Bronchiolitis in Infants Placebo Versus Epinephrine and Dexamethasone Study (BIPED)

• ClinicalTrials.gov Identifier: NCT03567473
• Recruitment Status: Recruiting
• First Posted: June 25, 2018
• Last Update Posted: May 3, 2022
• Sponsor: Children's Hospital of Eastern Ontario
• Collaborators: Canadian Institutes of Health Research (CIHR); Children's Hospital Research Institute of Manitoba; Research Manitoba; Women and Children's Health Research Institute, University of Alberta; Alberta Children's Hospital Research Institute; The Hospital for Sick Children; Department of Pediatrics, Western University; St. Justine's Hospital
• Information provided by (Responsible Party): Amy Plint, Children's Hospital of Eastern Ontario

Study Description

Brief Summary:

We hypothesize that infants with bronchiolitis treated with inhaled epinephrine in the Emergency Department (ED) and a 2-day course of oral dexamethasone will have fewer hospitalizations over 7 days compared to infants treated with placebo. To examine this hypothesis, we will conduct a phase III, multicentre, randomized, double-blind trial. Infants presenting to one of twelve study EDs will be enrolled to one of two study groups: (1) inhaled epinephrine and oral dexamethasone or (2) inhaled placebo and oral placebo. Our primary outcome will be admission for bronchiolitis by day 7 following the enrolment. As a planned secondary analysis, a between-group comparison of the primary outcome will be performed in those patients presenting with a first episode of bronchiolitis.

Condition or disease	Intervention/treatment	Phase
Bronchiolitis	Drug: Oral dexamethasone; Drug: Nebulized Epinephrine; Drug: Oral placebo; Drug: Nebulized normal saline; Drug: MDI Epinephrine; Drug: MDI placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 864 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: All study personnel (including study nurses, coordinators, investigators, data management staff, and statistical team), health care staff providing patient care, and patients/families will be blinded to the study group assignment.
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Trial Comparing Epinephrine and Dexamethasone to Placebo in the Treatment of Infants With Bronchiolitis
• Actual Study Start Date: December 13, 2018
• Estimated Primary Completion Date: October 2022
• Estimated Study Completion Date: October 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Active Intervention Arm; Oral dexamethasone and nebulized epinephrine OR Oral dexamethasone and inhaled epinephrine given by MDI	Drug: Oral dexamethasone; Two doses of oral dexamethasone, 0.6 mg/kg (maximum single dose 10 mg). One at the time of emergency department enrolment immediately prior to first nebulized treatment and one at approximately 24 hour later; Other Name: Dexamethasone; Drug: Nebulized Epinephrine; Two nebulized treatments of 3 mL 1:1000 epinephrine 30 minutes apart (+/- 15 minutes) at the time of emergency department enrolment; Other Name: Nebulized Adrenaline; Drug: MDI Epinephrine; Two doses of Epinephrine given by MDI plus spacer at 625 mcg (5 actuations of 125mcg) 30 minutes apart (+/- 15 minutes) at the time of emergency department enrolment.; Other Name: MDI Adrenaline
Placebo Comparator: Control Arm; Oral placebo (OraBlendTM in Canada and a compounded oral placebo solution at New Zealand/Australia sites) and nebulized saline. OR Oral placebo (OraBlendTM in Canada and a compounded oral placebo solution at New Zealand/Australia sites) and inhaled placebo given by MDI.	Drug: Oral placebo; Two doses of oral placebo, 0.6 mL/kg (maximum single dose 10 mL). One at the time of emergency department enrolment immediately prior to nebulized treatment and one at approximately 24 hour later . Oral placebo at Canadian sites is composed of OraBlendTM and in New Zealand and Australian sites will be a compounded solution.; Other Name: Placebo; Drug: Nebulized normal saline; Two nebulized treatments of 3 mL of normal saline 30 minutes apart (+/- 15 minutes) at the time of emergency department enrolment; Other Name: Saline; Drug: MDI placebo; Two doses of inhaled placebo given by MDI plus spacer, 30 minutes apart (+/- 15 minutes) at the time of emergency department enrolment.; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Admission to hospital for bronchiolitis within 7 days post enrollment [ Time Frame: 7 days post enrollment ]
   1) patient being admitted to inpatient ward, or 2) an ED length of stay 12 hours or greater or 3) a combined ED and observation unit stay of 12 hours or greater.

