Epinephrine + Dexamethasone for Bronchiolitis

(BIPED Trial)

Recruiting at 12 trial locations

Overseen By Natasha Wills-Ibarra

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Hospital of Eastern Ontario

Must not be taking: Corticosteroids, Beta-agonists

Disqualifiers: Chronic disease, Severe distress, Apnea, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 2 days

864 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that participants have not been treated with oral, inhaled, or IV corticosteroids in the last week and have not received any beta-agonists like salbutamol or epinephrine in the ED before enrollment. If you are currently taking these medications, you may need to stop before joining the trial.

What data supports the effectiveness of the drug combination of epinephrine and dexamethasone for bronchiolitis?

Research shows that while the combination of epinephrine and dexamethasone does not significantly reduce hospital admissions or length of stay for bronchiolitis, it does improve oxygen levels in infants. Additionally, a single injection of dexamethasone alone has been shown to reduce the time needed for symptom resolution and hospital stay in young children with bronchiolitis. ^{1 2 3 4 5}

Is the combination of epinephrine and dexamethasone safe for treating bronchiolitis in infants?

Research shows that the combination of epinephrine and dexamethasone is generally safe for infants with bronchiolitis, with no increase in serious adverse events compared to other treatments. ^{1 3 6 7 8}

How does the drug combination of epinephrine and dexamethasone differ from other treatments for bronchiolitis?

The combination of epinephrine and dexamethasone for bronchiolitis is unique because it combines a bronchodilator (epinephrine) with a corticosteroid (dexamethasone) to potentially improve oxygen levels, although it does not significantly reduce hospital admissions or stay lengths compared to other treatments. ^{1 3 4 6 9}

Research Team

Amy Plint, MD MSc

Principal Investigator

Childrens Hospital of Eastern Ontario (CHEO)

Eligibility Criteria

This trial is for infants under 12 months old who are experiencing their first episode of bronchiolitis, with symptoms like wheezing or crackles alongside an upper respiratory infection. They must not have severe respiratory distress, known chronic diseases affecting the heart/lungs, recent steroid treatment, a history of adverse reactions to steroids, prior beta-agonist treatment in the ED before enrollment, exposure to chickenpox without immunity, significant prematurity (<37 weeks and <60 days corrected age), or any barriers to follow-up.

Inclusion Criteria

My child under 1 year has wheezing or crackles and signs of a cold during RSV season.

I am between 2 months and less than 1 year old.

Exclusion Criteria

My child was born prematurely and is under 60 days old, adjusted for early birth.

You have had a bad reaction to glucocorticoid medications in the past.

You have had chickenpox or been in close contact with someone who has had chickenpox, but you have not had it before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Infants receive inhaled epinephrine and oral dexamethasone or placebo for 2 days

2 days

1 visit (in-person)

Follow-up

Participants are monitored for hospital admissions and health care utilization

21 days

Follow-up via telephone or email at day 7 and 21

Long-term follow-up

Monitoring of respiratory illnesses and health care utilization up to 18 years of age

Up to 18 years

Treatment Details

Interventions

• Dexamethasone
• Epinephrine
• Normal Saline
• Placebo

Trial Overview The study tests if inhaling epinephrine and taking oral dexamethasone reduces hospital admissions within 7 days compared to a placebo. It's a phase III trial where infants at twelve EDs will be randomly assigned double-blindly into two groups: one receiving actual treatments and the other getting placebos (fake treatments).

Participant Groups

Group I: Active Intervention Arm Experimental Treatment 3 Interventions

Oral dexamethasone and nebulized epinephrine OR Oral dexamethasone and inhaled epinephrine given by MDI

Group II: Control Arm Placebo Group 3 Interventions

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.

Dexamethasone is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

Children's Hospital of Eastern Ontario

Lead Sponsor

Trials

134

Recruited

61,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Children's Hospital Research Institute of Manitoba

Collaborator

Trials

9

Recruited

3,400+

Research Manitoba

Collaborator

Trials

13

Recruited

17,500+

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

Collaborator

Trials

1

Recruited

860+

Alberta Children's Hospital Research Institute

Collaborator

Trials

12

Recruited

7,200+

The Hospital for Sick Children

Collaborator

Trials

724

Recruited

6,969,000+

Department of Pediatrics, Western University

Collaborator

Trials

1

Recruited

860+

St. Justine's Hospital

Collaborator

Trials

205

Recruited

87,300+

Findings from Research

A systematic review of 5 high-quality randomized controlled trials involving 1,157 infants found that combined therapy of epinephrine and corticosteroids did not significantly reduce hospital admission rates or length of stay for acute bronchiolitis.

While the combination therapy improved clinical severity scores and oxygen saturation levels, it was not more effective than using epinephrine alone, and there were no increased risks of serious adverse events associated with the combined treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review and Meta-Analysis of the Efficacy and Safety of Combined Epinephrine and Corticosteroid Therapy for Acute Bronchiolitis in Infants. Kua, KP., Lee, SWH.[2020]

In a study of 69 infants with acute bronchiolitis, the combination of nebulized L-epinephrine and intramuscular dexamethasone showed better outcomes on the fifth day compared to bronchodilators alone, indicating improved management of the condition.

