predictive equation, or a simple weight-based formula On average, this should not lead to a prescription of less than 30 kcal/kg Weight Pre-burn dry weight should be used when calculating energy needs. For patients with a BMI > 35 kg/m 2, if your standard practice is to adjust for obesity, follow your standard practice. If you do not have an obesity adjustment practice, use the formula below. Adjusted Body Weight (ABW) = Ideal Body Weight (IBW) based on a BMI of 25 + [(pre-burn dry weight – IBW) x 0.25] 1) Prescribed Energy Needs Standardization of Nutrition Practices

73. Calculated According to % body surface area burn If > 50% burns, use 1.5g/kg/day to 2.5g/kg/day If < 50% burns, use 1.2g/kg/day to 2 gm/kg/day Pre-burn dry weight should be used when calculating protein needs. For obese patients, if your standard practice is to adjust for obesity, follow your standard practice. If you do not have an obesity adjustment practice, use the formula below. Adjusted Body Weight (ABW) = IBW (BMI 25) + [(pre-burn dry weight – IBW) x 0.25] Standardization of Nutrition Practices 2) Prescribed Protein Needs

74. Should be given as follows or depending upon blood levels (if blood testing is done as part of routine practice): Vitamin C: 0-1000 mg/day Vitamin A: 0-10,000 IU/day Vitamin D: according to serum levels Vitamin E: 0-420 mg/day Zinc (not elemental): 0-220 mg/day Copper Sulfate: 0-4.5 mg/day Selenium: 0-500 micrograms/day Magnesium:0-600 mg/day Folate: 0-1500 mg/day Thiamin: 0-110 mg/day Standardization of Nutrition Practices 3) Vitamin & Mineral Prescription

75. Early supplementation by high dose IV Vitamin C (66 mg/kg/hr) within the first 48 hrs is allowed. Standard multivitamin/mineral preparations are allowed (IV, NG or po). These ranges of vitamins/minerals/trace elements may be provided as supplementation over and beyond what is present in the standard enteral/parenteral nutrition. OR These ranges of vitamins/minerals/trace elements may be provided as the total amounts. This means that the amounts received from enteral/parenteral nutrition are to be subtracted from the total ranges and the remainder is given as supplements. Standardization of Nutrition Practices 3) Vitamin & Mineral Prescription (cont.)

76. i.Arginine enriched formulas (formulas that contain >6gms arginine/L) Pivot ® (13 g/L) Perative ® (8 g/L) would not be allowed ii.Glutamine supplements or formulas enriched with glutamine Impact ® Glutamine (15 g/L) VIVONEX ® Plus (13.5 g/L) GLUTASOLVE ® (15 g/L) /other glutamine powders Juven ® (7 g/L) Formulas with glutamic acid inherently present are allowed To minimize any potential contamination, patients that have received glutamine for >24 hrs before randomization, should NOT be included. Standardization of Nutrition Practices 4) Specialized nutritional formulas are not allowed such as:

77. Enteral nutrition is preferred over parenteral nutrition Minimize interruptions to the delivery of EN – use strategies such as: o Elevating the Head of the Bed o Gastric residual volume threshold of 250 ml o Motility agents o Small bowel feeding tubes Monitor EN volume delivery daily Implement an action plan to ensure prescription is delivered Standardization of Nutrition Practices 5) Optimization of the Delivery of Enteral Nutrition:

79. Encourage the use of a glycemic control protocol (or insulin) to: o Avoid hyperglycemia o Minimize risk of iatrogenic hypoglycemia Maintain glucose levels between the following ranges: o 80 mg/dL (min) to 180 mg/dL (max) o 4.4 mmol/L (min) to 10 mmol/L (max) Standardization of Nutrition Practices 6) Glycemic control:

80. Record Energy and Protein Needs Record Timing of Start and Stop of EN & PN

81. If the patient’s energy and protein needs change  record the date and new prescription. Record up to 6 Prescriptions

82. Case Report Form worksheets provided to aid in data collection

83. Collect and record daily nutrition received Review nutrition intake daily so action can be taken to ensure patient receives prescribed nutrition