Secondary Outcome Measures :

1. Admission to hospital for bronchiolitis at the time of the enrollment ED visit [ Time Frame: Enrollment visit ]
   1) patient being admitted to inpatient ward, or 2) an ED length of stay 12 hours or greater or 3) a combined ED and observation unit stay of 12 hours or greater.
2. All cause admission to Hospital within 21 days following enrollment ED visit [ Time Frame: up to 21 days post enrollment ]
   1) patient being admitted to inpatient ward, or 2) an ED length of stay 12 hours or greater or 3) a combined ED and observation unit stay of 12 hours or greater.
3. All cause Health care provider visits (including ED visits) by day 21 following enrollment ED [ Time Frame: up to 21 days post enrollment ]
   Visits to ED, other clinic, primary care provider, or any visit to see a nurse or physician following enrollment
4. Health Care related costs within the 21 days following enrollment ED visits. [ Time Frame: up to 21 days post enrollment ]
   Health care related costs

Other Outcome Measures:

1. Safety outcome 1: Gastrointestinal bleeding [ Time Frame: up to 21 days post enrollment ]
   involving melena or frank blood per rectum (and not attributable to other causes, as determined by the treating physician)
2. Safety outcome 2: Serious Bacterial Infection [ Time Frame: up to 21 days post enrollment ]
   meningitis, osteomyelitis or septicaemia
3. Safety outcome 3: Severe Varicella [ Time Frame: up to 21 days post enrollment ]
   All of the following including: arthritis, osteomyelitis, symptomatic hepatitis, pancreatitis, cerebritis, pneumonitis, glomerulonephritis, disseminated intravascular coagulation, thrombo-cytopenia, prolonged vesicular rash (<3 weeks), fasciitis, septicaemia, ocular complications, orchitis, myocarditis, intensive care admission and death
4. Safety outcome 4: Death [ Time Frame: up to 21 days post enrollment ]
   Death
5. Exploratory Outcome 1: Admission to hospital for bronchiolitis within 21 days following enrollment ED visit [ Time Frame: up to 21 days post enrollment ]
   1) Patient admitted to inpatient ward, or 2) an ED length of stay 12 hours or greater or 3) a combined ED and observation unit stay of 12 hours or greater.
6. Exploratory Outcome 2: Admission to ICU within 21 days following enrollment ED visit for bronchiolitis and requiring intubation or continuous positive airway pressure (CPAP) [ Time Frame: up to 21 days post enrollment ]
   Physician admitting patient to ICU for bronchiolitis and requiring oxygen or ventilatory support
7. Exploratory Outcome 3: All cause admission to hospital with 7 days following enrollment ED visit [ Time Frame: up to 7 days post enrollment ED visit ]
   1) Patient admitted to inpatient ward, or 2) an ED length of stay 12 hours or greater or 3) a combined ED and observation unit stay of 12 hours or greater.
8. Exploratory Outcome 4: All cause ED visits within 21 days following enrollment ED visit [ Time Frame: up to 21 days post enrollment ED ]
   Visits to the ED after initial enrollment ED visit
9. Exploratory Outcome 5: Length of stay for the enrollment ED visit (in hours) [ Time Frame: Enrollment ED visit ]
   defined as discharge time minus oral study medication time, for participants discharged at the enrollment ED
10. Exploratory Outcome 6: Length of hospital admission for those patients admitted at their enrollment visit [ Time Frame: Admissions at enrollment ED visit ]
    time of hospital discharge minus the time of oral study medication
11. Exploratory Outcome 7: Resolution of symptoms as documented on a standardized questionnaire during the telephone or email at day 7 and 21 days. [ Time Frame: up to 21 days post enrollment ]
    cough, noisy breathing, respiratory distress, sleep and ability to feed
12. Exploratory Outcome 8: Out of pocket expenses [ Time Frame: up to 21 days post enrollment ]
    transportation, days of missed work, missed leisure activities
13. Exploratory Outcome 9: Age dependent variation in the efficacy of epinephrine and dexamethasone [ Time Frame: up to 21 days post enrollment ]
    to determine if treatment efficacy varies by age
14. Exploratory Outcome 10: Health care utilization (including ambulatory visits, ED visits, hospitalization) for respiratory illness [ Time Frame: Up to 18 years of age ]
    future health care utilization
15. Exploratory Outcome 11: Development of respiratory illnesses [ Time Frame: Up to 18 years of age ]
    asthma, wheezing and other respiratory illnesses

