1. 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

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

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

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

6. 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

7. 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

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

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

10. 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

11. 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

12. Study Overview
Imp Manual p 8

13. 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

14. (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)

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

16. 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

17. Investigational Product Dosing of Glutamine Pharmacy Procedures

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

19. 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

20. 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

21. 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

22. Missed Doses
Imp Manual p 15

23. Pharmacy Procedures

24. Training and Delegation Log
Imp Manual, appendix E

25. 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

26. 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#

27. 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:
One password per pharmacy (shared amongst other pharmacy staff)

28. 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

29. 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

30. 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

31. Dosing
Imp Manual, appendix F

32. Imp Manual, Study Tools
Dosing Weight Chart

33. 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

34. Dispensing Log
Imp Manual, appendix G

35. Accountability Logs
Imp Manual, appendix H, I

36. Storage and Temperature Logs
Imp Manual p 24
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

37. 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

38. 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

39. Imp Manual Appendix C

40. Feeding Intolerance/high GRVs?
Imp Manual p 16

41. 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

42. 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

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

44. Research Coordinator

45. 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

46. 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)

47. 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”

48. 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?

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

50. 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.

51. 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.

52. 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

53. 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....”

54. 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

55. 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.

56. 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.

57. 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

58. 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

59. 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

60. 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

61. 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.

62. 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 

63. 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!)

64. 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

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

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

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

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

69. 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

70. 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

71. 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

72. 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.

73. MD orders
Imp Manual p 38, Appendix C

74. 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

75. 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)

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

77. 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

78. 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 # )
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 # ).
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

82. Case Report Forms
CRFs Sep 10th 2010

83. Rules: Data Collection
CRFs, page 3

84. 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

85. CRFs p12-13
Definition page 12

86. CRFs p 16-17

87. 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

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

89. CRFs p 24-25

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

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

92. From ICU admit to 10 days post last graft
CRFs p
From ICU admit to 10 days post last graft

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

94. 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

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

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

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

98. CRFs p 39-39

99. CRFs p 40-41

100. CRFs p 42-43

101. CRFs, p 44-45

102. 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.

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

104. 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

105. Resources online