For Administrative Use Only
REB File Number: / Date Received: / Initials:/ The University of British Columbia
Clinical Research Ethics Board
Office of Research Services
Room 210, Research Pavilion, 828 W. 10th Avenue, Vancouver, BC V5Z 1L8
Phone: (604) 875-4111 ext. 68918 Fax: (604) 875-4167
APPLICATION FOR CLINICAL ETHICAL REVIEW (see Guidance Note #1)
to be completed with reference to CREB Guidance Document
All information requested on this form must be typewritten in the space provided. Incomplete submissions will not be reviewed by the CREB.
(Do not leave any box blank--- indicate “not applicable” by typing N/A. Limited additional space is available under item 45.)
The Principal Investigator must have a UBC Faculty Appointment or a staff appointment at an affiliated institution.
1. Principal Investigator / Faculty AdvisorSurname: Whitehouse Given Name(s): Sandra
Academic Rank: Clinical Assoc Prof
UBC Faculty / Department:Med/Pediatrics
UBC Division (If applicable): Ped Emerg Med
Hospital Department (if applicable):Pediatrics
Hospital Division (if applicable):Emerg Med
Phone Number: 604-875-5217 Fax Number: 604-875-xx
E-mail Address: / 2. After reviewing Guidance Note #2, please indicate whether your proposal falls under the “minimal risk” criteria and can be considered for Expedited Review.
YesNo
3. Have you included the CREB fee with this Application? Complete Page 12 of this application for all industry- sponsored research. (see Guidance Note #3)
YesNo
4. Indicate the sites where the research will be carried out. (see Guidance Note #4) Studies carried out at PHC must also be submitted to the PHC REB.
UBC Campus VCHA-VGH VCHA-UBCH C&W PHC BCCA AC Other:
5. Title of Research Proposal (see Guidance Note #5):
CanBEST: Canadian Bronchiolitis Epinephrine Steroid Trial
Proposed Project Period (day/month/year): From: 01 October 2004To: 30 September 2007
Is this proposal closely linked to any other proposal previously/simultaneously submitted to the CREB? (see Guidance Note #5)YesNo
If Yes, describe relationship of this proposal to this primary study:
REB File Number of primary study:
6. Provide a full and accurate listing of all documents submitted with this Application for Ethical Review. List reference numbers, version numbers, and/or dates. Incomplete submissions will not be reviewed. (see Guidance note #6)
Correct # of copies included?Reference # / Version # + Date
Protocol (3 copies, or see (*) below.)Yes
Amendmentsto Full Protocol (3 copies*)YesN/A
Peer Review Reports (3 copies; see box 11*)YesN/A
Investigator’s Brochure (1 copy)YesN/A
Application form (signature copy + 19 copies*)YesN/A
Advertisement to recruit subjects (20 copies*)YesN/A
Letter of initial contact (20 copies*)YesN/A
Subject consent form (20 copies*)YesN/A
Normal/Control subject consent form (20 copies*)YesN/A
Tissue/Blood Banking consent form (20 copies*)YesN/A
Other consent forms (20 copies*)YesN/A
Assent form (20 copies*)YesN/A
Questionnaires, tests, interview scripts, etc. (20 copies*)YesN/A
* If this application can be considered for Expedited Review (when “Yes” has been checked, under Question #2), only ONE copy is required.
7. (see Guidance Note #7) Principal Investigator / Faculty Advisor:
I agree to abide by the Tri-Council Policy for Ethical Conduct for Research Involving Human Subjects.
______
SignatureDate
Department Head / Dean:
I confirm that the Principal Investigator has the qualifications, experience, and facilities to carry out this research.
______
SignatureDate
______
Printed Name / 8. Provide the name of ONE contact person for ALL correspondence. The original Certificate of Approval will be mailed to the address given here. (see Guidance Note #8)
Name:Sandra Whitehouse MD
Title:Director, Ped Emerg Dept
Address:Pediatric Emergency Dept.
Children's & Women's
4480 Oak St. Vancouver,
B.C. V6H 3V4
Phone Number:604.875.5217
Fax Number:
E-mail Address:
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Version approved: 26 March 2002 (Revision #1 15 Nov 2002; Revision #2 08 Apr 2003; Revision #3 31 July 2003; Revision #4 19 Sept 2003).