Eligibility Criteria

• Ages Eligible for Study: 60 Days to 12 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Presenting to the ED with an episode of bronchiolitis. Bronchiolitis will be defined as an episode of wheezing or crackles in a child < 12 month of age associated with signs of an upper respiratory tract infection (e.g. cough, coryza, nasal congestion) during the period deemed to be peak season for RSV bronchiolitis (approximately December to April in Northern Hemisphere and June to October in Southern Hemisphere). We have chosen not to define bronchiolitis as the first episode of wheezing or crackles to better reflect the clinical guidelines and clinical practice internationally.
2. Age 60 days to less than 12 months. Children younger than 60 days will not be enrolled due to the risk of concomitant infection and other issues pertaining to glucocorticoid use in the very young. Children older than 12 months will not be enrolled to minimize the risk of enrolling children with asthma.

Exclusion Criteria:

1. Respiratory distress assessment instrument (RDAI) score of less than or equal to 3. This RDAI will ensure children with very mild respiratory diseases are not enrolled. This is the lower limit of the RDAI range used in CanBEST.
2. Previously known chronic disease that may affect cardiopulmonary status of the patient, such as bronchopulmonary dysplasia currently receiving oxygen, cystic fibrosis, congenital heart disease and immune deficiency. These children may be at higher risk for developing severe illness.
3. Severe respiratory distress evidenced by a sustained pulse rate > 200 beats/min, a sustained respiratory rate > 80 breaths/min, profound lethargy (as deemed by the treating physician), or requiring resuscitation room care. We will exclude these children as they are likely to be admitted due to severity of illness.
4. Presenting with symptoms of apnea prior to enrollment.
5. Treatment with oral, inhaled, or IV corticosteroids within the last 1 week.
6. History of adverse reaction to glucocorticoids.
7. Treatment with any beta-agonists (salbutamol/albuterol or epinephrine/adrenaline) in the ED prior to study enrolment.
8. Presence of varicella or recent (less than 3 weeks) close contact (defined as any household or daycare contact, or greater than 15 minutes of face to face contact, or greater than 1 hour of being in the same dwelling with an individual) without a history of prior infection. These patients are not enrolled to reduce any risk of developing severe varicella with corticosteroid use.
9. Insurmountable language barrier (patient's parent/guardian is unable to understand English or French to give informed consent and participate in follow-up).
10. Any child born at less than 37weeks gestation who is younger than 60 days corrected age. We will not enroll these children to lower any risk of exposing young infants to corticosteroids.
11. Previous enrolment in the trial.
12. Unavailability for follow-up period.
13. Certain admission to hospital.