However, the effectiveness of the L-epinephrine and dexamethasone combination was not significantly different from that of the salbutamol and dexamethasone combination, suggesting both treatments are similarly effective in the late phase of bronchiolitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Additive effects of dexamethasone in nebulized salbutamol or L-epinephrine treated infants with acute bronchiolitis. Kuyucu, S., Unal, S., Kuyucu, N., et al.[2016]

Nebulized epinephrine significantly improves clinical scores and reduces hospital admission rates in children with bronchiolitis, while nebulized albuterol shows short-term benefits but does not affect admission rates.

For croup, nebulized budesonide and oral dexamethasone improve symptoms and reduce hospitalization needs, with a combination potentially offering the best outcomes, although further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in the treatment of bronchiolitis and laryngitis. Klassen, TP.[2019]

In a study of 162 infants with moderate-to-severe bronchiolitis, combining oral dexamethasone with nebulized epinephrine or salbutamol did not reduce hospital admission rates compared to bronchodilators alone.

While clinical parameters improved for all treatment groups, the findings suggest that corticosteroids like dexamethasone do not provide additional benefits in managing bronchiolitis in young infants without a history of atopy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of combined dexamethasone therapy with nebulized r-epinephrine or salbutamol in infants with bronchiolitis: A randomized, double-blind, controlled trial. Bawazeer, M., Aljeraisy, M., Albanyan, E., et al.[2021]

A single intramuscular injection of dexamethasone significantly reduced the time to resolution of respiratory distress in 174 young children hospitalized with acute bronchiolitis, demonstrating its efficacy as a treatment option.

Dexamethasone also led to shorter durations of symptoms, oxygen therapy, and hospital stays, indicating that it can improve overall recovery times for affected children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of dexamethasone injection for acute bronchiolitis in hospitalized children: a randomized, double-blind, placebo-controlled trial. Teeratakulpisarn, J., Limwattananon, C., Tanupattarachai, S., et al.[2013]

In a study of 30 children aged 2 to 24 months with moderate to severe bronchiolitis, nebulised epinephrine showed significant improvements in respiratory rate, respiratory distress, and oxygen saturation compared to salbutamol.

Nebulised epinephrine was found to be safe, with no significant side effects reported, and it also resulted in a shorter hospital stay for patients, indicating its efficacy as a treatment for bronchiolitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Nebulised Epinephrine versus Salbutamol in Hospitalised Children with Bronchiolitis. John, BM., Patnaik, SK., Prasad, PL.[2020]

Racemic epinephrine significantly improves respiratory distress in hospitalized infants with bronchiolitis, as indicated by better scores on the Respiratory Distress Assessment Instrument (RDAI) during their stay.

While racemic epinephrine is safe for use, it does not shorten the length of hospital stay compared to salbutamol, and many parents report ongoing respiratory symptoms in their children even one week after discharge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Racemic epinephrine compared to salbutamol in hospitalized young children with bronchiolitis; a randomized controlled clinical trial [ISRCTN46561076]. Langley, JM., Smith, MB., LeBlanc, JC., et al.[2018]

In a study of 72 children hospitalized for croup, a single dose of 0.6 mg/kg dexamethasone significantly improved recovery and reduced hospital stay compared to placebo.

While nebulized racemic epinephrine also helped alleviate symptoms, its effectiveness was less pronounced in patients who received dexamethasone, indicating that dexamethasone is the more effective treatment for acute spasmodic croup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized double-blind, placebo-controlled trial of dexamethasone and racemic epinephrine in the treatment of croup. Kuusela, AL., Vesikari, T.[2019]

Nebulized epinephrine combined with high-dose dexamethasone or nebulized hypertonic saline shows potential as effective treatments for viral bronchiolitis in young infants.

Despite these promising strategies, more research is necessary to establish clear guidelines and recommendations for their use in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pediatrics. New treatment options for viral bronchiolitis]. Rochat, I., Hafen, G.[2013]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Systematic Review and Meta-Analysis of the Efficacy and Safety of Combined Epinephrine and Corticosteroid Therapy for Acute Bronchiolitis in Infants. [2020]

2. Australia pubmed.ncbi.nlm.nih.gov

Additive effects of dexamethasone in nebulized salbutamol or L-epinephrine treated infants with acute bronchiolitis. [2016]

3. United States pubmed.ncbi.nlm.nih.gov

Recent advances in the treatment of bronchiolitis and laryngitis. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

Effect of combined dexamethasone therapy with nebulized r-epinephrine or salbutamol in infants with bronchiolitis: A randomized, double-blind, controlled trial. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy of dexamethasone injection for acute bronchiolitis in hospitalized children: a randomized, double-blind, placebo-controlled trial. [2013]

6. India pubmed.ncbi.nlm.nih.gov

Efficacy of Nebulised Epinephrine versus Salbutamol in Hospitalised Children with Bronchiolitis. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Racemic epinephrine compared to salbutamol in hospitalized young children with bronchiolitis; a randomized controlled clinical trial [ISRCTN46561076]. [2018]

8. Sweden pubmed.ncbi.nlm.nih.gov

A randomized double-blind, placebo-controlled trial of dexamethasone and racemic epinephrine in the treatment of croup. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Pediatrics. New treatment options for viral bronchiolitis]. [2013]