84. ENTERAL NUTRITION: If EN was not received, indicate all of the reasons (see list below):  NPO for endotracheal extubation or intubation or other bedside procedure  NPO for operating procedure  NPO for radiology procedure  High NG drainage  Increased abdominal girth, abdominal distention, or patient discomfort  Vomiting, emesis, or nausea  Diarrhea  No enteral access available/enteral access lost, displaced, or malfunctioning  Inotropes, vasopressor requirement  Patient deemed too sick for enteral feeding  On oral feeds  Reason not known  Other, please specify: __________________ Daily Nutrition: Enteral Nutrition (EN)

85. If EN was received: Record the name of the formula(s) given Record up to 3 formulas each day. If more than 3 formulas were given, enter the 3 that provided the most volume Record the total kcals received from EN Record the total grams of protein received from EN Daily Nutrition: Enteral Nutrition (EN) (cont.)

86. If a Protein Supplement was received: Record the name of the protein supplements given Record the total kcals received from the protein supplement Record the total grams of protein received from the protein supplement Daily Nutrition: Protein Supplements

87. If PN was received: Record the total kcals received from PN Record the total grams of protein received from PN If Propofol was received for > 6 hours: Record the total volume (mL) of Propofol received If Oral Nutrition received: Record that oral nutrition was received Daily Nutrition: PN, Propofol, Oral Intake

88. If oral nutrition was given, indicate the adequacy of intake via the oral route: Daily Nutrition: Oral Intake percentages

89. Primary Outcome: 6 month mortality Secondary Outcome: Time to discharge alive Health-related quality of life (SF-36 @ 6 months) Incidence of acquired bacteremias due to Gram negative organisms Hospital Mortality Duration of mechanical ventilation ACU stay and hospital stay Teritiary Outcomes: Outcomes

90. 6 Month Survival 6 Month Mortality is the Primary Outcome of this Study It is vital that EVERY resource possible is used to obtain the 6 Month Survival Status of each study Patient If survival status is not obtained, please complete the form to confirm all attempts were made to obtain the information.

91. Use the contact log to record all attempts to contact the patient and document completion of the 6 Month Follow-up Questionnaires Contact Log

92. Following data are recorded on the Hospital Overview form: ACU discharge information Hospital discharge information If deceased – death date, time, & cause of death Hospital Overview

93. Record ACU readmission until 3 months post ACU admission to a maximum of 5 admissions (including the initial admission) Hospital Overview (cont.)

94. Note: Do not record episodes of temporary ventilation (defined as < 48 hrs) Stop date: Record actual stop date or mechanical ventilation up to study day 90 in the ACU. If transferred to another institution vented, record transfer date as ventilation stop date.

95. Record ONLY Gram negative bacteremias from venous or arterial blood. Date (yyyy-mm-dd) 1) Time (hh:mm) -Gram Negative Culture Number(s) 2) Time (hh:mm) -Gram Negative Culture Number(s) 3) Time (hh:mm) -Gram Negative Culture Number(s) 4) Time (hh:mm) -Gram Negative Culture Number(s) Do not record results from catheter line tip specimens MICROBIOLOGY

96. Do NOT record Gram Positive bacteria Gram Negative bacteria

97. SF-36 ADL (Activities of Daily Living) IADL (Instrumental Activities of Daily Living) Employment Status Assessment The following questionnaires are completed 6 months after ACU admission +/- 2 weeks: Questionnaires may be administered via a telephone call or in person. Keep the completed questionnaires with your study documents. Questionnaires may be completed over several calls or visits if necessary. NOTE: Late data is better than missing data. Please make every attempt to complete the questionnaires, even if outside of the time parameters. 6-Month Follow-up Assessments

98. Read each question and the response options to the patient. Mark the patient’s response in the corresponding box. SF-36

99. SF-36 (cont.)

103. Katz ADL

104. Record the patient’s highest functional level. What is the patient able to do? Example: If the patient does not do the laundry, but is able, indicate her/his level of ability. Lawton IADL

105. Data collected to compare pre- and post-burn employment status, and occupation. Employment Status

106. Employment Status (cont.)

110. Employment Status – occupation list

111. The following table provides a variety of patient outcome scenarios and a guide to which 6 month follow-up forms need to be completed. Guide to 6 month Follow-up forms

