Implementation Manual

Transcription

1 RandomizEd Trial of ENtERal Glutamine to minimize Thermal Injury Implementation Manual Intended Audience: Research Coordinators & Pharmacists This study is registered at Clinicaltrials.gov. Identification number NCT Oct NP 1

2 Table of Contents Table of Contents...2 Glossary... 4 Study Contacts... 5 Participating Sites... 6 Study Synopsis... 7 Study Overview... 8 Roles & Responsibilities... 9 Research Sites... 9 Study Preparation Activities... 9 Required Activities & Documentation... 9 Department of Defense (DOD)... 9 Coordinating Centre Delegation of Authority Inclusion and Exclusion Criteria Inclusion Criteria Exclusion Criteria Investigational Product Administration Pharmacy Procedures Ordering of the Investigational Product Training, Delegation of Authority Log Dispensing Procedures...19 Nursing Procedures Research Coordinator Procedures Training Screening & Eligibility Obtaining Consent...27 Patient Confidentiality...29 Medical Chart Entry...29 Study Orders...29 Blood Draws Other Study Procedures...31 Protocol Violations/Incident Reports Serious Adverse Events...33 Time Frames for Reporting to CERU...35 SAEs on REDCAP...36 Initial SAE Report...37 Initial SAE Report worksheet...40 Follow UP/Final SAE Report...41 Follow Up/Final SAE Report worksheet...43 SAE Follow Up...45 Unblinding...45 Data Collection & Electronic Case Report Form Completion...46 Study Days...46 Duration & Type of Data Collection...46 Nutritional Assessment/Timing and Daily Nutrition data...47 Source Documentation...47 Infection Adjudication...48 Oct NP 2

3 Follow-up (6 months)...48 Appendices...49 A. Delegation of Authority Log...50 B. Dosing Weight Chart...53 C. Standardization of Nutrition Practices...55 D. Investigational Product Order/Shipment Form...59 E. Pharmacy Delegation & Training Log...60 F. Investigational Product Worksheet...61 G. Investigational Product Dispensing Log...63 H. Investigational Product Accountability Log (Nutrestore )...64 I. Investigational Product Accountability Log (Maltrin M100)...65 Oct NP 3

4 Glossary RE-ENERGIZE RandomizEd Trial of ENtERal Glutamine to minimize Thermal Injury CERU ecrf CRS GCP ICF ICU IP LAR PL QI RC SDM Clinical Evaluation Research Unit at Kingston General Hospital (Methods Centre) Mock Case Report Form Central Randomization System Good Clinical Practice Informed Consent Form Intensive Care Unit Investigational Product Legally Acceptable Representative Project Leader Qualified Investigator, sometime referred to as Site Investigator Research Coordinator Substitute Decision Maker Oct NP 4

5 Study Contacts RE-ENERGIZE Sponsor Contacts Dominique Garrel, MD Université de Montreal Department of Nutrition 2405, ch. de la Côte Ste-Catherine Pavillon Lilian-de-Stewart Room Montréal, QC H3T 1A8 Phone: ext.1739 Hospital: Cell: Paul Wischmeyer, MD University of Colorado Denver Department of Anesthesiology East 19 th Avenue RC2, Room 7119 Aurora, CO Phone: Fax: Clinical Evaluation Research Unit Contacts Rupinder Dhaliwal, RD Project Leader Phone: ext Cell: Maureen Dansereau Project Assistant Phone: ext Clinical Evaluation Research Unit Angada 4 Kingston General Hospital 76 Stuart Street Kingston ON K7L 2V7 All questions related to study procedures should be directed to the Project Leader. Oct NP 5

6 Participating Sites Institution University of Colorado Denver, CO Site Investigator Paul Wischmeyer Oregon Burn Center, Portland, OR Nathan Kemalyan Firefighter's Burn Unit Edmonton, AB Edward Tredget University of Iowa, Iowa City, IA Lucy Wibbenmeyer St. John s Mercy Burn Center, St. Louis, MO Jonathan Pollack Ross Tilley Burn Centre, Toronto, ON Marc Jeschke Joseph M Still Burn Center, Augusta, GA, Bruce Friedman Hotel-Dieu Montreal, QC Marc Jacques Dubois Site numbers will be assigned by CERU when access to the Central Randomization System is granted. Oct NP 6

7 Study Synopsis The aim of this pilot study is to test the feasibility of a multi-center trial that will test the following hypothesis: enteral glutamine supplementation decreases mortality and infectious morbidity in severely burned patients. Rationale: Enteral glutamine has been found to decrease mortality in critically ill patients and blood infection in trauma patients. In our pilot study (Critical Care Medicine, 2003, 31:2444) we found the same protective effect of glutamine against blood infection in severely burned adult patients. In addition, a significant decrease in mortality was observed with glutamine. These results should be tested with a multi-center trial because our study was small and did not have mortality as an end point. Since such a large multi center study has never been conducted in burn patients, a pilot study that will test its feasibility seems warranted. The mechanism of action of glutamine is controversial. Improvement in T cell immune functions, anti-oxidant properties and a newly discovered action on heat shock proteins could all be involved. If our clinical hypothesis is supported by the results of this trial, additional grant proposals will be made to test several mechanistic hypotheses, using blood samples obtained from a randomly determined sub-group of patients stratified for severity of the injury. The specific aims of the pilot study will be to determine recruitment rates, compliance with nutritional burn management protocol and with study intervention. Clinical outcomes will be: mortality, incidence of infectious episodes, and clinical status during the ICU stay and length of care. Methods: The study will be a multi-center, prospective, double blinded randomized controlled clinical trial. Randomization will be concealed and stratified for burn severity. Patients will be adults, between 18 and 80 years, admitted within 48 hrs post burn, and with a Total Burn Surface Area (TBSA) + Age score between 40 and 119, TBSA being 20% in patients ages years and 10% in patients ages years and requiring grafting. The pilot study will include approximately 8 burn centers, 3 in Canada and 5 in the US and enroll 200 patients over three years. Compliance with study protocols and with study intervention will be assessed through regular on-site visits, regular phone contacts and teleconferences. Glutamine or a placebo/control will be given every 4 hours at 0.5 gm/kg/day as boluses, until complete healing, defined as 7 days after the last successful grafting. Resuscitation, nutritional support, pain management, infection control and surgical care will be done according to standardized procedures. Approximately 30 ml samples of blood will be obtained on day 4, 7, 14 and 21 to test the effect of glutamine on inflammatory response and the time-course of inflammation, immunosuppression and the production of heat shock proteins The Primary end points will be: recruitment rates, compliance with study protocols and compliance with study intervention. Secondary end points will be: mortality, incidence of infectious episodes, ICU length of care, length of care, and multiple organ functions. The costeffectiveness of glutamine administration will also be measured if the results show a decrease in length of care or a reduced incidence of infections with glutamine. These outcomes will be measured but not analysed during this pilot trial. Data processing and Statistical analysis: Data will be collected and managed by the Clinical Evaluation Research Unit, in Kingston, Ontario. Oct NP 7

8 Study Overview Below is a diagrammatic representation of the RE-ENERGIZE Study. Refer to appropriate sections of the Implementation Manual for further details concerning specific activities. Diagram 1: Overview of the RE-ENERGIZE Study ICU Admission Time from ICU admit to consent & randomization = 72 hours Patient Eligibility RANDOMIZATION Consent Obtained Length of study treatment = from randomization to 7 days post last successful graft or burn unit discharge or 6 months from ICU/burn unit admission, whatever comes first Study Treatment Initiated Glutamine or Placebo/Control ICU Discharge Outcomes ICU/Hospital Mortality Laboratory Samples Approximately 30 ml blood draws on 4 7, 14 and 21 days post start of the study intervention (± 48 hrs) Duration of daily data collection = from ICU admission to 10 days post last successful graft or burn unit discharge or 6 months from ICU /burn unit admission, whatever comes first 6 month survival follow-up Oct NP 8

9 Roles & Responsibilities CERU is responsible for the following: Providing procedures and tools for study implementation Providing training on procedures and tools Supplying a username and password for access to the Central Randomization System (CRS) Providing ongoing support for research site activities Data validation and verification Distribution of data queries Research Sites The Site Investigator and any applicable delegates at the research site are responsible for the following: Supplying a computer with internet access for the CRS Maintenance of local computer equipment Notifying CERU of any technical difficulties or malfunctions related to the CRS Allowing only authorized study personnel to access the CRS. Screening & enrolling eligible patients Informed Consent of potential research participants (or appointed substitute decision maker) Data collection Electronic Case Report Form (ecrf) completion on REDCAP Data query resolution Review and adjudication of all suspicion of infection Study Preparation Activities Required Activities & Documentation Department of Defense (DOD) Prior to initiation of screening activities, each participating US site must obtain approval from the United States Army Medical Research and Material Command (USAMRMC), Human Research Protection Office (HPO) of the DOD. At the time of submission to local Institutional Review Board (IRB)/Research Ethics Board (REB): Each US site must submit the following DOD documents to their IRB/REB along with the Study Submission documents: Completed Site-Specific Protocol Addendum. Log Number A These documents will be provided by the Project Leader before the start of the trial. Oct NP 9

