REDOXS Training: Introduction & Site Investigator 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 November 2008

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

Effect of glutamine on INFECTIONS META ANALYSIS Effect of glutamine on INFECTIONS 4

Effect of glutamine on LOS META ANALYSIS: Effect of glutamine on LOS

Effect of glutamine on mortality 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

Objectives (Pilot Study) Recruitment rate Compliance with experimental procedure 3. Compliance with data collection and transfer to the Coordinating Centre (CERU) 8

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

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

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

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

(per Site Investigator) 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 NPO not an exclusion 96 hrs if resuscitation before ICU admission Consent 24 hrs from admit (per Site Investigator)

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

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

Investigational Product Dosing of Glutamine Pharmacy Procedures

MALTRIN® Maltodextrin Imp Manual p 13-16 Study Intervention OR MALTRIN® Maltodextrin

supplement vs. nutrition Imp Manual p 15 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 supplement vs. nutrition

Delivery of Supplement REDOXS Training Delivery of Supplement REDOXS Training: RD & Pharmacy Imp Manual p 15 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 October 2007 November 2008 20

Duration of Study Intervention Imp Manual p 16 ICU admission 7 days post last successful graft Study Intervention Randomization 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 Imp Manual p 18 Before trial starts, CERU will arrange for intial product to be delivered from Colorado For subsequent orders, complete Product Order/Shipment Form

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

CRS Pharmacy Login Imp Manual p 19 CERU to assign access to Central Randomization System (CRS) after web access log signed Pharmacist to access Central Randomization System (CRS) at: https://ceru.hpcvl.queensu.ca/randomize/ One password per pharmacy (shared amongst other pharmacy staff)

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

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

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

Dosing Imp Manual, appendix F

Imp Manual, Study Tools Dosing Weight Chart

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

Dispensing Log Imp Manual, appendix G

Accountability Logs Imp Manual, appendix H, I

Storage and Temperature Logs Imp Manual p 24 cool, dry area, 25C (77 F) excursions allowed 15-30 C (59-86F) cool, dry area, below 32 C (90 F) MALTRIN® Maltodextrin Will be asked to send logs/documentation to CERU

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 Imp Manual Appendix C 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

Give RD a copy Energy and Protein Needs Case Report Forms p 14-15 Energy and Protein Needs Timing of start and stop of EN and PN Give RD a copy

at least for 1 week after EN stopped Case Report Forms p 22-23 at least for 1 week after EN stopped 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 appendix p 3 Give RD a copy R Coordinator to enter in CRFs

Research Coordinator

Delegation of Authority Logs Imp Manual p 10, appendix A “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)” Completed Log to be sent to CERU before start of trial

Eligibility confirmation Imp Manual p 13 Document in the medical chart or Sign worksheet by MD and keep as source Prompted at time of Pre randomization Patient enrolled to the RE-ENERGIZE study at time hrs on date. Patient met all the inclusion criteria and none of the exclusion criteria as confirmed with Dr. ____________________. Consent obtained from _____________ (relationship to patient) on dd/mmm/yyyy at time hrs. All questions & concerns addressed with patient/family member at this time. Copy of consent was given to patient/family member. Sample Progress note entry (Imp Manual p 36)

Obtaining Informed Consent Imp Manual pages 35-37 Obtaining Informed Consent Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans “Free and informed consent refers to the dialogue, information sharing and general process through which prospective subjects choose to participate in research involving themselves”

Timing : When? Who obtains consent? Consent must be obtained within 48 hrs of admission to ICU Site Investigator or delegate i.e. sub investigator or research nurse must be specified on the Delegation of Authority Log Who obtains consent?

Whom to get consent from? Patients are often incapable given acuity of illness Substitute decision maker (SDM) or patient’s legally acceptable representative

Pre-Consent Check to see if patient has refused participation in research in general. Ensure patient meets the inclusion & no exclusion criteria Familiarize yourself with the patient’s history Discuss the eligibility criteria and appropriateness of enrolment with Site Investigator.

Involve nursing staff Approach bedside nursing staff/medical staff for and update on the family’s involvement and their degree of knowledge of the patient’s condition. Inform the appropriate nurse you are considering this patient for the RE-ENERGIZE Study. Ask RN when family member is expected.

At the time of Consent Arrange for a quiet, private location for discussion with family member(s) with the Site Investigator/delegate. The Site Investigator will provide an overview of the study to the family members and inform them that their family member is appropriate for participation in the RE-ENERGIZE study. The Site investigator will then introduce the Research coordinator to the family. State that you are seeking permission for the patient to participate in a research study Highlight that your hospital promotes improving patient care through research

Language Use simple and clear language Avoid medical jargon Do NOT coerce family member Personalize the discussions i.e. “Patients like your family member, may benefit from participating in this study....”