9. Co-Investigators and Students: Use box 45 if additional space is needed.
Surname (ALL CAPS):BharyaGiven Name(s):Simi
Academic Rank: Clinical Instructor
UBC Faculty / Department:Med/Pediatrics
UBC Division (If applicable): Ped Emerg
Hospital Department (If applicable):Pediatrics
Hospital Division (If applicable):Emerg / Surname (ALL CAPS):
Given Name(s):
Academic Rank:
UBC Faculty / Department:
UBC Division (If applicable):
Hospital Department (If applicable):
Hospital Division (If applicable):
Surname (ALL CAPS):
Given Name(s):
Academic Rank:
UBC Faculty / Department:
UBC Division (If applicable):
Hospital Department (If applicable):
Hospital Division (If applicable): / Surname (ALL CAPS):
Given Name(s):
Academic Rank:
UBC Faculty / Department:
UBC Division (If applicable):
Hospital Department (If applicable):
Hospital Division (If applicable):
Surname (ALL CAPS):
Given Name(s):
Academic Rank:
UBC Faculty / Department:
UBC Division (If applicable):
Hospital Department (If applicable):
Hospital Division (If applicable): / Surname (ALL CAPS):
Given Name(s):
Academic Rank:
UBC Faculty / Department:
UBC Division (If applicable):
Hospital Department (If applicable):
Hospital Division (If applicable):
Surname (ALL CAPS):
Given Name(s):
Academic Rank:
UBC Faculty / Department:
UBC Division (If applicable):
Hospital Department (If applicable):
Hospital Division (If applicable): / Surname (ALL CAPS):
Given Name(s):
Academic Rank:
UBC Faculty / Department:
UBC Division (If applicable):
Hospital Department (If applicable):
Hospital Division (If applicable):
10. Provide the NAME of the funding source (see Guidance Note #10): CIHR
Classify the type of funding:
For-profit sponsor Grant Grant-in-aid UBC internal No funding Other
What is the status of the funding?
AwardedPending
11. Has this research proposal received any independent scientific/methodological peer review?(see Guidance Note #11)YesNo
If Yes, provide full details in 11a or 11b as relevant. Include the names of committees or individuals involved in the review. State whether the peer review process is ongoing or completed.
11a. External Peer Review Details: Funded by CIHR
Full review by the Randomized Controlled Trials committee of the CIHR
11b. Internal (UBC or hospital) Peer Review Details: n/a
11c. If No, explain why no independent scientific/methodological review has taken place: n/a
12. For clinical trials involving investigational drugs/devices or marketed drugs/devices outside of their indications (including positron-emittingradiopharmaceuticals (PERs)), indicate whether or not approval has been obtained from the appropriate federal regulatory agency for this purpose. (see Guidance Note #12)
YesName of agency: Health CanadaDate of approval (day/month/year)
No
Request for Approval has been submitted. (Please notify the Clinical Research Ethics Office when approval is obtained.)
Not applicable
13. Summarize the research proposal under the following headings: 1) Purpose, 2) Hypothesis, 3) Justification, 4) Objectives, and 5) Research Method. Under Research Method, please justify the use of placebo in this study, if it is placebo-controlled. See boxes 14 to 20 to avoid duplicating information. The CREB requires sufficient background information and clear details of the research design in order to assess the scientific merit of the proposal in relation to ethical issues. (see Guidance Note #13)
Purpose:
The goal of this study is to determine, through a large multicentre trial, if the treatment of infants with bronchiolitis presenting to the Emergency Department (ED) with either nebulized epinephrine, a short course of oral dexamethasone or both, results in a reduction in the number of admissions.
Hypothesis:
We hypothesize that children presenting to the ED with bronchiolitis and who are treated with nebulized epinephrine and/or oral dexamethasone will have fewer hospitalizations and a shorter, less severe illness.