10 After approval has been obtained by the local IRB/REB: Each US site must also obtain approval from the DOD. The following documents must be submitted to the DOD: IRB/REB Study Submission including protocol, consent and all supporting documentation Completion of Protocol Site Specific Addendum Documentation of Qualified Investigator on Human Subjects Protection Training CV/Resume/Biographical Sketch of QIs CV/Resume/Biographical Sketch of all co-qis The Project Leader will provide the site with the contact details of the DOD person responsible for approval. For Canadian Sites, approval from the DOD is not required, unless otherwise specified, however approval from the local REB and Health Canada is needed. A No Objection Letter from Health Canada will be forwarded to the Canadian Sites by the Coordinating Centre before enrollment starts. Coordinating Centre Prior to the initiation of screening activities, each site must ensure the following tasks and/or documentation has been completed, and forwarded to the Project Leader: Signed Protocol Signature Page Fully-executed Site Agreement IRB/REB Study Submission and Approval IRB/REB approval of Informed Consent Form (ICF) Completed IRB/REB Attestation Form and Qualified Investigator Undertaking Form (Canadian Sites) Completed Self-Evident Query (SEQ) Agreement Regulatory Documentation: o CVs & medical licenses for QIs o CVs for site coordinators (SC) o CVs for lead Research Pharmacist o CV for laboratory technician o Delegation of Authority Log (see section below) o Training Logs o Local laboratory reference ranges o Local laboratory accreditation Following completion of site start-up training, the above referenced documentation is to be sent to the Project Leader/delegate. All materials required for the implementation and conduct of the RE- ENERGIZE Study will be forwarded to the research site by the Coordinating Centre. Patient screening can commence following confirmation of receipt of necessary documentation by the Project Leader/delegate. Delegation of Authority The Qualified Investigator at each site must provide CERU with a completed site Delegation of Authority Log (See Appendix A). The purpose of this log is to delineate the key delegated tasks assigned to appropriately qualified individuals on the RE-ENERGIZE Study research team. The site Delegation of Authority Log should be completed as follows: i. Identify each individual that is involved in the conduct of the RE-ENERGIZE Study and to whom the Qualified Investigator (QI) has delegated key tasks. ii. Each individual assigned to the study should complete the log including the effective start date of their activities. (The end date will be the time when the individual no longer has any association with the study). iii. Refer to the sample key delegated tasks below. If you are in agreement with this list of tasks you may use this to record the various responsibilities of your site personnel. Oct NP 10

11 iv. Update this log during the course of the study. v. Fax this log, including any updated versions, to the Project Leader at (613) Sample Key Delegated Tasks for the RE-ENERGIZE Study Screening subjects for eligibility Conducting informed consent discussions for eligible patients Obtaining written informed consent Patient enrollment/randomization and follow-up Daily monitoring of patient health, safety and study compliance Data collection, including: Electronic Case Report Form entries Electronic Case Report Form corrections Data query resolution Source documentation maintenance, including: Study worksheets, checklists, monitoring sheets Data from electronic & hard copy medical chart Reporting of Protocol Violations/Unanticipated Problems involving risk Identification of Serious Adverse Events and documentation Maintenance of Regulatory Documents REB submissions and communications Perform study specific training Performing clinical assessments including burn outcomes, SAEs and ICU infection adjudication Confirmation of completeness and accuracy of data collected Optimizing delivery of nutrition and compliance with Clinical Practice Guidelines Maintenance of IP inventory Checking of treatment assignment online IP dispensing & accountability, including maintenance of logs Drawing of blood samples Processing and Storage of blood supplies Batch shipping of frozen samples Oct NP 11

12 Inclusion and Exclusion Criteria Each patient admitted to your burn unit should be screened within 72 hrs of admission to see if they meet the inclusion criteria or exclusion criteria as listed below. All screening data will be entered into the Central Randomization System (CRS), see CRS and REDCAP Manual for detailed instructions. In addition, the mock ecrfs pages 4-9 may be used as worksheets when screening patients. Inclusion Criteria Patients must meet all three of the criteria to be included in the study. # Inclusion Criteria 1 Total Burn Surface Area (TBSA) 20% in patients age years Total Burn Surface Area (TBSA) 10% in patients age years This is an assessment that is to be made by the attending surgeon/physician based on his/her clinical judgment. The Lund Browder chart (Appendix 1 mock ecrfs may be used to help make this assessment, if needed). This information must be obtained from the attending surgeon/delegate before randomization can occur. 2 Deep 2 nd and/or deep 3 rd degree burns requiring grafting The presence of deep 2nd degree or deep 3rd degree burns requiring grafting is an assessment that must also be made by the attending surgeon/physician. This information must be obtained from the attending surgeon/delegate before randomization can occur. 3 Age + TBSA = The total of the patient s age and TBSA must be between the range of Consent must be obtained within 72 hrs of admission to the ICU (burn unit) To be eligible, admission to the unit must occur within 48 hrs of burn injury. In the event that the patient received standardized burn care and resuscitation prior to admission to ICU, this may be extended to 96 hrs. In this case, consent must be obtained within 24 hrs of admission to burn ICU Oct NP 12

13 Exclusion Criteria Choose all exclusion criteria that apply. If a patient meets any of the exclusion criteria, they are not eligible to participate in the study. # Exclusion Criteria 1 > 72 hrs from admission to ICU to time of consent 2 Patients > 80 years or < 18 years of age (age of maturity for an eligible patient to obtain consent is 18 years in Canada and the US) 3 Liver cirrhosis -Child s class C liver disease 4 Pregnancy (urine/blood tests for pregnancy will be done on all women of childbearing age by each site as part of standard of ICU practice) 5 Absolute contra-indication for EN: intestinal occlusion or perforation, abdominal injury. (Intestinal occlusion or perforation, abdominal injury. Being NPO is not considered a contraindication for Enteral Nutrition). 6 Patients admitted > 48h post burn (for patients that receive standardized burn care and resuscitation prior to admission to ICU, this exclusion criteria may be extended to patients admitted more than 96 hrs post burn: in this case consent must be obtained within 24 hours of admission to burn ICU) 7 Patients with injuries from high voltage electrical shock 8 Patients who are moribund (this may be defined as not expected to be in the ICU for more than 48 hours due to imminent death). 9 Patients with extreme body sizes: BMI < 18 or > 50 kg/m 2 10 Enrollment in another industry sponsored ICU intervention study (co-enrollment in academic studies will be considered on a case by case basis) 11 Received glutamine supplement for > 24 hours prior to randomization. 12 Known allergy to maltodextrin, corn starch, corn, or corn products. Patient eligibility must be confirmed by the Site Investigator/MD delegate Oct NP 13

14 Investigational Product Administration Patients randomized to the RE-ENERGIZE Study will receive one of the following: Name of Group Intervention Glutamine Nutrestore (L-Glutamine) Placebo/Control Maltrin M100 Maltodextrin Nutrestore (L Glutamine) Nutrestore is an amino acid (L Glutamine) powder that is approved for oral use in short bowel syndrome by the FDA. L Glutamine is produced normally by the body and has important functions in regulation of gastrointestinal cell growth, function, and regeneration. Under normal conditions, glutamine concentration is maintained in the body by dietary intake and synthesis from endogenous glutamate. Data from clinical studies indicate that the role of and nutritional requirements for glutamine during burns, catabolic illness, trauma, and infection may differ significantly from the role of and nutritional requirements for glutamine in healthy individuals. Glutamine concentrations decrease and tissue glutamine metabolism increases during many catabolic disease states, and thus glutamine is often considered a "conditionally essential" amino acid. Maltrin M100 Maltodextrin MALTRIN M100 maltodextrins are bland, low sweetness, pharmaceutical grade, white carbohydrate powders. Maltodextrins are Generally Recognized As Safe (GRAS) as direct human food ingredients at levels consistent with current good manufacturing practices. They are prepared as a white powder by partial hydrolysis of corn starch with safe and suitable acids and/or enzymes. The MALTRIN M100 maltodextrin is produced by Grain Processing Corporation (GPC) and then packaged by Anderson Packaging for the trial. Please refer to Product Information sheet (monographs) for more details. The Nutrestore and the MALTRIN M100 maltodextrin will be available in 5 gm pre-packaged packets that bear the following information: Caution: New Drug-Limited by Federal law to investigational use Unique Lot # (one lot # for Nutrestore and a separate lot # for Maltrin). The investigational products will be delivered to the participating site before the start of the trial. Oct NP 14

