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Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. STUDY COORDINATING CENTRE (SCC) Children’s Hospital of Eastern Ontario Clinical Research Unit (CHEO CRU) Support from the Methods Centre at the Ottawa Hospital Research Institute (OHRI) Data management Randomization system CO-INVESTIGATORS & STEERING COMMITTEE Anand Acharya Karen Choong (Steering Committee member) Lynda Khalaf Margaret Lawson (Steering Committee member) Lauralyn McIntyre (Steering Committee member) Dayre McNally (Steering Committee member) Timothy Ramsay (Steering Committee member) Hector Wong (Steering Committee member) ER/ICU physicians, Site Research Coordinators & Site Investigators will have 24/7 pager support from a member of the Steering Committee for clinical queries and concerns REGULATIONS Phase IV study Must adhere to GCP, TCPS and Health Canada Food and Drug Regulations with the following exceptions C.05.006 Authorization: A CTA from Health Canada is not required for Phase IV studies C.05010 (i) Good Manufacturing Practises: do not apply (responsibility of the manufacturer) C.05.012 (e) Records regarding shipment, receipt, disposition, return and destruction of drug: Only Phase I to III studies where a marketed drug is being used outside it’s approved indications, must do drug accountability C.05.011 Labelling: It is acceptable for the marketed drug to be labelled in accordance with its marketing authorization provided that the labelling on the marketed drug is appropriate for the trial. The label information should not compromise the blinding and the expiration date needs to be identifiable. TODAY 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Recruitment, Enrolment & Consent Randomization ICU Procedures Pharmacy Procedures BREAK Lab Procedures eCRF and Data Collection DMSC Monitoring Administrative Information, Other QUESTIONS? Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. OVERVIEW Exclusion criteria present. Patient not eligible. Patient aged newborn to 17 years with shock is started on any vasoactive agent in the PICU or the Emergency Room → Care team notifies study staff Study staff will verify inclusion and exclusion criteria Patient is eligible Enrolled using Deferred Consent OR Informed Consent obtained Patient must be randomized within 6 hours of being started on a vasoactive agent Patient must receive first dose of study drug within 8 hours Randomize Blood sample INTRAVENOUS INTRAVENOUS NORMAL HYDROCORTISONE SALINE PLACEBO IDENTIFICATION OF PARTICIPANTS Where: Identified in the PICU or the Emergency Room Who: ER/PICU nurses, physicians, trainees When: At the time any vasoactive agent(s) of any dose is started for the treatment of shock ELIGIBILITY CRITERIA - INCLUSION Inclusion Criteria 1. Children newborn to 17 years; and 2. On any dose of any vasoactive infusion for at least one hour but ≤ 6 hours. ELIGIBILITY CRITERIA - EXCLUSION Exclusion Criteria 1. 2. 3. 4. 5. 6. 7. 8. Known or suspected HPA axis disease; Received more than one dose of systemic steroids in the last 10 days or any dose of systemic steroids in the last 24 hours; Expected to have treatment withdrawn; Premature infants (<38 weeks corrected GA); Pregnant; Post cardiac surgery; First dose of vasoactive infusion received >24 hours after PICU admission Patient no longer on vasoactive infusion at time of enrollment and/or expected to no longer be on vasoactive infusion at the time first study drug dose would be administered Exclusion Criteria con’t 9. Primary cardiogenic shock is strongly suspected (e.g. clinical signs of heart failure, large heart on chest radiograph etc.); 10. Spinal shock is strongly suspected (e.g. history and physical findings compatible with spinal injury and/or mass); and 11. Hemorrhagic or hypovolemic shock is strongly suspected (e.g. history suspicious of blood or fluid loss). **Criteria #9 to 11 are based on the clinical judgment of the treating physician. ** Consult with MRP to verify exclusion criteria #9 to 11 SCREENING LOG Any patient who is started on a vasoactive infusion within the first 24 hours of PICU admission should be screened for eligibility and included on the study screening log Screening log faxed to Study Coordinating Centre (SCC) first Monday of every month PRISM III score: if collected by your site can enter just the score. Otherwise you