Justification:
Bronchiolitis is the most common disease of the lower respiratory tract during the first year of life. In Canada 35/1000 children less than one year of age are hospitalized annually and a conservative estimate is that this costs Canadian taxpayers more than $23 million dollars per year (1). The current treatment of bronchiolitis is controversial. We have just completed a prospective cohort study of children diagnosed with bronchiolitis in Canadian emergency departments, finding substantial variability between centres, and – overall - that 74% were treated with bronchodilators and 5% were treated with steroids (Appendix A)(2). Furthermore, while our findings are consistent with the published literature regarding the use of bronchodilators (with reported rates of 66-95%), our findings differ substantially regarding the use of steroids (with reported rates of 34-80%) (3-6). We have also completed a meta-analysis that suggests that epinephrine may decrease clinical symptoms and reduce hospitalizations more so than either placebo or salbutamol (7). However the strength of the effect is small and all published studies are extremely small, therefore a significant publication bias may exist (7). For this reason, we and others have suggested that a large multicentre randomized controlled trial (RCT) be performed (7-9). Two meta-analyses have suggested that steroids may have some benefit but given the heterogeneity of the studies both authors called for a large trial of steroid use (10;11). More recently, a small ED based RCT showed a significant reduction in admission rates with high dose dexamethasone as compared to placebo (12). Most of the studies assessing the efficacy of steroids and epinephrine have enrolled in-patients and have small sample sizes so may be underpowered. Given the large health care burden of bronchiolitis and the conflicting results of small individual studies and meta-analyses, the role of steroids and nebulized epinephrine in outpatients with bronchiolitis needs to be urgently addressed by a large RCT. Furthermore, the outcomes assessed should be of interest to parents, clinicians and health systems – such as rates of hospitalization, costs of care, and risk of adverse events (9).
Objectives:
Primary question: To determine if the treatment of infants with bronchiolitis presenting to the ED with either two doses of nebulized epinephrine, five days of oral dexamethasone or both, results in a reduction in the percentage of children admitted to hospital by day 7 as compared to placebo?
Secondary questions:
a) Is there a difference in the time to discharge in patients receiving active treatment versus placebo? b) Is there a difference in length or severity of symptoms in patients receiving active treatment versus placebo as measured by the daily symptom diary? c) Is there a difference in clinical parameters (i.e., the Respiratory Distress Assessment Instrument score, oxygen saturation, and co-interventions) in patients receiving active treatment versus placebo? d) Is there a difference in the response of patients who have risk factors for atopy (personal or family history of atopy) compared to those with no risk factors? e) Is there a difference in the response of patients who are early in the course of their illness compared to those who are later in the course of their illness?
RESEARCH METHOD:
We plan a randomized, double-blind trial with a 2 by 2 factorial design. The four study groups will be (1) oral dexamethasone plus nebulized epinephrine, (2) oral placebo plus nebulized epinephrine, (3) oral dexamethasone plus nebulized placebo, and (4) oral placebo steroid plus nebulized placebo. Children, aged 6 weeks to 12 months inclusive, presenting with bronchiolitis will be enrolled from Emergency Departments (ED) of eight children’s hospitals across Canada. Bronchiolitis will be defined as the first episode of wheezing, in a child less than 12 months, associated with signs of an upper respiratory track infection during the period deemed to be peak season for RSV bronchiolitis (December to April). Patients will receive two treatments of nebulized epinephrine (3 mL of 1:1000) or placebo by nebulizer 30 minutes apart. Following completion of the first nebulization, the patient will also receive 1.0 mg/kg of dexamethasone or oral placebo. Children will also receive dexamethasone 0.6 mg/kg once daily for 5 days following study enrollment. The primary outcome measure will be admission to hospital up to 7 days after enrollment in the study. Secondary outcomes will include time to discharge from the ED or hospital, length and severity of symptoms (as documented on a standardized symptom diary), and change in clinical score (respiratory distress assessment index) from baseline at time 60, 120, 180 and 240 minutes. An economic analysis is also planned. Our estimated sample size, based on detecting a clinically 10% difference in proportion of admissions, an overall type I error rate of 0.05 and type II error rate of 0.20 is 800 patients. We anticipate this study will take 2 years to complete enrollment.