15 When to start the intervention? Given that the sooner the glutamine is started, the more likely it will be that it will have a treatment effect, the study intervention (either Nutrestore or Maltrin ) must start within 2 hrs from randomization (preferably within hrs of admission to ICU). Every effort must be taken to start the intervention within this time frame. How will the intervention be given? The study intervention is to be mixed in 50 mls of water per 5 gm packet and given as a bolus every 4 hours via the enteral route. Clearly, resuscitative strategies will take priority but the intervention will begin as soon as possible, regardless of whether the patient is ready to receive enteral nutrition. The boluses are to be given via a nasogastric/levine tube in the event that the patient does not have a feeding tube in place. The boluses are to be given via a feeding tube once the latter has been inserted. When the patient is tolerating oral feeds, the boluses may be switched to TID or QID via the oral route according to the patient s preference, as long as the patient receives the daily prescribed number of packets. When the intervention is administered orally, it may be mixed with one of the following: Apple juice Koolaid Oatmeal Do NOT mix the study intervention with orange juice, grapefruit juice or lemonade. Do all patient s receive the intervention q 4hrs while on enteral nutrition? Since the dosing of the intervention is based on pre-burn weight, in the event that the patient weighs < 54 kgms, the interval between some of the doses will be longer (i.e. up to 8 hrs). Refer to Appendix B (Dosing Weight Chart) for more details. What about interruptions in the boluses or missed doses? Interruptions or missed doses of the intervention should not occur and it is strongly recommended that in-services with the nursing/medical staff occur to explain the importance of delivering the full daily dose of the intervention. Do not hold the intervention for procedures or surgery. In the event that an interruption or a missed dose does happen, the following steps are to be followed: If >1 hour left before the next scheduled dose Give single dose asap If <1 hour left before the next scheduled dose Give the missed dose and the scheduled dose at the next scheduled interval. Do NOT give more than double the dose at any time. If the total dose received for that day is < 80% of the prescribed (i.e. # packets actually received in the 24 hrs period is < 80% of what the patient should have received), the Research Coordinator will need to report this as a Protocol Violation the next day. Please refer to the Protocol Violation section of the Implementation Manual. Oct NP 15

16 How long will the intervention be given? The intervention will continue until 7 days after the last successful grafting operation or burn unit/icu discharge or 6 months from ICU admission, whatever comes first regardless of whether the patient is receiving enteral/parenteral nutrition or ventilation status. In the event that the patient is discharged to another facility before the 7 days after the last successful grafting operation, the intervention stops at discharge. Call the Project Leader if you have any questions about the duration of the study intervention in your specific patient(s). Randomization Study Treatment Initiated Glutamine or Maltodextrin 7 days post last successful grafting Duration of Study Intervention What to do in the event of feeding intolerance/high gastric residual volumes? High gastric residual volumes are a common occurrence in patients that are receiving enteral nutrition. The administration of the study intervention should continue despite high gastric residual volumes, unless there is an absolute need to stop the intervention i.e. severe vomiting, ileus, bowel obstruction or a decision has been made by the Site Investigator/delegate (i.e. Serious Adverse Event that is felt to be related to the study intervention). To avoid interruptions in the delivery of the study intervention and enteral nutrition, ensure that strategies such elevating the head of the bed, use of motility agents and small bowel feeding tubes, etc have been adopted. Refer to the Enteral Feeding Protocol (in Appendix C Standardization of Nutrition Practices) for more details. Co-Interventions Each site will provide resuscitation, pain management, infection control and surgical care according to standardized procedures at the site. 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 prescription of enteral and parenteral nutrition, micronutrient delivery and practices related to withholding feeds for high gastric residual volumes and use of motility agents in these patients. Please refer to the Standardization of Nutrition Practices document (Appendix C) that lists the nutrition practices and ranges for these practices within which all participating sites fall. Oct NP 16

17 Pharmacy Procedures Ordering of the Investigational Product The investigational products will be delivered to the participating site before the start of the trial in cartons. The exterior of the cartons will bear labels that are compliant with both FDA and Health Canada drug labelling regulations (see templates below). Exterior Carton Label for Nutrestore (L-Glutamine) Caution: New Drug - Limited by Federal (or United States) law to investigational use Investigational Product Attention : Nouvelle Drogue - Limité par loi fédérale (ou les États-Unis) au drogue de recherche d'utilisation d'investigation Investigational Product/Drogue de recherche (To be used by a qualified investigator/ À être utilisé par un agent qualifié) Nutrestore (L-Glutamine) Study/ L étude: The RE-ENERGIZE Study ID #: #NCT US Sponsor/ Promoteur États-Unis: Dr. Paul Wischmeyer Clinical Evaluation Research Unit, Kingston General Hospital, 76 Stuart St, Kingston, ON K7L 2V7 Canadian Sponsor/ Promoteur Canadien: Dominique Garrel Clinical Evaluation Research Unit, Kingston General Hospital, 76 Stuart St, Kingston, ON K7L 2V7 Lot#: Expiry date/date d expiration: Storage: Keep in cool, dry area at 25ºC (77 F), excursions allowed to ºC (59-86 ºF) Stokage: Maintenez dans le secteur frais et sec à 25 C (77 F), excursions permises à C. Oct NP 17

18 Exterior Carton Label for Maltrin M100 Maltodextrin Caution: New Drug - Limited by Federal (or United States) law to investigational use Investigational Product Attention : Nouvelle Drogue - Limité par loi fédérale (ou les États-Unis) au drogue de recherche d'utilisation d'investigation Investigational Product/Drogue de recherche (To be used by a qualified investigator/ À être utilisé par un agent qualifié) Maltrin M100 Maltodextrin Study/ L étude: The RE-ENERGIZE Study ID #: #NCT US Sponsor/ Promoteur États-Unis: Dr. Paul Wischmeyer Clinical Evaluation Research Unit, Kingston General Hospital, 76 Stuart St, Kingston, ON K7L 2V7 Canadian Sponsor/ Promoteur Canadien: Dominique Garrel Clinical Evaluation Research Unit, Kingston General Hospital, 76 Stuart St, Kingston, ON K7L 2V7 Lot#: Expiry date/date d expiration: Storage: Keep in cool, dry area under 32 C (90 F) Stokage: Maintenez dans un milieu frais et sec à moins de 32 C. To order more investigational products during the study, complete the Investigational Product Order/Shipment Form (Appendix D) and fax to Elizabeth Luzier at the University of Colorado. Training, Delegation of Authority Log Prior to the start of the trial, the main pharmacist at each site must ensure that all pharmacy staff that have a material effect on The RE-ENERGIZE Study have been: delegated duties/tasks related to The RE-ENERGIZE Study and trained on the study procedures. A Pharmacy Delegation & Training Log (See Appendix E), or similar log is to be kept by the Pharmacy and sent to CERU upon request. Oct NP 18

19 Dispensing Procedures Only the Pharmacist is unblinded Dispensing is to be done within 2 hrs of randomization 1. After the Research Coordinator has confirmed eligibility and randomized the patient using the Central Randomization System, the research coordinator will immediately notify the pharmacy and provide: the 8 digit randomization # (automatically generated online), the patient s pre-burn weight and other details required by the pharmacist i.e. patient medical record ID#. 2. The Pharmacist will access the RE-ENERGIZE Central Randomization System Login Page at: To access the CRS with Pharmacy user access, enter your assigned User name and Password. Click LOGIN. NOTE: Access to the web-based Central Randomization System (CRS) will be assigned to the main pharmacist at each site by The Clinical Evaluation Research Unit (CERU) upon receipt of a signed Central Randomization Access Log. One password will be assigned per pharmacy and this password may be shared amongst other pharmacy staff. 3. After you Login, you will be brought to the Home Screen below. The Home screen lists all clinical trials in which your site is participating with CERU. Click on RE- ENERGIZE. Oct NP 19

20 4. You will then be brought the following screen. Your site name will be displayed as below RE-ENERGIZE 5. The pharmacist/delegate will check the treatment assignment on the CRS which will be one of the following two: Name of Group Intervention Glutamine Nutrestore (L-Glutamine) Placebo Maltrin M100 Maltodextrin The treatment allocation is concealed, therefore you will only see the codes displayed for randomized patients. As a new patient is randomized the code will be revealed on the list as below. Will be displayed as Glutamine (Nutrestore) OR Placebo (Maltrin Maltodextrin) 6. The only patient identifiers to be shown on the Treatment Allocation page will be an 8 digit # showing Site ID, and Enrollment (randomization) number (see next page). The Pharmacist will use the 8 digit ID number provided by the Research Coordinator to confirm the treatment allocation for the correct patient. Oct NP 20