will need to complete the PRISM III worksheet for eligible, non-randomized patients INCLUSION & EXCLUSION CHECKLIST Paper inclusion and exclusion checklist completed during screening and filed in study binder Inclusion and exclusion criteria will also be entered into the randomization system and recorded in the electronic case report form (eCRF) CONSENT PROCESS DEFERRED CONSENT Approved by CHEO REB Use of MICYRN REB to facilitate approval at other sites If deferred consent is not approved at your centre, follow normal informed consent process DEFERRED CONSENT PROCESS 1. Patient eligibility confirmed 2. Study staff obtaining consent determines if legal guardian is present 3. If present, study staff determines if (1) MRP has already spoken to legal guardian about child’s medical condition AND (2) there is adequate time to conduct true informed consent o If “YES” to # 1 and #2 use informed consent model o If “NO” to #1 and/or #2 OR if legal guardian is not present use deferred consent model (document in consent note) 4. Patient enrolled and randomized 5. Poster hung at patient’s bedside to state patient has been enrolled in STRIPES study 6. Deferred consent pamphlet given to health care team. Health care team to give pamphlet to family as soon as is appropriate. DEFERRED CONSENT PROCESS 7. Study staff works with MRP and circle of care to determine an appropriate time to speak with legal guardian (all attempts to obtain consent, including asking circle of care if time is appropriate, must be documented in a note to file) 8. Before approaching legal guardian, member of circle of care asks legal guardian if study staff can speak to them 9. Study staff approaches legal guardian for informed consent o Informed consent obtained continue with study procedures o Informed consent refused study drug stopped, study staff to ask legal guardian if data collection can continue and/or if any collected blood can still be analyzed Bedside Poster DEFERRED CONSENT What if a patient enrolled using deferred consent dies before informed consent is obtained? MRP will notify the legal guardian of child’s enrollment into the STRIPES study and ask if Site Investigator can speak to them. If legal guardian says “Yes” • Site Investigator will fully inform legal guardian of all aspects of the study. Legal guardian will decide what to do with any data collected about their child prior to death. DEFERRED CONSENT What if a patient enrolled using deferred consent dies before informed consent is obtained? If legal guardian says “No” • Data that has been collected will be retained, all further data collection will stop. If legal guardian says “No, we do not believe in research” • Data that has been collected will be destroyed. ENROLMENT TIME LINE Time Zero is when patient is started on first dose of any vasoactive agent Vasoactive Infusion started TIME 0 Regardless of consent model used (deferred or informed) randomization must occur between 1 to 6 hours following the first dose of the vasoactive infusion Window for Enrolment and Randomization 1 HR 2 HR 3 HR 4 HR 5 HR First dose of study drug must be administered within the 8 hours following the first dose of the vasoactive infusion First dose of study drug 6 HR < 8 HR Once eligibility is confirmed, but before randomization, study staff should phone the pharmacy to ensure study drug can be dispensed within the 8 hour time frame QUESTIONS? Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. RANDOMIZATION PROCESS BEFORE RANDOMIZATION: Study staff must call pharmacy to ensure study drug can be dispensed within the 8 hour time frame 1. Research Coordinator/Assistant will log in to the randomization system and enter inclusion and exclusion criteria. 2. Research Coordinator/Assistant will receive an email with a pharmacy ID number (ID number will also appear on screen) 3. Each site pharmacy will be given a randomization schema list. RANDOMIZATION PROCESS 4. Research Coordinator/Assistant will indicate ID number from randomization system on order given to pharmacy 5. Pharmacy will match the ID number to the randomization list to determine allocated treatment 6. Research Coordinator/Assistant will print randomization sheet and file in study binder RANDOMIZATION WEBSITE • Developed and hosted by the Methods Centre at the OHRI • https://dms.ohri.ca/Stripes SAMPLE EMAIL Participant Randomization Number