Contacts and Locations

Contacts

Contact: Kristina I Vogel; 613-737-7600 ext 3348; kvogel@cheo.on.ca

Contact: Candice McGahern; 613-737-7600 ext 4111; CMcGahern@cheo.on.ca

Locations

Australia

Women and Children's Hospital; Recruiting

Adelaide, Australia, 5006

Contact: Gaby Nivea gaby.nieva@sa.gov.au

Principal Investigator: Amit Kochar, MD

Monash Medical Centre; Recruiting

Melbourne, Australia, 3168

Contact: Jennifer Grant jennifer.grant1@monash.edu

Principal Investigator: Simon Craig, MD

Perth Children's Hospital; Recruiting

Perth, Australia, 6008

Contact: Sharon O'brien Sharon.O'Brien@health.wa.gov.au

Principal Investigator: Meredith Borland, MD

Canada, Alberta

Children's Hospital of Alberta; Recruiting

Calgary, Alberta, Canada, T3B 6A9

Contact: Kelly Kim 403-955-5451 kelly.kim@albertahealthservices.ca

Principal Investigator: Graham Thompson, MD

Stollery Children's Hospital; Recruiting

Edmonton, Alberta, Canada, T6G 2C8

Contact: Nadia Schular 587-588-7231 nadiaschular@ualberta.ca

Principal Investigator: Andrew Dixon, MD

Canada, Ontario

Childrens Hospital at London Health Sciences; Recruiting

London, Ontario, Canada, N6A 5W9

Contact: Leslie Boisvert Leslie.Boisvert@lhsc.on.ca

Principal Investigator: Gary Joubert, MD

CHEO; Recruiting

Ottawa, Ontario, Canada, K1H 8L1

Contact: Kristina Vogel 613-737-7600 ext 3348 kvogel@cheo.on.ca

Contact: Candice McGahern 613-737-7600 ext 4111 CMcGahern@cheo.on.ca

Principal Investigator: Amy Plint, MD MSc

Canada, Quebec

CHU Sainte-Justines Hospital; Recruiting

Montréal, Quebec, Canada, HT3 1C5

Contact: Stephanie Pellerin 514-345-4931 ext 3827 stephanie.pellerin.hsj@ssss.gouv.qc.ca

Principal Investigator: Serge Gouin, MD

Canada, Winnipeg

Children's Hospital of Winnipeg; Recruiting

Sherbrook, Winnipeg, Canada, R3A 1S1

Contact: Lise Bourrier lbourrier@chrim.ca

Principal Investigator: Scott Sawyer, MD

New Zealand

Starship Children's Hospital; Recruiting

Auckland, New Zealand, 1142

Contact: Megan Bonisch MBonisch@adhb.govt.nz

Principal Investigator: Stuart Dalziel, MD

Kidz First Hospital; Not yet recruiting

Auckland, New Zealand, 2025

Contact: Chris Lash christopher.lash@middlemore.co.nz

Principal Investigator: Christopher Lash, MD

Waikato Hospital; Recruiting

Hamilton, New Zealand, 3240

Contact: Julia Laing julia.laing@waikatodhb.health.nz

Principal Investigator: Alex Wallace, MD

Sponsors and Collaborators

Children's Hospital of Eastern Ontario

Canadian Institutes of Health Research (CIHR)

Children's Hospital Research Institute of Manitoba

Research Manitoba

Women and Children's Health Research Institute, University of Alberta

Alberta Children's Hospital Research Institute

The Hospital for Sick Children

Department of Pediatrics, Western University

St. Justine's Hospital

Investigators

• Principal Investigator: Amy Plint, MSc, MD; Childrens Hospital of Eastern Ontario (CHEO)

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lan J, Plint AC, Dalziel SR, Klassen TP, Offringa M, Heath A; Pediatric Emergency Research Canada (PERC) KIDSCAN/PREDICT BIPED Study Group. Remote, real-time expert elicitation to determine the prior probability distribution for Bayesian sample size determination in international randomised controlled trials: Bronchiolitis in Infants Placebo Versus Epinephrine and Dexamethasone (BIPED) study. Trials. 2022 Apr 11;23(1):279. doi: 10.1186/s13063-022-06240-w.

• Responsible Party: Amy Plint, MD, MSc, FRCPC, Research Chair in Pediatric Emergency Medicine, Children's Hospital of Eastern Ontario
• ClinicalTrials.gov Identifier: NCT03567473
• Other Study ID Numbers: CTO 1423
• First Posted: June 25, 2018
• Last Update Posted: May 3, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Bronchiolitis; Bronchitis; Respiratory Tract Infections; Infections; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Dexamethasone; Dexamethasone acetate; Epinephrine; Racepinephrine; Epinephryl borate; BB 1101; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Adrenergic alpha-Agonists; Adrenergic Agonists