Human Subjects
14. Is this a multi-centre trial? YesNoHow many subjects, including controls, will be enrolled in the entire study? 800
Of these, how many will be participating at the UBC/institution site? 100
How many normal subjects will be enrolled in the study? 0
Of the normal subjects, how many will be participating at the UBC/institution site? 0
15. Describe who is being selected, and the criteria for their inclusion. (see also Box 34, and Guidance Note #15)
Target Population: All patients with bronchiolitis presenting to the ED of participating hospitals will be eligible. Bronchiolitis will be defined as a first episode of wheezing, in a child less than 12 months, associated with signs of an upper respiratory track infection (such as fever and corzya) during the period deemed to be peak season for RSV bronchiolitis (December to April). Setting: Recruitment and enrolment of patients will take place at eight pediatric emergency departments across Canada. The participating hospitals (members of PERC) are all tertiary care hospitals with annual census between 35,000 and 70,000.
Inclusion Criteria:
1. Age 6 weeks to 12 months. Children less than 6 weeks will not be enrolled due to the risk of concomitant infection (88). Children over 12 months will not be enrolled to minimize the risk of enrolling children with their first episode of asthma.
2. Respiratory distress assessment instrument (RDAI) score of > 3 and < 15 (Appendix D). This range of RDAI will ensure enrollment of children with a range of respiratory distress but excluding the extremes – those with mild and severe respiratory distress.
16. Describe which subjects will be excluded from participation. (see Guidance Note #16)
1. Previous diagnosis of asthma by a physician or any previous episode of wheezing and/or cough treated with bronchodilators.
2. Chronic disease that may affect cardiopulmonary status of the patient, such as bronchopulmonary dysplasia, cystic fibrosis, congenital heart disease, and immune deficiency.
3. Severe respiratory distress as evidenced by pulse rate > 200 beats/min, a respiratory rate > 80 breaths/min, RDAI > 15, or profound lethargy.
4. Recent treatment with oral or inhaled steroids (within 2 weeks) and history of reaction to steroids.
5. Presence of varicella or recent close contact (less than 3 weeks) without a history of prior infection.
6. Insurmountable language barrier (for example, patient is unable to understand French or English well enough to give informed consent and participate in the follow-up).
7. Any child born at less than 37 weeks gestation who is less than 6 weeks corrected age.
17. Describe how potential subjects will be contacted and by whom. In addition, describe how the potential subjects will be identified, including the source of the contact information (see Guidance Notes #17.1.1 and 17.1.2). Outline who originally collected the contact information and for what purpose it was originally collected. Attach copies of initial letters of contact and any other recruitment documents. Note that UBC CREB policy does not allow initial contact by phone, unless in the case of emergencies (see UBC CREB Policy #2 in Guidance Note #17.5.2). Initial contact should not be made by the subject’s primary caregiver (see Guidance Note #17.2.1)
Children who present to the Pediatric Emergency Dept. meeting the inclusion criteria will be asked by a triage nurse if they would be interested in learning more about the trial from a research assistant. Patients who agree would have the trial explained to them by a research assistant and informed consent would be obtained from those wishing to participate.
18. Describe the selection and/or recruitment procedures for normal subjects, if these differ from the above. Attach copies of initial letters of contact and any other recruitment documents.
n/a
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Version approved: 26 March 2002 (Revision #1 15 Nov 2002; Revision #2 08 Apr 2003; Revision #3 31 July 2003; Revision #4 19 Sept 2003).
Description of Procedures (Must be written in the space provided)
19. Which of the following procedures are involved in this study? (Check all that apply.)Drug administration
Surgical procedures
Experimental medical devices
Imaging studies (e.g., X-ray, MRI) / Collection of blood
Collection of other tissue
Individual interview
Group interview / Questionnaires
Home visits
Video/Audio Recording
Use of medical records
20. Summary of Procedures: Describe any specific manipulations: type, quantity, and route of administration of drugs and radiation, operations, tests, use of medical devices that are prototypes or altered from those in clinical use, interviews or questionnaires. Also, specify what procedures in this project involve an experimental approach, in that there may be diagnostic procedures or treatment dictated by the protocol differing from those required for standard patient care. (see Guidance Note #20)
During the study period, a research assistant will be present in the ED to recruit patients on their arrival and begin interventions and measurements. Patients will have a nasal pharyngeal aspirate sent for RSV culture and baseline measurements will be done after the patient has settled. The patients will receive two treatments of 1:1000 epinephrine (3 ml per treatment) or placebo by nebulizer at time 0 and time 30 minutes. A Hudson 1730 Updraft II nebulizer with oxygen at 6 L/min will deliver the study drug. Following completion of the first nebulization, the patient will also receive 1.0 mg/kg of dexamethasone or oral placebo. Children with oxygen saturation less than 92% will receive continuous oxygen to keep their oxygen saturation above 92%. Any child who vomits their study drug within 30 minutes will have it repeated. Children will also receive dexamethasone 0.6 mg/kg once daily for 5 days following study enrollment. Any febrile child (rectal temperature > 38 C) will be treated with 15 mg/kg acetaminophen. Rationale for size of dose: No dose range studies have been published for either epinephrine or steroids. The epinephrine dosage used is based on previous studies that demonstrated efficacy (26;28;29;35;45) and this treatment reflects the current standard of care at several participating hospitals (2). The steroid dosage is based on the only study to show significant benefit of steroids (Schuh 2003}. Although this dose is large, we think it essential to replicate it since the size of dosing may account – at least in part - for these authors’ findings.