to be included on order given to pharmacy Pharmacy will use this number to determine treatment allocation WHAT IF THE RANDOMIZATION SYSTEM IS NOT WORKING? Bring the order form to pharmacy, and inform pharmacy staff Pharmacy staff will assign patient the next sequential number on the site randomization list and allocate treatment Study staff: ensure you get the ID assigned from pharmacy for use on study documents and eCRF Notify the Methods Centre at [email protected] as soon as possible after enrolling patient and inform them of the randomization number that was used Web-based system will be adjusted so the manually assigned number will not be re-assigned later QUESTIONS? Select the red “+” sign to randomize a new participant Complete the inclusion and exclusion criteria, then select “Proceed to Randomize this Participant” Randomization # appears here and in email Print and file in site regulatory binder Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. ICU PROCEDURES: STUDY DRUG *Escalation of Therapy defined as an increase in vasoactive infusion(s) OR any fluid bolus(es) including saline, ringer’s lactate, albumin or blood products for low blood pressure, elevated heart rate or signs of poor perfusion Bolus Dose: 2mg/kg 1 mg/kg q6h until there has been no escalation of therapy* for at least 12 hours If following the initial study drug wean, the patient requires fluid boluses and/or an increase in vasoactive infusion(s), study drug should be increased back to 1 mg/kg q6h until they meet stability criteria again (i.e. no escalation in therapy for at least 12 hours) No escalation in therapy should be determined together with the resident, fellow or staff physician twice daily during morning and evening rounds 1 mg/kg q8h until the patient is off all vasoactive agents for 12 hours Study drug should be continued for a maximum of 7 days/168 hours No wean necessary ICU PROCEDURES: BLOOD SAMPLE • A single blood sample will be collected for analysis of free and total cortisol, vitamin D metabolites, and stratification biomarkers • 3 mL of blood in red top tube (supplies will be provided by the SCC) • Drawn through existing lines or with clinically-indicated bloodwork (no needle poke solely for research test) • Drawn following randomization but prior to initiation of study drug o If access not available prior to study drug, but becomes available within first 24 hours, sample should still be drawn o If < 3 ml can be obtained, sample should still be drawn ICU PROCEDURES: BLOOD SAMPLE • The person who draws the blood sample will need to complete the requisition to indicate how the site laboratory should separate the sample • If drawn before study drug: all cryovials should be checked off on form • If drawn after initiation of study drug, only blue and pink cryovials should be filled (no cortisol analysis) REQUISITION FORM ICU PROCEDURES: CO-INTERVENTIONS • The requirement for co-interventions will be left to the discretion of the treating physician. • The Surviving Sepsis Guidelines Flowchart should be given to the health care team for easy reference but it’s use is not mandated. ICU PROCEDURES: OPEN-LABEL STEROIDS • We encourage attending physicians to avoid open-label hydrocortisone use. • If open-label hydrocortisone is used: o The research assistant will speak with the treating physician to determine the reason(s) why o Patient will remain in the study • Open-label hydrocortisone use is not considered a protocol violation ROLE OF THE ICU/ER MEDICAL TEAM (NURSE AND PHYSICIANS) • Notify study staff as soon as a patient with shock is started on any vasoactive agent • Assist study staff to determine exclusion criteria #7 to 9 • Assist study staff to identify an appropriate time to approach legal guardian about consent, ask legal guardian permission for study team to approach • Administer study drug according to protocol (includes determining stability criteria) • Draw blood sample and complete requisition form BEDSIDE PACKAGE The bedside package should include: Deferred consent pamphlet Bedside poster Blood sample supplies pre-labelled collection tube, cryovials, specimen bag, lab requisition provided by SCC Blood sample instruction sheet Pre-printed order form Surviving Sepsis flowchart Study information sheet for PICU staff Study procedure flowchart Site study team contact information All the above documents will be available on the study website QUESTIONS? Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. PHARMACY PROCEDURES Specific pharmacy procedures will vary from site to site depending on local pharmacy SOP No central pharmacy for this study, but site pharmacists can contact the Manager of Drug Distribution at the SCC with questions/concerns Contact information will be included in pharmacy SOP ORDERING & PREPARING STUDY DRUG Each site pharmacy responsible for procuring and storing the study drug for participants enrolled at their site. Recruitment will be capped at 24 patients per site Expected that each site will recruit between 6-12 patients Pharmacies prepare hydrocortisone and placebo solutions for the patients enrolled at their centre Hydrocortisone : made up as a 10 mg/ml intravenous solution Placebo : normal saline solution made up in equivalent volume TIMELINE First dose of the study drug must be administered within 8 hours from the time when the patient was first started on a vasoactive agent (Time 0) Before entering patient information into randomization system, study staff will contact pharmacy to ensure study drug can be dispensed before 8 hour cut-off If study drug is given beyond the 8 hour window, the Site Research Coordinator will record this as a protocol violation and inform the SCC RANDOMIZATION & BLINDING Randomization lists: only accessible to Methods Centre at OHRI and to pharmacy staff at each site Should not be seen by anyone else directly involved with the study Pharmacies must maintain a list of randomized patients and treatment allocation Pharmacy staff should ensure that any labels used on the study drug package do not unblind the participant PHARMACY HOURS OF OPERATION & ENROLMENT Hours during which patients can be enrolled into the study will vary from site to site depending on the availability of the oncall research coordinator and the hours of operation of the pharmacy. Prior to initiation of the study, meet with your pharmacy team to determine during which hours study patients can be enrolled. Consider 8-hour limit to dispense the study drug when determining the time window for study enrollment. OPTION TO ENROLL DURING PHARMACY OFF-HOURS • Site pharmacy prepares numbered medication kits following the randomization list and stores them in PICU • Stock solutions rather than patient specific volumes • Nurse would have to withdraw the appropriate volume required for the bolus (2mg/kg) • Pharmacy would take over preparing the doses once they opened • Kits would need to be re-made every X number of days (depending on storage time your pharmacy uses) QUESTIONS? Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. BLOOD SAMPLE SUPPLIES Instruction sheet for bedside nurse will be available on the study website SOP for lab staff Lab supplies provided to each site by SCC Blood sample supplies (pre-labelled collection tube, cryovials, specimen bag, research requisition) Pre-labelled storage boxes (1 x -80°C and 1 x -20°C box) TDG approved shipping supplies BLOOD SAMPLE PROCEDURES - LAB Centrifuge collected blood sample Aliquot serum into pre-labeled 2mL cryovials according to study requisition and according to prioritization order Store cryovials in -20°C or -80°C as indicated on requisition Samples stored at site until end of the study recruitment period (maximum of 12 months) Cryovials will be colour-coded to facilitate the above SHIPMENT OF SAMPLES Samples shipped to SCC at end of storage period Notify Study Coordinator by email when the samples are shipped. Include in the email a complete inventory list of the samples being sent. The person shipping the samples must be trained in the Transportation of Dangerous Goods (TDG). Samples must be shipped from each site on dry ice according to the TDG Regulations for a Class 6.2 and 9.0, Category B specimen Packed according to the appropriate International Air Transport Association (IATA) packing instructions CENTRAL LAB Eastern Ontario Regional Laboratory Association (EORLA) laboratory at the Ottawa Hospital TOH will act as the central lab Central Lab Contact Information: Carol Ann Jodouin, Manager, Clinical Research Operations EORLA/ALERO Site: The Ottawa Hospital, General Campus 501 Smyth Road, Ottawa, Ontario K1H 8L6 Phone: 613-737-8899 ext. 79010 or ext. 16038 Email: [email protected] QUESTIONS? Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. REDCAP REDCap (CHEO RI instance) Data stored on secure servers at CHEO CRU Unique user ID and password Notify study coordinator who will need access from your site Each site will only see data from their own site REDCAP BASICS The following instructions will also be included in the eCRF SOP https://redcap.cheori.org/ How to access project Staring a new record Editing a record Saving data form Form status Validation of entry fields ECRF SECTIONS 1. Patient Eligibility Criteria & Enrolment Information 2. General Demographic Baseline Information 3. PICU Admission PRISM III 4. PELOD-2 Organ Dysfunction Score on Admission and Daily Until Off of Vasoactive Agents 5. Duration of Vasoactive Infusions Administered During PICU Admission 6. Daily Administration of Vasoactive Agents During PICU Admission 7. Fluid Bolus and Intake/Output 8. Mechanical Ventilation 9. Acute CPAP or BiPAP Ventilation 10. Research Blood Sampling & Adrenal Testing 11. Use of Ranitidine, Pantoprazole or Lanzoprazole 12. Red Blood Cell Transfusions and Hemoglobin 13. Gastrointestinal Bleeding 14. Daily Insulin Infusion 15. Lab Results 16. Cultures & Antibiotics 17. Outcome Information 18. Study Drug 19. Unblinding and Open-Label Steroid Use 20. Economic Variables 21. Protocol Deviation/Violation Reports 22. Serious Adverse Event Reports 23. Co-Enrolment 24. Case Report Sign Off 25. Research Blood Sample Results & Group Assignment **THIS SECTION WILL BE COMPLETED BY THE SCC** DATA COLLECTION TIMELINE Data can be collected on a daily basis or at the end of PICU admission with the following exceptions: 1. Economic Variables Some of the data collected in this section may not be recorded in the patient’s chart and will need to be collected in real time. Examples: Nurse: Patient ratio Where caregiver is staying Caregiver work status DATA QUERIES Data queries will be addressed using the Data Resolution Workflow in REDCap 1. 2. 3. 4. 5. SCC will open data query within the Data Resolution Workflow application SCC will notify Site Research Coordinator that a data query has been opened Site Research Coordinator must log into the eCRF, review and respond to the query Once the query has been resolved, the SCC will close the query REDCap system will record and document entire process PROTOCOL VIOLATIONS/DEVIATIONS Protocol deviations and violations must also be documented in the eCRF Examples of a protocol deviation in the STRIPES study are: Patient is randomized but does not receive the study drug Patient died before receiving study drug Examples of a protocol violation in the STRIPES study are: Patient is enrolled > 6 hours after being started on a vasoactive agent First dose of study drug is given > 8 hours after being started on a vasoactive agent Enrolment of a patient not meeting inclusion criteria Failure to report a serious adverse event Study medication dispensing or dosing error Study drug not weaned when patient meets weaning criteria Patient is un-blinded SAES TO BE REPORTED Screened from randomization to 28 days post-randomization or discharge (whichever is later) Severe gastrointestinal bleeding that requires transfusion or surgery; 2. Gastric perforation, or 3. Death. 1. • Since ICU patients commonly develop complications of critical illness, related or unrelated to the reason for their admission to the ICU (e.g. nosocomial infection, organ failure, myocardial infarction) these often expected events in the course of patients requiring life support will not be reported as SAEs in the STRIPES Pilot Study SAES TO BE REPORTED SAE reporting form completed in eCRF Notify study coordinator when a SAE report is completed at your site SAE report must be signed by Site Investigator E-signed or printed, signed and faxed to SCC Time frame for sending out depends on: SAE severity grading Relationship between SAE and study participation Reporting time frames will be specified in the study SOP ELECTRONIC SIGNATURE Site Investigators will be able to “e-sign” eCRF Sign-Off Page and SAE reports in REDCap Once section is e-signed, data cannot be changed https://redcap.cheori.org/ QUESTIONS? REDCAP BASICS How to access project 1. Enter your personal login information to access the eCRF. 2. Click on the “My Projects” tab at the top of the screen Select “STRIPES Pilot RCT” 3. This will take you to project homepage. REDCAP BASICS Starting a new