Explain Study Procedures Feeding via EN is standard of care Supplementation via Enteral or oral route Blood will be taken on 4 days to help us understand how glutamine works Follow up at 6 months to check on patients status

Glutamine Glutamine is an a building block for protein, and plays many important functions in the body. In burns, these nutrients are found to be in low levels. Purpose of the study is to see if giving glutamine will improve the survival and reduce infections of burn patients in the ICU, like your family member.

Risks and benefits We won’t know what your family member is receiving (blinded). Risks: No known risks but there maybe others that we do not know about. If the MD in charge of your family member feels that your family member is deteriorating because of the supplement, he can stop the study supplement. Your family member will be monitored daily Benefits: your family member may have a better chance of survival but we do not know for sure.

Other elements of ICF Voluntary participation If refuse participation, will still receive the same medical care. Consent may be withdrawn at any time No compensation, no cost Contact person for their rights and questions Data will be accessed but kept confidential

Provide ICF to SDM Provide a copy of the REB approved ICF to family for their review Give them sufficient time to ask questions and encourage them to speak to the Site Investigator. Ensure that they have understood that they are signing on behalf of their family member Provide contact numbers for questions or concerns

After consent obtained When the SDM has given consent, ensure that they have dated and signed the ICF. Provide them with one copy. Place a copy of the signed ICF in the medical chart and copies in your site files

Follow up with SDM Thank the SDM for the opportunity to include the patient in RE-ENERGIZE Provide the SDM with informal updates when you see them during future ICU visits, whether things are uneventful or not Ongoing contact with the SDM will help to make their exposure to medical research a positive experience

No Family around? Obtain consent by telephone Document in the medical chart that consent was obtained via telephone before the patient was randomized Follow up with the SDM to see that the ICF is signed as soon as possible.

Screening Log Imp Manual p 27 Enter all patients onto Central Randomization System that: meet inclusion criteria Even if they meet an exclusion criteria Even if you did not get consent Inclusion Criteria Present Exclusion Criteria Present Informed Consent Obtained Enter into CRS  NA 

CRS Login/Screening Log Imp Manual p 27,28 CERU to assign access to Central Randomization System (CRS) after web access log signed Research Coordinator to access CRS to enter Screening data at: ceru.hpcvl.queensu.ca/randomize/ One password per Research Coordinator (DO NOT SHARE!)

CRS Home Screen Imp Manual p 28 Once you have logged in successfully, you will be brought to the Home screen. Click on RE-ENERGIZE

CRS: Adding Patient Imp Manual p 29 To enter data for a new patient, select the Add patient link.

CRS: Inclusion Criteria Imp Manual p 30 Click the Inclusion Criteria . Complete the fields in the form as appropriateas

CRS: Exclusion Criteria Imp Manual p 31 Complete the exclusion criteria fields as appropriate

CRS Pre-Randomization Imp Manual p 32 If consent is NOT obtained

CRS Pre-Randomization Imp Manual p 32 If consent IS obtained, DD-MMM-YYYY format Times: 24-hour (military) clock, must use colon (:) to be saved

CRS Randomization Contact Pharmacist and inform them of the following: Imp Manual p 33 Contact Pharmacist and inform them of the following: Patient enrollment number (8 digit number) Pre-burn weight (in Kg) Any other patient details requested by the pharmacist (patient medical ID#) Print a copy of the Randomization Web Form

Site Status Page Imp Manual p 34 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

Patient Status Page Imp Manual p 35 Indicates the status of each data entry form for the patient Status Symbol Description Completed All data has been completed and saved. Not Completed Data has not yet been entered on the fm. Locked The patient has been randomized and the data is no longer able to be edited by the site user.