21 8 digit patient ID # Site # Patient # 7. The pharmacist/delegate will print off the treatment assignment. This treatment assignment page must be signed by 2 pharmacists/delegates and filed in the Pharmacy Study files. 8. Click the Logout button to end the session. 9. The pharmacist/delegate will calculate how many grams (packets) of investigational product (IP) is needed for one day according to the patient s pre-burn weight (as obtained from the Research Coordinator) as follows: 0.5 gms/kg/day, divided by 5 gms (each packet) and then rounded up to the nearest full packet. See Dosing Weight Chart below (Appendix B) and example below. Patient s weight is 99 kg. Dose of IP is 0.5 gm X 99 kg = 49.5 gm/day divided by 5 gm = 9.9 packets rounded off to10 packets/day. c. Record this on the Investigational Product Worksheet (Appendix F). NOTE: Since the patient s pre-burn weight is to be used, do not change the dose of the product according to subsequent fluctuations in weight. Oct NP 21

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23 10. The pharmacist/delegate will obtain the appropriate product according to the treatment assignment. 11. The pharmacist/delegate will prepare blinded labels and affix one label to each packet of the product. When affixing the label, it is imperative that the lot# gets covered to an extent that it is not visible (must be blinded). The pharmacist will prepare enough labels to last one week for each patient that is randomized. For the example on the previous pages, this would be for a total of 70 packets. Blinded Labelling Template Study: The RE-ENERGIZE Study ID #: NCT Enteral Supplement powder for Investigational Use (L-Glutamine/Maltodextrin) US Sponsor: Dr. Paul Wischmeyer Canadian Sponsor: Dr. Dominique Garrel Patient Name: Enrollment #: Hospital Patient ID #: Dosing Weight: kg Date: Directions: Mix each packet with 50 mls of water, shake well and give as a bolus via feeding tube or with meals at the following times (or refer to Study Orders): 02:00 - Packet(s) 06:00 - Packet(s) 10:00 - Packet(s) 14:00 - Packet(s) 18:00 - Packet(s) 22:00 - Packet(s) Store at room temperature 12. The pharmacist/delegate will send the packets (enough to last one week) of the investigational products with the blinded labels attached to the ICU. The product is to be stored at room temperature in the ICU, preferably in a locked cabinet (based on discussions with the Research Coordinator at your site). 13. The pharmacist/delegate will complete the patient specific Investigational Product Dispensing Log (patient s name, date, what product dispensed, expiry date, lot #, etc) and the Investigational Product Accountability Logs (amount received, destroyed, batch #, etc) (see Appendices G, H & I) and keep these in the Pharmacy study files. 14. Pharmacist to repeat steps 7-9 weekly for duration of intervention = 7 days after the last successful grafting procedure (anticipated to be an average of 40 days) 15. Pharmacist to destroy all expired products as per local procedures after recording this on the appropriate Investigational Product Accountability Log (Appendices H & I). Oct NP 23

24 16. Pharmacist will be asked to provide the following, upon request: Documentation that product is maintained at the suggested temperature. Minor changes to these procedures to meet local pharmacy practices may be permissible upon approval by the Project Leader Oct NP 24

25 Nursing Procedures The Research Coordinator is to instruct the bedside nurse on these nursing procedures. 1. Determine the number of packets of the investigational product to be given to the patient and the dosing time according to Dosing Weight Chart (Appendix B, see below). 2. At each dose time, open the number of packages of the investigational product needed and pour into a sterile specimen cup. 3. Using a 60 ml syringe, add 50 mls of sterile water/tap water to each 5 gm packet (as per your standard practice for enteral nutrition formulas) to the cup and mix well. 4. Transfer the mixture into the 60 cc syringe. 5. Infuse the prescribed amount (for the dose time) through the feeding tube as boluses every 4 hours. Give via Nasogastric/Levine tube if the feeding tube is not in place. 6. When the patient is tolerating oral feeds, mix the study intervention in appropriate liquid/food (apple juice, koolade or oatmeal) and give TID or QID with meals/snacks. There is flexibility with the timing of the boluses and they may be given according to the patient s preference or RN discretion as long as: a. the patient receives the daily prescribed number of packets b. patient does not receive more than double the prescribed dose at any time Do NOT mix the study intervention with orange juice, grapefruit juice or lemonade. Oct NP 25

26 7. Record the number of packets given at each scheduled interval over the 24 hrs period (according to flow sheet) on the Medication Administration Record as RE-ENERGIZE supplement. 8. Do NOT stop the bolus infusion for procedures or surgery. In the event of a missed dose or interruption in the bolus, follow these steps: If >1 hour left before the next scheduled dose Give single dose asap If <1 hour left before the next scheduled dose Give the missed dose and the scheduled dose at the next scheduled interval. Do NOT give more than double the dose at any time. 9. The bolus infusion is to be administered as close as possible to the scheduled time. In the event that there is a delay in the administration, the bolus will need to be shaken to resuspend the powder. 10. Keep all the unused packages in a bag with the patient s ID on it and give to Research Coordinator. 11. Inform Research Coordinator of any interruptions in the boluses. 12. Continue with administering boluses of the investigational product until 7 days after the last successful grafting or until burn unit discharge or 6 months from ICU/burn unit admission, whatever comes first (Research Coordinator to notify when this will be). Oct NP 26

27 Research Coordinator Procedures Training Each member of the site research team should be qualified by education, training and experience to assume responsibility for the proper conduct of the trial. (GCP section 4.1.1) For each delegated task, an individual should have appropriate training documentation filed in the regulatory binder, including any in-services held for bedside nursing staff. Screening & Eligibility Each patient admitted to your burn unit should be screened within 72 hrs of admission to see if they meet the inclusion criteria or exclusion criteria as listed below. Use the Screening Worksheets provided with the Mock Case Report Forms (ecrfs) to help determine eligibility. All screening data MUST be entered into the Central Randomization System (CRS). For eligible patients, the screening data must be entered onto the CRS in a timely manner in order to randomize the patient and start the study intervention as soon as possible. For eligible patients that refuse consent or meet exclusion criteria, the screening data can be entered onto the CRS at a later time. Screening numbers will be assigned by the Central Randomization System. Refer to the CRS and REDCAP Manual for further instructions. Obtaining Consent Free and informed consent refers to the dialogue, information sharing and general process through which prospective subjects choose to participate in research involving themselves. - Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans Following confirmation of patient eligibility, the site must seek consent for the patient to participate in the RE-ENERGIZE Study from the patient s SDM or legally accepted individual. All patients should be consented and randomized within 48 hours of the admission to ICU. Before you approach for consent: 1. Confirm patient eligibility and appropriateness of enrollment with the QI or a sub-qi 2. Check to see if the patient has refused to participate in research in general 3. Familiarize yourself with the patient s history 4. Approach bedside staff/medical staff for an update on the family s involvement and their degree of knowledge of the patient s condition Oct NP 27

28 Recommended Procedures for Obtaining Informed Consent The nature of the RE-ENERGIZE Study population is such that patients are critically ill and may not be able to grant consent themselves. A Substitute Decision Maker (SDM) or Legally Acceptable Representative (LAR) may consent on behalf of patients who are unconscious, severely ill or cognitively impaired. The patient should be monitored for the duration of the study, once their ability to consent returns, they should be consented. The following procedures should be followed when obtaining informed consent for a potential RE- ENERGIZE Study patient: 1) The study team member obtaining consent is qualified to do so, and is knowledgeable in the study procedures, and the clinical area being studied. (Those individuals of the study team obtaining informed consent should be listed on the Delegation of Authority Log.) 2) Review the study details with the SDM in a quiet, private location. 3) Do not coerce or unduly influence the SDM for the patient to participate, or continue to participate in the study. 4) Assess the patient s, or if appropriate, the SDM s competence to consent to research, and document if you deem this individual incompetent. 5) Fully inform the SDM of all pertinent aspects of research, in non-technical language that is easy to understand. If the SDM does not speak English, the informed consent discussion must take place in the preferred language. 6) Provide a copy of the ICF and allow for ample time to read the ICF and ask questions. 7) Ask the SDM questions to assess their comprehension of the material reviewed. Ensure he/she fully understands the information. 8) Ascertain the SDMs willingness to participate. Document the decision of any SDM who declines to participate. 9) Sign and date & time the ICF: a. The SDM b. The person conducting the informed consent discussions 10) Document the consent process in the patient medical chart. See Sample Medical Chart Entry below. Sample Medical Chart Entry This patient is enrolled in IRB study ID#, Randomized Trial of Enteral Glutamine to Minimize Thermal Injury (The RE-ENERGIZE study). 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. Date/time of entry: Signature of Research Coordinator: Oct NP 28

