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

A Randomized Controlled Trial Comparing Epinephrine and Dexamethasone to Placebo in the Treatment of Infants With Bronchiolitis

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.

Study Overview

• Status: Completed
• Conditions: Bronchiolitis
• Intervention / Treatment: Drug: Oral dexamethasone; Drug: Nebulized Epinephrine; Drug: MDI Epinephrine; Drug: Oral placebo; Drug: Nebulized normal saline; Drug: MDI placebo

• Study Type: Interventional
• Enrollment (Actual): 864
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5006
    • Women and Children's Hospital
  • Melbourne, Australia, 3168
    • Monash Medical Centre
  • Perth, Australia, 6008
    • Perth Children's Hospital
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A9
      • Children's Hospital of Alberta
    • Edmonton, Alberta, Canada, T6G 2C8
      • Stollery Children'S Hospital
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Childrens Hospital at London Health Sciences
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children'S Hospital Of Eastern Ontario
  • Quebec
    • Montréal, Quebec, Canada, HT3 1C5
      • CHU Sainte-Justines Hospital
  • Winnipeg
    • Sherbrook, Winnipeg, Canada, R3A 1S1
      • Children's Hospital of Winnipeg
• New Zealand
  • Auckland, New Zealand, 1142
    • Starship Children's Hospital
  • Auckland, New Zealand, 2025
    • Kidz First Hospital
  • Hamilton, New Zealand, 3240
    • Waikato Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 1 year (Child)
• Accepts Healthy Volunteers: No

Description

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.

   *Adjustment for COVID-19: The COVID-19 pandemic has resulted in unseasonal RSV and bronchiolitis seasons. As such, adjustments will be made to study recruitment to ensure recruitment occurs during peak RSV times. In order to achieve this aim, the study may in some sites recruit for 12 months of the year.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Admission to hospital for bronchiolitis within 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.	7 days post enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Admission to hospital for bronchiolitis at the time of the enrollment ED 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.	Enrollment visit
All cause admission to Hospital within 21 days following enrollment ED 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.	up to 21 days post enrollment
All cause Health care provider visits (including ED visits) by day 21 following enrollment ED	Visits to ED, other clinic, primary care provider, or any visit to see a nurse or physician following enrollment	up to 21 days post enrollment
Health Care related costs within the 21 days following enrollment ED visits.	Health care related costs	up to 21 days post enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcome 1: Gastrointestinal bleeding	involving melena or frank blood per rectum (and not attributable to other causes, as determined by the treating physician)	up to 21 days post enrollment
Safety outcome 2: Serious Bacterial Infection	meningitis, osteomyelitis or septicaemia	up to 21 days post enrollment
Safety outcome 3: Severe Varicella	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	up to 21 days post enrollment
Safety outcome 4: Death	Death	up to 21 days post enrollment
Exploratory Outcome 1: Admission to hospital for bronchiolitis within 21 days following 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.	up to 21 days post enrollment
Exploratory Outcome 2: Admission to ICU within 21 days following enrollment ED visit for bronchiolitis and requiring intubation or continuous positive airway pressure (CPAP)	Physician admitting patient to ICU for bronchiolitis and requiring oxygen or ventilatory support	up to 21 days post enrollment
Exploratory Outcome 3: All cause admission to hospital with 7 days following 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.	up to 7 days post enrollment ED visit
Exploratory Outcome 4: All cause ED visits within 21 days following enrollment ED visit	Visits to the ED after initial enrollment ED visit	up to 21 days post enrollment ED
Exploratory Outcome 5: Length of stay for the enrollment ED visit (in hours)	defined as discharge time minus oral study medication time, for participants discharged at the enrollment ED	Enrollment ED visit
Exploratory Outcome 6: Length of hospital admission for those patients admitted at their enrollment visit	time of hospital discharge minus the time of oral study medication	Admissions at enrollment ED visit
Exploratory Outcome 7: Resolution of symptoms as documented on a standardized questionnaire during the telephone or email at day 7 and 21 days.	cough, noisy breathing, respiratory distress, sleep and ability to feed	up to 21 days post enrollment
Exploratory Outcome 8: Out of pocket expenses	transportation, days of missed work, missed leisure activities	up to 21 days post enrollment
Exploratory Outcome 10: Health care utilization (including ambulatory visits, ED visits, hospitalization) for respiratory illness	future health care utilization	Up to 18 years of age
Exploratory Outcome 11: Development of respiratory illnesses	asthma, wheezing and other respiratory illnesses	Up to 18 years of age

Collaborators and Investigators

• Sponsor: Children's Hospital of Eastern Ontario
• Collaborators: The Hospital for Sick Children; Canadian Institutes of Health Research (CIHR); Alberta Children's Hospital Research Institute; St. Justine's Hospital; Research Manitoba; Children's Hospital Research Institute of Manitoba; Women and Children's Health Research Institute, University of Alberta; Department of Pediatrics, Western University
• Investigators: Principal Investigator: Amy Plint, MSc, MD, Childrens Hospital of Eastern Ontario (CHEO)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2018
• Primary Completion (Actual): January 7, 2025
• Study Completion (Actual): May 21, 2025

Study Registration Dates

• First Submitted: June 13, 2018
• First Submitted That Met QC Criteria: June 13, 2018
• First Posted (Actual): June 25, 2018

Study Record Updates

• Last Update Posted (Actual): July 28, 2025
• Last Update Submitted That Met QC Criteria: July 23, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Bronchiolitis; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Enzyme Inhibitors; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Adrenergic beta-Agonists; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Dexamethasone; Dexamethasone acetate; BB 1101; Epinephrine; Racepinephrine; Epinephryl borate
• Other Study ID Numbers: CTO 1423

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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