112. Data Collection and Entry Protocol Violations Data Collection and Entry: REDCap

113. DATA COLLECTION REDCap™ (Electronic Data Capture System) REENERGIZE - Definitive Access REDCap™ at the following web address: https://ceru.hpcvl.queensu.ca/EDC/redcap/

114. Data MUST be collected according to calendar day as described above Do NOT collect data according to your flow sheet unless it runs from 00:00-00:00 Study days are defined as follows and data must be collected according to study days: Example: A patient is admitted to the ACU on Sept 8th, 2015 at 4:00 PM (16:00). The study days would be: Study Day 1 = 2015-09-08 from 16:00 to 2015-09-08 at 23:59 Study Day 2 = 2015-09-09 from 00:00 to 2015-09-09 at 23:59 Study Day 1 = ACU admit date (not randomization) and time until 23:59 the same day. Study Day 2 = the subsequent day starting at 00:00 to 23:59 that day Study Days and Data Collection

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

116. Randomized patients auto-populate in REDCap. After randomization of the first patient, you will need to enter the lab units for your site DATA ENTRY SCREEN

117. After your first patient has been randomized: Select Arm 2 and enter lab units LABORATORY UNITS ENTRY

118. A grid with only one dot will display Select the units each of the 9 labs are reported in at your site Record Lactate from arterial blood LABORATORY UNITS GRID

119. General Instructions Complete all of the information by placing a √ in the appropriate box. Duration of Data Collection These data are to be collected once, at baseline. Laboratory Units Indicate the units each laboratory test is reported in by placing a √ in the appropriate box. T- bilirubin  mg/dL  µmol/L Glucose  mg/dL  µmol/L Lactate  mg/dL  µmol/L  mEq/L Ammonia  µg/dL  µmol/L Urea  mg/dL  µmol/L Platelets  10^3/µL  10^9/L Serum Creatinine  mg/dL  µmol/L Albumin  g/dL  g/L WBC  10^3/µL  10^9/L LABORATORY UNITS worksheet

120. PATIENTS AUTOMATICALLY POPULATE Select a patient from the dropdown list

121. Click on any dot to open the corresponding form EVENT GRID

122. EVENT GRID – NAVIGATING THE TABS

123. Outcomes and 6 Month Follow-up forms, including Survival Assessment are on the grid after Day 90. Click on the 3 rd tab at the top of the grid and scroll all the way to the right to find and complete these forms EVENT GRID – AFTER DAY 90

124.  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 Worksheets and Instructions Electronic Case Report Form (eCRF)

125. 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

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

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

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

129. MAP (if not available) Calculation: 1/3 lowest systolic BP + 2/3 corresponding diastolic BP Web link: http://www.mdcalc.com/mean-arterial-pressure-map/ Collected once at baseline

130. Date and Time first dose of study intervention administered (yyyy-mm-dd) (hh:mm) (24 hour clock) Was Study Intervention started > 2 hours after Randomization?  Yes  No If Yes, indicate the reason:  Pharmacy delay  Patient NPO for surgery  Awaiting tube placement and/or verification  Patient not available (procedure)  Nurse not available  Other (specify): ______________________________ Date and Time the last dose of study intervention administered (yyyy-mm-dd) (hh:mm) (24 hour clock) Initial Study Intervention Prescription grams/day Did the prescription change during the study?  Yes  No If Yes, record the new prescription and the date/time of the change grams/day (yyyy-mm-dd) (hh:mm) (24 hour clock) If the prescription changed again, record the new prescription and the date/time of the change grams/day (yyyy-mm-dd) (hh:mm) (24 hour clock) Timing of Study Intervention

131. Record each dose of investigational product given everyday from randomization to >7 days post last graft, discharge, or 3 months from ACU admission, whichever comes first. Prescribed # _______ gm/day Daily Monitoring

132. Record lab data Daily: Study Days 1 – 14 Weekly: Study Days 15 – 90 Date (yyyy-mm-dd) Creatinine, serum (highest) T-bilirubin (highest) Urea (highest) PaO2/FiO2 (lowest) Glucose closest to 08:00 am Ammonia (highest) Albumin (highest) Lactate (highest) Platelets (lowest) WBC (highest) WBC (lowest) Highest or lowest as indicated Glucose: closest to 8:00 A.M. WBCs – if only one for the day record as both highest and lowest Lactate from arterial blood draw Daily/Weekly Laboratory Data