29 11) Provide the SDM with a copy of the signed document. 12) File the originally signed ICF with the study-related documentation. Place a copy in the patient s medical chart. The research site should always follow local procedures pertaining to obtaining informed consent of patients in the ICU. Remember to: Communicate any important new information that becomes available, and that may be relevant to the patient s/sdms continuing consent Assess the patient through the duration of the study for competency to grant consent for themselves Document the informed consent process in the source documents, including the following details: o SDMs comprehension of the material reviewed o SDM being given ample opportunity to review the ICF and decide whether or not to participate in the research o o Adequate time being given to answer all questions satisfactorily Informed consent having been obtained prior to initiating any study related procedures Refer to the Consent Training Module, complete the Consent Training Record and return it to the Project Leader at CERU, Fax# Patient Confidentiality By definition, and in the context of a clinical trial, confidentiality refers to prevention of disclosure, to other than authorized individuals, of a Patient s identity and of records that could identify a Patient. Care and diligence in protecting confidential Patient information must be exercised throughout the duration of the RE-ENERGIZE Study. With this in mind, prior to forwarding any documentation (i.e. as attachments to a Serious Adverse Event [SAE] report) to CERU, all patient identifiers other than the Patient s Initials should be masked. Medical Chart Entry The Research Coordinator will add an entry in the Medical Chart confirming that consent was obtained, from whom, time, eligibility assessed, patient randomized. See Sample entry on the previous page. Study Orders 1. Following the receipt of the study intervention from the pharmacy, the Research Coordinator will determine how many packets of the intervention the patients should receive. This should be listed on the pharmacy generated blinded label and should be checked against the Dosing Weight Chart (Appendix B). 2. The Research Coordinator should prepare and/or facilitate the completion of study specific Medical/Physician Orders. See Sample Study Orders on next page. Oct NP 29

30 Sample Study Orders This patient is enrolled in IRB study ID#, Randomized Trial of Enteral Glutamine to Minimize Thermal Injury, (RE-ENERGIZE study). Administer (total # for day) packets of study supplement per day Q4h via: OGT/NGT/FEEDING TUBE: dissolve each 5 gm packet in 50ml water by shaking well in a clean specimen container, give as a bolus and flush tube as usual OR PO: dissolve in mls juice and change to give with meals TID. Administer study supplement at the following times (enter # packets): 02:00 - Packet(s) 06:00 - Packet(s) 10:00 - Packet(s) 14:00 - Packet(s) 18:00 - Packet(s) 22:00 - Packet(s) A missed dose should be given as soon as possible and may be doubled at next scheduled time. Please save all unused packages in labelled bag in patient s room for Research Coordinator to pick up. Call Research Coordinator (name) with any questions or concerns at (pager or extension) 3. A copy of the completed RE-ENERGIZE Study Physician s Orders should be filed by the Research Coordinator. Blood Draws The Research Coordinator will proceed with blood draws at 4, 7, 14 and 21 days post start of study intervention, as defined in the Mock Case Report Forms and the Lab Manual. The table below details each blood draw. You will note that there is a window of 2 days for each sample collection, except on day 4. This window ensures samples will not be missed over weekends. Sampling Time Details Draw # 1 (4 days post start of study intervention) + 48 hrs Approximately 30 mls blood Draw # 2 (7days post start of study intervention) ± 48 hrs Approximately 30 mls blood Draw # 3 (14 days post start of study intervention) ± 48 hrs Approximately 30 mls blood Draw # 4 (21 days post start of study intervention) ± 48 hrs Approximately 30 mls blood Refer to the Lab Manual and training module for procedures related to lab processing, storage and shipment to the cental lab. Remember to complete the Quiz at the end of the Lab Training Module and return it to the Project Leader at CERU, Fax# Oct NP 30

31 Other Study Procedures The Research Coordinator will follow study specific procedures related to the following: a. Daily monitoring of patient s health and safety b. Identification and reporting of Protocol Violations/deviations c. Identification and reporting of Unexpected Serous Adverse Events d. Monitoring of compliance with Investigational Product (see Mock Case Report Form on Daily Monitoring) e. Data Collection including resolution of data queries f. Source Documentation maintenance g. Maintenance of Regulatory Documentation h. IRB submissions and communications Protocol Violations/Incident Reports A Protocol Violation is defined as non-compliance with the study protocol and/or procedures that may impact study participant safety, the integrity of study data and/or study participant willingness to participate in the study. For the RE-ENERGIZE Study, a Protocol Violation occurs when any of the following have occurred: Investigational Product (IP) Daily dose delivered is < 80% prescribed. Example: if the daily dose is 5 packets and the daily dose delivered is less than 4 packets (80% prescribed), this is a protocol violation IP dispensing/dosing error (an incorrect dose/product was given to patient) Accidental unblinding of IP (the integrity of the study blind has been compromised) Enrollment of a patient that does not fulfill inclusion/exclusion criteria Unapproved procedures performed (failure to obtain consent, taking blood on an extra day, etc.) 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. These are to be reported as Incident Reports. All Protocol Violations and Incident Reports must be reported to the Project Leader within 24 hrs of becoming aware. A protocol violation form must be completed on REDCAP, printed and faxed to the Project Leader at (613) Depending upon the type of the violation the site may need to report the violation to their ethics board. It is the responsibility of the site to determine this at the time of the violation. Refer to the Protocol Violation Form (in the Mock CRFs/worksheets). See next page. Oct NP 31

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33 Serious Adverse Events This section refers to the procedures followed by the participating site for the reporting of Serious Adverse events to the Clinical Evaluation Research Unit (CERU). CERU will forward these reports to the appropriate regulatory bodies, the Medical Monitor for the study and the US Department of Defense, as needed, within the established timelines Each participating site must also check their local institutional review board s requirements for any additional reporting that may need to occur (i.e. adverse events). A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose: Results in death. Is life-threatening (refers to an event in which the study participant was, in the opinion of the qualified investigator (QI), at risk of death from the event if medical intervention had not occurred. NOTE: This does not include an event that hypothetically had it occurred in a more serious form, might have caused death). Requires in patient hospitalization or prolongation of existing hospitalization. Results in persistent or significant disability/incapacity (i.e. a substantial disruption in an individual s ability to conduct normal life functions). Is a congenital anomaly or birth defect. Other medically important condition (Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious events when, based on medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed above). Unexpected Serious Adverse Event (SAE) For the purposes of the RE-ENERGIZE Study, given the population of burn patients and their prolonged length of stay, an unexpected SAE is defined as an event that is serious, i.e. fits the above definition, and is NOT expected due to the progression of the underlying disease or comorbid illnesses. All events that are serious AND unexpected MUST be reported to Clinical Evaluation Research Unit (CERU) within 24 hrs of becoming aware of the event, regardless of the relationship of the intervention to the event. Examples of serious and unexpected SAEs and hence MUST be reported to CERU within 24 hrs of becoming aware of the event: Cardiac arrest in a patient without a history of cardiac disease. New seizure in the absence of a previous seizure disorder. Worsening encephalopathy in the absence of liver disease. What about unexpected death? All serious events that result in unexpected death MUST be reported to CERU within 24 hrs of becoming aware of the event. For example: a burn patient is improving and getting better but then dies unexpectedly the next morning. This is a serious adverse event (results in death) and was unexpected and is to be reported immediately. Oct NP 33

34 What about expected death? For example, a patient with severe burns develops fulminant sepsis is not improving, now has multi-organ system failure. Family has agreed to withdraw treatment and patient dies. This is a serious adverse event but death was expected due to the progression of the underlying disease (sepsis). Do not need to report to CERU. NOTE: As a guideline, events that are captured in the electronic data capture system such as newly acquired infections, bleeding complications, organ dysfunction, etc are considered to be expected events and hence do not need to be captured as SAEs unless they are considered to be related to the study intervention. As with any study there may be other risks or side effects that we do not know about with administration of these study supplements. The Site Investigator must adhere closely to the ICH- GCP Guidelines, however when in doubt he/she can contact the Project Leader for the study. Serious Events Related to Study Intervention For the purposes of the RE-ENERGIZE study, all serious events that are felt to be related to the study intervention must be reported to CERU within 24 hpurs of becoming aware of the event, regardless of expectedness. All events that are serious AND related MUST be reported to Clinical Evaluation Research Unit (CERU) within 24 hrs of becoming aware of the event, regardless of the expectedness of the event. Related events can be defined as one of the following: o Possibly related: Suggests that the association of this SAE with the study supplements is unknown and the event is not reasonably supported by other conditions. o 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. Adverse Events Adverse events are any untoward medical occurrences in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Given the high acuity of diseases and morbidity related to burns, adverse events are NOT to be reported to CERU. Role of Site Investigator While the Research Coordinator may identify a Serious Adverse Event, it is the responsibility of the Site Investigator to confirm the presence of the Serious Adverse Event, to determine the relationship of the event to the underlying disease and it s relationship to the study intervention. When reporting a SAE, the Research Coordinator MUST consult with the Site Investigator/delegate. The latter must sign both the initial and follow up SAE forms. Oct NP 34