After informed, written consent (Appendix B) is obtained, patients will be allocated to their study group. The Alberta Research Centre for Child Health Evidence (ARCHE) will produce a permeated block randomization list, stratified by study site, using random-number generating software. Stratification by site will ensure that any practice pattern variations specific to each site should be equally represented in each study group. Since respiratory viruses vary throughout the season (and could theoretically influence response to therapy) the use of permeated block randomization will ensure comparable distribution of the patients for each group throughout the bronchiolitis season. Block size will vary from 4 to 6 to limit the investigator’s abilities to predict which treatment is being given.
21. Does the study involve research to be carried out in physician’s private offices?YesNo
22a. How much time (i.e., how many minutes/hours over how many weeks/months) will a subject be asked to dedicate to the project beyond that needed for normal care? The subject will dedicate 0 extra time during the inifial ED visit but will be required to respond to telephone questioning daily for the first week, every second day during the second week and every third day during the 3rd week (120 - 130 minutes over 22 days).
22b.How much time (i.e., how many minutes/hours over how many weeks/months) will a normal volunteer (if any) be asked to dedicate to the project?n/a
23. Describe what is known about the risks of the proposed research. Include any information about discomfort or incapacity that the subjects are likely to endure as a result of the experimental procedure, along with the details of any known side effects which may result from the experimental treatment.
(see Guidance Note #23)
Nebulized epinephrine is used routinely in the treatment of severe croup and often for bronchiolitis. Overall it appears well tolerated. None of the trials to date of epinephrine in bronchiolitis have demonstrated serious side effects or clinically significant increases in heart rate and blood pressure. There has, however, been one case report of myocardial infarction after racemic epinephrine administration in croup (86). This patient, who presented in severe respiratory distress secondary to croup, had an initial room air oxygen saturation of 80 % and eventually required intubation for on-going respiratory distress. During his treatment with multiple doses of epinephrine he developed ventricular tachycardia and mild chest tightness. Subsequent investigation revealed showed a small myocardial infarct. Since he had normal cardiac anatomy, concern was raised whether the sympathomimetic actions of epinephrine contributed to his infarct. Given this one case report, we will not enroll any children with extreme respiratory distress requiring resuscitation room care in our trial. There are no studies addressing the safety of steroids in bronchiolitis per se but there are several studies examining their safety in other childhood diseases. Children treated with corticosteroids after exposure to varicella virus may have an increased risk of developing severe complications of varicella. GI bleeding was seen in two of 102 children with meningitis who were treated with dexamethasone for four days (69) and in one of 33 children treated with dexamethasone for the prevention of postextubation airway obstruction versus none in the 33 children in the placebo group (70). However this does not appear to be a significant issue in children with less critical illnesses who do not require ICU care, endotracheal intubation, and repeated high doses of steroids. In our trial, symptoms of GI bleeding and the occurrence of varicella will be addressed during telephone follow-up.
24. Describe the benefits to the subject that would arise from his or her participation in the proposed research. (see Guidance Note #24)
None
25. Describe any reimbursement for expenses or payments/gifts-in-kind (e.g. honoraria, gifts, prizes, credits) to be offered to the subjects. Provide full details of the amounts, payment schedules, and value of gifts-in-kind. (see Guidance Note #25)
None
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