133. Record each burn related operative procedure from ACU admission to 10 days after the last graft, or stop of study intervention plus 3 days, discharge, or 3 months from ACU admission, whichever comes first. Date (yyyy-mm-dd) Was the Operative procedure planned or unplanned?  Planned  Unplanned  Planned  Unplanned  Planned  Unplanned  Planned  Unplanned  Planned  Unplanned Type of Operative Procedure (Select all that apply) Surgical excision (tangential or fascial)  Extension and temporary covering (xenograft, allograft and artificial skin)  Excision and autograft  Delayed autograft  Excision and primary closure/composite tissue transfer  Other (Please specify) Burn Related Operative Procedure

134. Record only the medications (or types of medications) listed here. Daily from ACU admission to 10 days after the last graft, or stop of study intervention plus 3 days, discharge, or 3 months from ACU admission, whichever comes first. Do NOT record stool softeners CONCOMITANT MEDICATIONS

135. Record all Beta-Blockers given each day CONCOMITANT MEDICATIONS (cont.)

136. Record both the highest and the lowest heart rate. If only one heart rate is available, record it as both the highest and the lowest for that day. This data is entered on the Concomitant Medication form HEART RATE

137. Report a Protocol Violation when any of the following occur: Investigational Product (IP) 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 Dispensing/dosing error of IP Accidental unblinding Enrollment of a patient that does not fulfill inclusion/exclusion criteria Open label glutamine given Unapproved EN formula given Other (specify) Protocol Violations

138. Determine the percentage of IP received each day and indicate if a PV is being reported Dose Related Protocol Violation (PV)

139. Must be entered into REDCap ™ within 24 hrs of becoming aware Enter up to 6 PVs per day by answering ‘Yes’ to the question ‘Another PV to add?’ Protocol Violations

140. When all of you data is entered for a patient, click on the ‘Completed Data Entry’ button at the bottom left of the grid. If the data is incomplete, an error message will pop up indicating what needs to be completed before moving the patient to the Queries stage. Data Entry Completion

141. Data Quality Management Source Verification Bench Mark Reporting Data Quality Checks and Monitoring

142. Simple and complex data query checks are implemented to ensure, complete, accurate, and consistent data is entered SimpleComplex  Blank field checks  Numeric ranges  Open text (manual DM checking)  Date Logic/Ranges (e.g. no dates in future)  Complex ranges – calculations (e.g. BMI)  Cross-form checks – consistency between forms (e.g. sex listed differently on demographics and SAE forms)  Required forms that are not done (e.g. protocol violation forms)  Blank forms Data Query System

143. Monitoring visits to conduct source verification and confirm study compliance with the protocol and regulatory processes will be conducted throughout the course of the study. After a minimum of 2 patients have been enrolled at a site, the central study team will schedule a time to conduct either an onsite or remote monitoring visit. Visits may include review of: Regulatory documents and binders Source verification for specific enrolled subjects Confirmation the study protocol is being followed Training and delegation of authority logs Monitoring

144. The central study team will review recruitment reports monthly to identify and address slow enrollment and areas of concern Recruitment Reports

145. Data Quality reports will be generated every 4-6 months. Each site with >10 finalized patients will receive an individualized site report. Quality Reports

146. Resources online www.criticalcarenutrition.com

147. From the CCN website, you can access:  CRS  REDCap™  Study Tools SPM; CRFs; Training Slides; Questionnaires; Logs; Forms Critical Care Nutrition

148. Potential Impact! If the RE-ENERGIZE trial shows positive results, we can immediately implement this simple, inexpensive product around the world in both hospitals and ‘in the field’ settings. Thus, we will: »Save lives »Reduce infections »Shorten stays in hospital »Improve the physical recovery of burn injured victims »Save money

149. Conclusions RE-ENERGIZE trial –Will ask a clinically important question –Has the potential to save lives and reduce morbidity whether positive or negative –Largest burn trial ever! –Results immediately translatable into practice Thank you for your interest and support