35 Time Frames for reporting to CERU This reporting to CERU is done in 2 phases: 1. The Serious Adverse Events Initial Report must be completed in REDCAP, printed and faxed to CERU within 24 hrs of becoming aware of each event. 2. The Serious Adverse Events Follow-up/Final Report must be completed in REDCAP, printed and faxed to CERU within 10 days from becoming aware of the event. The Project Leader will collaborate with the Site Investigator to assess the need for additional details and further follow-up reporting. An Unexpected Adverse Event, regardless of relatedness A Serious Adverse Event + OR A Related Adverse Event, regardless of expectedness Site Investigator or Research Coordinator identifies SAE Research Coordinator completes Initial SAE Report in REDCAP, prints and faxes report to CERU Project Leader within 24 hours of becoming aware of the event (Fax # ) Research Coordinator reports SAE to local Ethics Board as per required timelines Research Coordinator completes Follow-up/Final SAE Report in REDCAP, prints faxes report to CERU Project Leader within 10 days from becoming aware of the event (Fax # ). The Project Leader will collaborate with the Research Coordinator to assess the need for additional details and further follow-up reporting. Oct NP 35

36 SAEs on REDCAP SAE forms must be completed on REDCAP, the web-based system that will be used for the RE-ENERGIZE Study. REDCAP may be accessed via or directly at: The SAE forms are listed at the bottom of the Event Grid. Refer to the worksheets provided for the data elements required. All SAEs must be entered in real time into REDCAP. Upon completing the form, save the form. After saving the form, save as a PDF using the button shown below onto your desktop. Print the PDF copy. The Site Investigator must sign the hard copy of the form. Fax the signed form to CERU along with the SAE Cover Sheet found in the Tools section of the Study Procedures Manual at Include all additional documents indicated on the SAE form with the fax. Oct NP 36

37 Initial SAE Report All Serious Adverse Events that are unexpected or related must be reported to CERU within 24 hrs of becoming aware of the event by filling out the Serious Adverse Events Initial Report on REDCAP, printing and faxing the form to (see worksheet on next page). This form must be completed by the Site Investigator/delegate in consultation with the Research Coordinator and requires the signature of the Site Investigator. Only include those SAEs that occur during the study period. This includes the period from the time of randomization to the end of the study period (10 days post last successful grafting or ICU/burn unit discharge or 6 months from ICU admission, whatever comes first). For a SAE that occurred during the study period and is still not resolved by the end of the study period, refer to section on SAE follow up. All known data elements on the form must be completed within 24 hrs of discovery of the event. It may be that certain aspects of the form may change (for example, the date of recovery may not be known at the time of reporting) and this should be made clear in the narrative form that will follow at a later date. The following fields of the Initial form must be completed: Patient identification o Your RE-ENERGIZE site number o RE-ENERGIZE enrollment number o Age o Gender, select male or female o Height o Weight Name of Site Investigator Name of person reporting the SAE SAE #: Record the sequential SAE # for the patient; i.e. for the first SAE for the patient, enter 01. For the second SAE for the patient, enter 02. Serious Adverse Event Reported (only one per form): Record the event that you are reporting (must be serious and unexpected). Do NOT record death (outcome) as a SAE but the underlying cause of death. Do not record respiratory failure as a SAE but what was felt to cause the respiratory failure i.e. sepsis. Date SAE reported Date became aware of SAE Seriousness of the SAE: (select all that apply): o patient died (if so, record this date in the Outcomes section) o life threatening o requires or prolongs hospitalization o results in persistent or significant disability/incapacity o may require medical or surgical intervention to prevent one of the other outcomes. o congenital anomaly/birth defect o other serious medical event Oct NP 37

38 Outcomes: Select the most appropriate at the time of the initial report: o complete recovery/return to baseline (include date of recovery) o alive with sequelae o death (include date of death) o SAE persisting o unknown/lost to follow up Record the date (dd/mmm/yyyy format) and time (hh:mm) for the following: o Onset of SAE o ICU admission o Start of study supplement o Stop of study supplement (if available at the time of this report) Action taken: Select all that apply from the following o none o uncertain o procedure or physical therapy o blood or blood products o prescription drug therapy o non-prescription drug therapy o hospitalization o IV fluids o Other Action taken with Study Supplements: Select only one of the following: o none (including not on study supplements) o dose reduced, interrupted or therapy delayed (include date/time) o study supplements stopped permanently due to SAE (include date/time). Relationship of SAE to the study supplements: The determination of the relationship of the event to the supplements is to be done by the Site Investigator/delegate in collaboration with the Research Coordinator. To assist the Investigator in making this assessment, the following definitions have been provided (select only one): o o o o Not related: A serious adverse event that is clearly due to extraneous causes (disease, environment, etc.) and does not meet the criteria for drug relationship listed under Possibly or Probably. Unlikely related: A serious adverse event that is more likely due to other causes than the study supplements Possibly related: Suggests that the association of this SAE with the study supplements is unknown and the event is not reasonably 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. Oct NP 38

39 Once SAE form completed, save by clicking PDF with saved data, print and fax to CERU along with the SAE Fax Cover Sheet found in the Tools section of the Study Procedures Manual at # Attention: Project Leader RE-ENERGIZE See the following page for the Initial Report Worksheet. Oct NP 39

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41 Follow-up/Final SAE Report For every SAE that was reported, a Serious Adverse Events Follow-up/Final Report must be completed in REDCAP, printed and faxed to CERU within the following time frame: within 10 days from becoming aware of the event. In the event that the event has not resolved, been explained or stabilized, the Project Leader will collaborate with the Research Coordinator for additional details and further follow-up reporting. This form must be completed by the Site Investigator/designate by reviewing the Serious Adverse Events Report (Initial) and the patient s medical chart. To make this process easier, it is strongly recommended that this be done as close to the event as possible. Since the information in the Follow-up/Final Report will be reviewed by the Data Monitoring Committee, it must include details on the patients admitting diagnosis, co-morbidities, a chronological complete narration of the events leading to the SAE, the nature of the SAE, action taken with the study supplements, the outcome and the relationship of the event to the study supplements. The following additional documentation is required and is to be attached to the follow-up/final report: Medication the patient received in the 48 hours before the onset of the SAE Laboratory results related to the SAE must also be provided. o Examples: if the event is cardiac arrest, provide cardiac enzymes; if the event is cholestasis/pancreatitis, provide liver function tests & amylases. For further clarification about which lab tests are relevant, the Research Coordinator is encouraged to ask the Site Investigator. All data fields in the Follow-up/Final form must be completed: Patient identification: Site #, enrollment # and SAE # can be copied from the initial reporting form. Patient medical history, co-morbid illness and reason for admission to hospital: provide a detailed narrative of this information. Admitting diagnosis to ICU and chronological events leading to the SAE: provide a detailed narrative of this information Chronological events proceeding the SAE until time of report: provide a detailed narrative of this information and attach other reports/details as needed. Concomitant Medications: list all medications given within 48 hrs before the onset of the SAE. Laboratory Results and Investigations: record all lab results and investigations done that are pertinent to the SAE. For example, cardiac enzymes, ECG results in the event of a cardiac arrest. Confirmation of Unexpected nature of the SAE: record the pertinent clinical features that, in the opinion of the Site Investigator, made him/her think that the event was unexpected vs. due to the progression of underlying disease. Relationship of SAE to the Study supplements: The determination of the relationship of the event to the supplements is to be done by the Site Investigator/delegate in collaboration with the Research Coordinator. To assist the Investigator in making this assessment, the following definitions have been provided: o Not related: A serious adverse event that is clearly due to extraneous causes (disease, environment, etc.) and does not meet the criteria for drug relationship listed under Possibly or Probably. o Unlikely related: A serious adverse event that is more likely due to other causes than study supplement. Oct NP 41

42 o o Possibly related: Suggests that the association of this SAE with the study supplement is unknown and the event is not reasonably supported by other conditions. Probably related: Suggests that a reasonable temporal sequence of this SAE with study drug administration exists and the association of the event with the study supplement seems likely. Rationale for relationship of the SAE to the study supplements vs. progression of underlying disease: If the event is considered to be related to the study supplement, record the pertinent clinical features that, in the opinion of the Site Investigator, made him/her think that the event was related to the study supplements vs. the progression of underlying disease. Refer to the definitions of degree of relationship to the study supplements (not related, unlikely related, possibly related, probably related). Outcomes: Select the most appropriate at the time of the FOLLOW-UP report o complete recovery/return to baseline (include date of recovery) o alive with sequelae o death (include date of death) o SAE persisting o unknown/lost to followup Action taken: Select all actions taken from the onset of SAE, including those that occurred between the initial report and the follow-up report: o none o uncertain o procedure or physical therapy o blood or blood products o prescription drug therapy o non-prescription drug therapy o hospitalization o IV fluids o Other Action taken with Study Supplements: o none (including not on study supplements) o dose reduced, interrupted or therapy delayed (include date/time) o study supplements stopped permanently due to SAE (include date/time). Event reported to IRB (Institutional Review Board) / REB (Research Ethics Board): indicate whether this event was reported to your IRB/REB. For Medical Monitor Section: this is to be filled out by the Medical Monitor. Further Details: add any further details concerning the SAE. The completed Follow-up/Final Report must be signed by the Site Investigator and faxed to CERU with copies of the relevant medication and lab documentation to: Fax # Attention: Project Leader, RE-ENERGIZE See the following page for the Follow-up/Final Report Worksheet. Oct NP 42