MD orders Imp Manual p 38, Appendix C

Bedside Nursing Procedures Imp Manual, page 25-26 Determine # packets per interval (see Dosing Chart) At each dose, open the # packets needed and pour into a sterile specimen cup Using a 60 ml syringe, add 50 mls of sterile water/tap water for each 5 gm package (as per standard practice for EN) mix well. Transfer the mixture into a 60 cc syringe Infuse as a bolus q 4 hrs unless po, then mix in liquid and give TID with meals/snacks Record all dosages given on the Medication Administration Record as “RE-ENERGIZE supplement” as # packets per interval. To keep all the unused packages in a bag with the patient’s ID on it and give to Research Coordinator Double up at next interval when dose is missed. Inform Research Coordinator of interruptions

Lab Procedures Training Module to follow Lab Manual Lab Procedures Training Module to follow Blood draws on Day 4 (  48 hrs) Day 7 (  48 hrs) Day 14 (  48 hrs) Day 21 (  48 hrs)

Role of Site Investigator  Delegation of Authority  Patient Eligibility SAE identification/assessment ICU Infection adjudication Investigator Confirmation

Adverse Event must be serious and unexpected to be reported Imp Manual p 41-51 SAE Identification A serious adverse event is any untoward medical occurrence that at any dose, Results in death Is life threatening Requires or prolongs in-patient hospitalization Results in persistent or significant disability/incapacity May require medical or surgical intervention to prevent one of the other outcomes to defining serious Is a congenital anomaly/birth defect An unexpected adverse event is that event that is NOT expected due to the progression of the underlying disease or co-morbid illnesses.   Adverse Event must be serious and unexpected to be reported

An unexpected adverse event* SAE Reporting Events must be Serious Adverse Events and unexpected + A serious adverse event An unexpected adverse event* RC completes Initial SAE Report faxes the SAE initial report to the Project Leader within 24 hours of becoming aware of the event (fax #613-548-2428) RC reports SAE to local Ethics Board as per required timelines Research Coordinator (RC) or Site Investigator (SI) identifies SAE RC faxes the SAE follow-up/final report to the Project Leader within 10 days from becoming aware of the event (fax # 613- 548-2428). The Project Leader will collaborate with the Study Coordinator to assess the need for additional details and further follow-up reporting. *Examples of unexpected events Cardiac arrest in a pt without a history of cardiac disease. New seizure in the absence previous seizure disorder. Worsening encephalopathy in the absence of liver disease. Ischemic bowel in the absence of massive fluid resuscitation or increased abdominal pressure/abdominal compartment syndrome

Case Report Forms CRFs Sep 10th 2010

Rules: Data Collection CRFs, page 3

Using Lund Browder Chart by attending surgeon CRFs p 10-11 Using Lund Browder Chart by attending surgeon Also to be done by the attending surgeon

CRFs p12-13 Definition page 12

CRFs p 16-17

While ventilated from ICU admit to 10 days last graft day as: CRFs p18-19 While ventilated from ICU admit to 10 days last graft day as: Day 1-14 = daily, day 15 onwards weekly

REDOXS Training: Introduction & Site Investigator CRFs p 20-21 From ICU admit to 10 days post last graft November 2008

CRFs p 24-25

From ICU admit to 10 days post last graft CRFs p 26-27 From ICU admit to 10 days post last graft

From ICU admit to 10 days post last graft CRFs p 28-29 From ICU admit to 10 days post last graft

From ICU admit to 10 days post last graft CRFs p 30-31 From ICU admit to 10 days post last graft

From ICU admit to 10 days post last graft CRFs p 32-33 From ICU admit to 10 days post last graft

From ICU admit to 10 days post last graft CRFs p 34-35 No routine surveillance swabs No contaminants (except in blood) Do not record “NO growths” From ICU admit to 10 days post last graft

Infection Adjudication Site Investigator to make determination of a newly acquired infection based on antibiotic and microbiology data

CRFs p 36-37 Needs to be done for every suspicion that is triggered by an antibiotic or organism

Determination must be made by SI Study Tools Determination must be made by SI

CRFs p 39-39

CRFs p 40-41

CRFs p 42-43

CRFs, p 44-45

Protocol Violations When any of the following occur: CRFs p 46-47 Protocol Violations When any of the following occur: Investigational Product (IP) Daily dose delivered is < 80% prescribed. Example: if the daily dose is 5 packages and the daily dose delivered is less than 4 packets, this is a protocol violation. IP dispensing/dosing error Accidental unblinding of IP Enrolment of a patient that does not fulfill inclusion/exclusion criteria Unapproved procedures performed All unanticipated problems involving risk to subjects or others participating in the study MUST be reported to the Project Leader for reporting to the Department of Defense.

Must be reported to the Project Leader within 24 hrs of becoming aware

Patient enrolment Screen patient Eligible patient (checked by MD) Research Coordinator obtains consent Randomizes patient on CRS Informs Pharmacist Writes sample entry Note in chart Facilitates Medical Orders in chart Pharmacist checks treatment on CRS Dispenses product for 7 days 48 hrs from admission Research Coordinator informs RN Patient started on intervention

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