record or Editing a record New participant: Select “Add/Edit Records” from the menu on the left-hand side of the screen Enter the new study ID code and press the “Tab” or “Enter” button Existing participant: Choose the participant ID code from the “Complete” or “Incomplete” drop down menu, or Enter their ID code and press the “Tab” or “Enter” button, or Select “Record Status Dashboard” and select the appropriate section of the eCRF. REDCAP BASICS Saving Data Form Forms do NOT save automatically Highly recommended to save as you go along Save Record: Will save & take you back to the project homepage. Save and Continue: Will save & remain on the same section. Save and go to Next Form: Will save & take you to the next section. REDCAP BASICS Form Status Gray Circle: No data has been entered Red Circle: Form saved as Incomplete Yellow Circle: Form saved as Unverified Green Circle: Form saved as Complete REDCAP BASICS Validation of entry fields Data entry fields validated when possible Range of expected values entered when possible Number of decimal places required validated Fields marked as required REDCAP BASICS E-Signature Data entry fields validated when possible Range of expected values entered when possible Number of decimal places required validated Fields marked as required Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. DMSC MEMBERS The Data Monitoring and Safety Committee will include: A senior biostatistician (Dr. Dean Fergusson, DMSC Chair) A pediatric endocrinologist (Dr. Alex Ahmet) A pediatric intensive care specialist (Dr. Ari Joffe) DMSC TERMS OF REFERENCE The DMSC will review all serious adverse events and will communicate directly with the principal investigator. There will be no stopping rules; DMSC can make recommendations to the PI who will communicate back to the Steering Committee at the end of the trial regarding any safety concerns for the full trial. The DMSC will meet every 3 months during the conduct of the study. If deemed necessary, the DMSC may meet more frequently. Between meetings, the DMSC will receive information concerning post-randomization serious adverse events from all participating centers. DMSC TERMS OF REFERENCE For each meeting, the Steering Committee will provide the DMSC with tabulated information on SAEs by intervention group and by study center (blinded as group A and B). After each meeting, the DMSC chair will provide the PI with a letter stating the general outcome of the meeting and any suggested changes to the design or conduct of the study. At completion of the trial, the Steering Committee will provide the DMSC with analyses by group. Relative rates of gastrointestinal bleeding, infections and hospital mortality. Controlled for centre and will provide both unadjusted analyses and analyses adjusted for age and PRISM score. QUESTIONS? Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. MONITORING VISITS A site monitoring visit may be conducted by the SCC up to 3 times during the course of the study: At study start up Mid-way through the recruitment period At study close out MONITORING REPORT SCC will provide the site with a monitoring report within 5 business days of visit/teleconference. Sites responsibility to respond to any observations within 30 days. There should not be any unresolved issues at the following monitoring visit. All monitoring correspondence should be stored in the site regulatory binder. QUESTIONS? Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong. STRIPES Website http://stripes.ccctg.ca/ All study documents available Contact information Links to REDCap and randomization web-site News and newsletters Will also send email when important updates/documents are posted Suggestions welcome MICYRN MICRYN REB application form must be submitted to your local REB with application Hope is that this will facilitate approval of deferred consent model across all sites Contracts Contracts have been sent out to each site along with site budget Contact Study Coordinator with any issues/concerns Travel Receipts Envelope provided in folder to send travel receipts to SCC for reimbursement Reimbursed according to CIHR policies Co-Enrolment Age of Blood in Children in Pediatric Intensive Care Units (ABC-PICU) Squeeze trial? Will be discussed with CCCTG group on June 17th Regulatory Binder SCC will provide each site with a regulatory binder QUESTIONS?