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45 SAE Follow up Any subject who experiences a serious adverse event during the study period, should be followed by the Research Coordinator until the event: o resolves o an outcome is reached, or o the event is otherwise explained or stabilized. The Project Leader will follow up with the Research Coordinator at the site to obtain documentation regarding the status of the subject. This information will be forwarded to the Data Monitoring Committee. If follow-up information reveals that the event no longer meets the serious, unexpected, or drug related criteria, this information will be provided to Health Canada, the Medical Monitor, the US Department of Defense, the Data Monitoring Committee, Steering Committee & the manufacturer of the investigational products Unblinding Final procedures related to unblinding will follow pending discussion by the Data Monitoring Committee (also known as the Data Safety Monitoring Board). Proposed procedure for unblinding is as follows: The investigational products used in the RE-ENERGIZE study are supplements that are not felt to be associated with risks and unlike investigational drugs, there are no antidotes to these supplements. Hence, in the event of an adverse event or medical emergency or accidental administration of the study intervention to a patient participating in the study, the treatment of the patient is not dependent on the knowledge of the study treatment code and if deemed necessary, the study intervention can be stopped. It has been proposed that Code breaking (or unblinding) procedures will only be requested by the Data Monitoring Committee. Oct NP 45

46 Data Collection & Electronic Case Report Form Completion For complete instructions on entering data on the electronic data capture system (REDCAP), refer to the CRS and REDCAP Manual. Study Days Data for the RE-ENERGIZE Study is to be collected according to Study days. Study Days are defined according to the calendar clock as below: Study days are defined as follows, regardless of when randomization occurs: Study Day 1 = ICU admission day i.e. from date & time of ICU admission to 23:59 of that same calendar day Study Day 2 = from 00:00 to 23:59 hrs the next day (24 hr period) Study Day 3 = from 00:00 to 23:59 hrs the next day (24 hr period) and so on Example 1. For a patient that is admitted before midnight i.e. on March 8th, 14:00: Study Day 1= 14:00 to 23:59 Study Day 2 = 00:00 to 23:59 Study Day 3 = etc... Example 2: When a patient is admitted after midnight patient is randomized Mar 9 th, 03:00 hrs, the study days would be: Study Day 1= 03:00 hrs to 23:59 Study Day 2 = 00:00 to 23:59 Study Day 3 = etc... Duration & Type of Data Collection The duration of data collection and frequency will vary depending upon each ecrf and is outlined below (and in the instructions in the Mock Case Report Forms): Collected once: Initial Burn Assessment Baseline Oct NP 46

47 Nutrition Assessment/Timing Hospitalization Overview: upon hospital discharge Follow-Up: at 6 months from time of admission to ICU Collected daily from randomization until 7 days post last successful grafting: Dose of study intervention received (as # packets per interval) Collected from Study Day 1 (ICU admission) until 10 days post last successful grafting: Daily o Organ Dysfunction (daily for first 2 weeks while ventilated) o Labs (while ventilated) o Daily Nutrition o Daily Monitoring (compliance with intervention, SAEs, Protocol Violations) o Burn related Operative Procedures o Blood Products o Concomitant Medications o Antibiotics/Antifungals/Antivirals o Microbiology Weekly/other specified intervals o Nutrition Assessment/Timing (weekly prescriptions) o Organ dysfunction (weekly while ventilated after first 2 weeks) o Study Blood Work o Infection Adjudication Nutritional Assessment/Timing and Daily Nutrition data The Research Coordinator is to work with the dietitian in the unit to ensure that she/he is trained on the type of nutrition data that needs to be collected. While the dietitian will collect the data on worksheets, the Coordinator will record the data on to REDCap. The following documents should be forwarded to the dietitian collecting the data for the study prior to the start of the trial: Standardization of Nutrition Practices (Appendix C) Mock Case Report Form: Nutritional Assessment/Timing Mock Case Report Form: Daily Nutrition Source Documentation As per ICH GCP (1.51) source documents are original documents, data and records. Site must ensure source documents are available to verify all data collected for the RE-ENERGIZE study. Patient Folders will be provided to the research sites in order to aid in the collection and organization of Patient-specific source documentation. The Patient Folders will contain the following sections: Signed Informed Consent Form Inclusion/Exclusion Worksheet Randomization Confirmation Mock Case Report Forms (ecrfs) Lab Sample Logs Protocol Violations/SAEs Investigator Confirmation Queries/Other Oct NP 47

48 Infection Adjudication In order to determine the incidence of infections in patients enrolled to the RE-ENERGIZE study, an assessment needs to be made by the Site investigator/md delegate as to whether a newly acquired infection exists and this requires adjudication. A suspicion of infection is determined by the antibiotics received by the patient and the data on positive cultures. All antibiotics and cultures that lead to a suspicion of infection will be recorded on the appropriate electronic case report form (i.e. REDCAP). Once a clinical suspicion of an infection has been identified, the Site Investigator/MD delegate MUST adjudicate the data to determine the following: Is there an infection or not Degree of certainty of the infection Category of Infection Since the data related to the Infection Adjudication process is generated electronically and the adjudication is to be conducted on REDCAP, please refer to the CRS/REDCAP Manual for detailed instructions. Follow-up (6 months) A follow up is to be conducted 6 months ( 14 days) after ICU admission. If a subject cannot be reached to obtain the information, an effort must be made to determine the reasons. It is encouraged to schedule reminders in your calendar for this follow up. Oct NP 48

49 Appendices A. Delegation of Authority Log B. Dosing Weight Chart C. Standardization of Nutrition Practices D. Investigational Product Order/Shipment Form E. Pharmacy Delegation & Training Log F. Investigational Product Worksheet G. Investigational Product Dispensing Log H. Investigational Product Accountability Log (Nutrestore ) I. Investigational Product Accountability Log (Maltrin M100) Oct NP 49

50 Delegation of Authority Log This log is used by the Qualified Investigator (i.e. Site Investigator) to indicate the Site Staff that have a material effect on the conduct of the Study and to whom the Investigator has delegated significant Study related duties/tasks. The signatures and details on this log will also facilitate tracking of edits/changes of the Site records. This log is to be kept by the Qualified Investigator and the Sponsor. Name of Qualified Investigator: Signature of Qualified Investigator: Print Name Signature Initials Study Role (Qualified Investigator*, sub- QI*, Research Coordinator (RC), Pharmacist, Technician, Dietitian Key Delegated Tasks Dates Reference numbers (see next page) Start End *Qualified Investigator: the Site Investigator responsible for the conduct of the RE-ENERGIZE study at your site. *Sub QI: Investigator other than the Qualified Investigator that is responsible for tasks related to the RE-ENERGIZE study at your site. September 10 th 2010 Reference: ICH GCP and

51 Delegation of Authority Log Print Name Signature Initials Study Role (Qualified Investigator, sub- QI*, Research Coordinator (RC), Pharmacist, Technician, Dietitian Key Delegated Tasks (see next page) Start Dates End September 10 th 2010 Reference: ICH GCP and

52 Key Delegated Tasks Delegation of Authority Log Reference Number Key Delegated Tasks 1 Screening subjects for eligibility 2 Conducting informed consent discussions for eligible patients 3 Obtaining written informed consent 4 Patient enrolment/randomization and follow-up 5 Checking eligibility criteria 6 Daily monitoring of patient health, safety and study compliance 7 Data collection, includes: Case Report Form entries Case Report Form corrections Data query resolution 8 Source documentation maintenance, includes: Study worksheets, checklists, monitoring sheets Data from electronic & hard copy medical chart 9 Reporting of Protocol Violations/Unanticipated Problems involving risk 10 Identification of Serious Adverse Events and documentation 11 Maintenance of Regulatory Documents 12 REB submissions and communications 13 Perform study specific training 14 Performing clinical assessments including burn outcomes, SAEs and ICU infection adjudication 15 Confirmation of completeness and accuracy of data collected 16 Maintenance of Product inventory 17 Checking of treatment assignment online 18 Study treatment dispensing & accountability, including maintenance of logs 19 Optimizing delivery of enteral nutrition and compliance with Guidelines for Nutrition 20 Drawing of blood samples 21 Processing and Storage of blood supplies 22 Batch shipping of frozen samples September 10 th 2010 Reference: ICH GCP and

53 Dosing Weight Chart Dose # Dose # Dose # Body Body Body weight kg Number of packs Total g/day weight kg Number of packs Total g/day weight kg Number of packs Total g/day September 10 th 2010

54 Dosing Weight Chart Dose # Dose # Dose # Body weight kg Number of packs Total g/day Body weight kg Number of packs Total g/day Body weight kg Number of packs Total g/day September 10 th 2010

55 Standardization of Nutrition Practices Given the metabolic complications and increased nutritional requirements in burns patients, the provision of nutrition support is a challenging task and variability in nutrition practices across burn units exists 1. 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 prescription of enteral and parenteral nutrition, micronutrient delivery and practices related to withholding feeds for high gastric residual volumes and use of motility agents in these patients. Based on the literature and providing for some flexibility for current practices across the participating sites, we are recommending compliance with the following nutritional practices for all patients enrolled in the study. After reviewing the practices at all the participating sites, these ranges below will allow for most current practices to continue. 1. Prescribed Energy needs should be calculated using one or more of the following methods: a) Measured Energy Expenditure by Indirect Calorimetry 2,3, preferred option, if available i. MEE X b) Basal Energy Expenditure (BEE) using Harris-Benedict Equation as follows: i. If 50% Burn Surface Area, use BEE x ii. If < 50% Burn Surface Area, use BEE x BEE Women: ( 9.6 x weight* in kilos ) + ( 1.8 x height in cm ) - ( 4.7 x age in years ) BEE Men: 66 + ( 13.7 x weight* in kilos ) + ( 5 x height in cm ) - ( 6.8 x age in years ) c) Predictive equations such as Carlson et al or Milner et al In the event that the patient requires parenteral nutrition, do not exceed energy intake of 5 mg/kg*/min of dextrose 6 * Weight: use pre-burn weight. For Obese patients, if your standard practice is to adjust weight for obesity, use the weight you would use. If not, use ideal body weight. Energy needs are to be adjusted according to the progression of wound healing. 2. Prescribed Protein needs should be calculated using the following: According to % burn surface area i. If > 50% burns, use 2g/kg*/day to 3g/kg*/day ii. If < 50% burns, use 1.5 g/kg*/day to 2 gm*/kg/day * Weight: use pre-burn weight. For Obese patients, if your standard practice is to adjust weight for obesity, use the weight you would use. If not, use ideal body weight. Protein needs are to be adjusted according to the progression of wound healing, urinary urea nitrogen, or other biochemical markers used in your standard practice. September 10 th

56 3. Vitamin & Mineral Prescription should be given as follows or depending upon blood levels (if blood testing is done as part of routine practice) : Vitamin C: mg/day Vitamin A: 0-10,000 IU/day Vitamin D: according to serum levels Vitamin E: mg/day Zinc (not elemental): mg/day Copper Sulfate: mg/day Selenium: micrograms/day Magnesium:0-600 mg/day Folate: mg/day Thiamin: mg/day Early supplementation by high dose IV Vitamin C (66 mg/kg/hr) within the first 48 hrs is allowed 7. Standard multivitamin/mineral preparations are allowed (I, 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. 4. Specialized nutritional formulas are not allowed such as: i. Arginine enriched formulas (formulas that contain > 6 gms arginine/l) Pivot (13 gm/l), Perative (8 gm/l) would not be allowed ii. Glutamine supplements or formulas enriched with glutamine Impact Glutamine Vivonex Plus Glutasolve/other glutamine powders 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. 5. Optimization of the Delivery of Enteral Nutrition: The use of enteral nutrition is preferred over parenteral nutrition in burn patients 2. Interruptions to the delivery of enteral nutrition should be minimized while adopting strategies such as elevating the head of the bed (unless otherwise contraindicated, gastric residual volume threshold of 250 ml, use of motility agents and small bowel feeding tubes). Refer to attached Enteral Feeding Algorithm on next page for more details. Ongoing monitoring of the volumes of delivery of enteral nutrition and an action plan to ensure that the recommended prescribed needs are being met is recommended as part of the study protocol. 6. Glycemic control: The use of a glycemic control protocol (or the use of insulin) to control blood sugars between the ranges of at least 80 mg/dl to a maximum of 180 mg/dl ( mmol/l) is recommended in order to avoid hyperglycemia, while minimizing the risk of both iatrogenic hypoglycemia and other harms associated with a lower blood glucose target. September 10 th

57 September 10 th

58 References 1 Masters B, Wood F. Nutrition support in burns--is there consistency in practice? J Burn Care Res Jul-Aug;29(4): Practice Guidelines for Burn Care, ABA, Journal of Burn Care and Rehabilitation, April Chan MM, Chan GM. Nutritional therapy for burns in children and adults. Nutrition 2009 Mar;25(3): Carlson DE, Cioffi WG Jr, Mason AD Jr, McManus WF, Pruitt BA Jr. Resting energy expenditure in patients with thermal injuries. Surg Gynecol Obstet Apr;174(4): Milner EA, Cioffi WG, Mason AD, McManus WF, Pruitt BA Jr. A longitudinal study of resting energy expenditure in thermally injured patients. J Trauma Aug;37(2): Dickerson RN. Estimating energy and protein requirements of thermally injured patients: art or science? Nutrition May;18(5): Tanaka H, Matsuda T, Miyagantani Y, et al.reduction of Resuscitation Fluid Volumes in Severely Burned Patients Using Ascorbic Acid Administration. A Randomized, Prospective Study. Arch Surg. 2000;135: September 10 th

59 Investigational Product Order/Shipment Form Ship to: <<NAME of Pharmacist/delegate>> <<Site Pharmacy>> <<Pharmacy Delivery Address>> Date Phone Fax Please send order attention: Elizabeth Luzier Fax: or Tel: NOTE: To maintain blinding, please order equal quantities of both products! Product Description Nutrestore (L-Glutamine) Quantity Investigational Product Shipment Details Requested Lot # Expiry Date Quantity Maltrin M100 (Maltodextrin) TO BE COMPLETED BY THE RECEIVER FOR SITE PHARMACIST/TECHNICIAN: Please carefully review the information below for this shipment of investigational product for the RE-ENERGIZE trial. Please acknowledge the receipt of this shipment by completing the information below and returning a copy via fax, Attention: Elizabeth Luzier (303) CONFIRMATION OF RECEIPT: Shipment complete and intact? Name: [ ]- Yes [ ]-No (printed) Damaged or incomplete Signature: Please describe: Date: Oct 26th 2010

60 Pharmacy Delegation & Training Log The participating site pharmacy at has established a Standard Operating Procedure for the RE-ENERGIZE Study. This log (or a similar log) is used by the Pharmacist at each site to: 1) Indicate the pharmacy staff that have been delegated duties/tasks related to The RE- ENERGIZE Study and 2) Ensure that all pharmacy staff that have a material effect on The RE-ENERGIZE Study have been trained on the study procedures. This log (or similar log) is to be kept by the Pharmacy and sent to the Sponsor upon request. Key Delegated Tasks 1. Checking the treatment assignment on the Central Randomization System 2. Preparation and checking of Investigational Product 3. Labeling of Investigational Product 4. Maintaining Dispensing Logs 5. Maintaining Investigational Product Accountability & Destruction Records 6. Other (specify): Pharmacy personnel listed in this log have been trained according to the Standard Operating Procedures. Name of Pharmacy contact*: Signature of Pharmacy Contact: Print Name Signature Study Role (Pharmacist, Technician, etc) Key Delegated Tasks Training (see above) Date of training Trained by *Pharmacy contact: is the main pharmacist/delegate that has been trained by the Methods Centre to carry out all pharmacy tasks related to the RE-ENERGIZE Study at the site. Version: September 10 th 2010 Reference: ICH GCP and

61 Patient Hospital ID# Enrollment # Investigational Product Worskheet Treatment Allocation: Nutrestore (L-Glutamine) or Maltrin M100 (Maltodextrin) 1. Patient s Pre-Burn Weight: kgms 2. Dose of Nutrestore /Maltrin (0.5 gm/kg/day) = 0.5 X #1 = gms Pre burn weight in kgms Total dose per day 3. Divide # 2 by 5 (each packet contains 5 gms of product) and round up* = # packets needed per day 4. Multiply # 3 by 7 = # packets needed per week 5. Prepare blinded labels for # packets needed for the entire week 6. Add labels to the packets ensuring that the code is not visible 7. Complete the Investigational Product Dispensing Log 8. Repeat steps 5-7 on a weekly basis * Alternatively, you may refer to the Dosing Weight Chart to determine the total # packets needed per day September10th 2010

62 September10th 2010 Patient Hospital ID# Enrollment #