A Randomized Double Blinded Placebo Controlled Trial of One Versus Two Doses of Oral Dexamethasone for the Treatment of Acute Asthma Exacerbation in the Pediatric Emergency Department (ED)
Phase: PHASE3
Conditions: Asthma
Sponsor: Geoffrey W Jara-Almonte

New York Methodist Hospital 
 
  
Trial of One Versus Two Doses of Dexamethasone for Pediatric Asthma Exacerbation 
 
NCT02725008 
 
Study Protocol and Statistical Analysis Plan 
 
Date 2/13/2015 
 

New York Methodist Hospital 
 
 
I   BACKGROUND AND SIGNIFICANCE  
 
Asthma is common cause of morbidity and mortality in Emergency Medicine. Oral steroids are a 
cornerstone of emergency management of asthma exacerbation.  The traditionally recommended steroid 
regimen consists of 3 - 5 days of oral prednisone or prednisolone.  However a growing body of literature 
supports the use of aone or two dose course of dexamethasone in lieu of prednisolone.  The theoretical 
benefits of a shorter duration of treatment include lower cost, less caregiver burden and greater likelihood 
of compliance.  The rationale behind the use of dexamethasone is its longer half-life and duration of action 
compared to prednisolone.  In addition it is less foul-tasting and more palatable to young children, therefore 
increasing the ease of administration for caregivers.i  
 
Several small to medium-sized randomized trials have compared dexamethasone to 
prednisoloneii,iii,iv,v,vi,vii,viii.  There has been significant heterogeneity in trials with respect to the dosing and 
route of administration of dexamethasone.  Two studies used a single dose of intramuscular 
dexamethasone, one study used a single oral dose, and two studies used two oral doses.  An additional 
study not included in the meta-analysis used nebulized dexamethasone. None have demonstrated a clear 
clinical benefit to one particular course of treatment.  A recent meta-analysisix analyzed several of these 
studies and did not show clinical superiority of one medication over the other.   
 
Based on this body of literature there is convincing evidence that dexamethasone is as effective as 
prednisolone or prednisone in the treatment of mild to moderate acute asthma exacerbations.  However the 
optimal dosing strategy is unclear.  Ideally one oral dose could be given in the emergency department, 
obviating the need to fill an outpatient prescription.  At least one editorial has recommended this practice 
based on the findings in the above-mentioned studies and the theoretically equivalent bioavailability of 
dexamethasone after both intramuscular and oral administrationx  However only one study actually used a 
single oral dose regimen.  They found no difference in their primary outcome, however there was a non-
significant increased risk of unplanned return to ED in the dexamethasone group8.   
 
As of yet no randomized double blinded placebo-controlled study has directly compared the effectiveness 
of single versus two dose of dexamethasone for asthma.  This question was addressed by a randomized 
open-label trial which found no significant difference.xi Another study investigated the question in a 
population of patients with first-time wheezing presumed to be bronchiolitis; again, no significant 
difference was found.xii  However steroids are largely ineffective for bronchiolitis, so it is impossible to 
apply the results of that study to the treatment of asthmaxiii. 
 
II. 
SPECIFIC AIMS  
 
Our aim is to compare the effect of single versus repeated doses of oral dexamethasone on the rate of 
treatment failure in patients treated for a mild to moderate acute asthma exacerbation in the pediatric 
emergency department of an urban community hospital.   
 
III. 
SUBJECT SELECTION 
 
Subjects will be children aged 18 months to 20 years with a history of asthma - defined as at least 2 prior 
episodes of respiratory illness involving coughing, wheezing, or shortness of breath that responded to 
inhaled bronchodilators - who present to the Pediatric Emergency Department with symptoms consistent 
with asthma exacerbation, an initial Pulmonary Index Score of 12 or less, who have persistent symptoms 
after one dose of nebulized short acting beta-agonist.   
 
Exclusion Criteria will include:  
1. Hospitalization for asthma or respiratory complaint in past two months 
2. Course of oral steroids within the past month 
3. History of chronic pulmonary disease including cystic fibrosis or bronchopulmonary dysplasia,  

New York Methodist Hospital 
 
4. History of any other severe chronic metabolic, endocrine, neuromuscular, cardiac, renal or hepatic 
disorder 
5. Severe asthma exacerbation (PIS >11)   
6. Girls and women over 14 years of age will need to complete a urine pregnancy test prior to 
enrollment, those currently pregnant will be ineligible.  Subjects who become pregnant during the 
study will be withdrawn.  
 
IV. 
SUBJECT ENROLLMENT 
 
Patients will be eligible for enrollment whenever a study investigator is present in the pediatric 
emergency department.   Families will be approached for enrollment and informed consent will be 
obtained after the decision to discharge the patient has been made by the ED provider.  Verbal assent will 
be obtained from children over 6 years of age.  
 
If enrolled participants will be randomized to receive either the study medication or placebo.  
Randomization will be in blocks by severity of exacerbation.  
 
The study investigator will enter patient demographic information on a registration form that will be 
placed in a locked file cabinet.  All further study information will be collected on forms identified only 
by an anonymous randomized study identification number.    
 
 
V. 
STUDY PROCEDURES 
 
As part of an ongoing quality improvement project designed to standardize treatment of patients with 
asthma  in the pediatric ED, all patients felt by the triaging RN to have symptoms consistent with an asthma 
exacerbation will be seen as soon as possible after arrival by a provider [ NP, resident, attending, fellow or 
4th year medical student].  The severity of their exacerbation will be determined using a validated clinical 
assessment tool, the Pulmonary Index Score.  The PIS will be charted in the medical record and used to 
select an appropriate clinical pathway corresponding to the severity of exacerbation.  As part of the 
standardization effort, all patients with a mild or moderate exacerbation [ PIS ≤ 11 ] will receive oral 
dexamethasone 0.6 mg/kg up to 16 mg orally as part of their ED therapy.   
 
Once the decision is made to discharge the patient, the family will be approached by the study investigator 
for enrollment and obtainment of informed consent.  If the family declines enrollment, then the decision to 
discharge home with an outpatient prescription for oral steroids will be made at the discretion of the ED 
provider caring for the patient.   
 
If the family agrees to enroll, the study investigator will record the patient’s name, contact information, 
preferred method of contact, primary care physician’s name and contact information and medical record 
number on the enrollment form which will be placed in a locked file cabinet.  The patient’s ED provider 
will place a computerized medication order for study medication.   
 
Once a medication order is place, our pharmacy will randomize the patient to either the treatment or control 
groups.  They will prepare a syringe with the appropriate volume of dexamethasone injectable solution 
mixed with cherry syrup, or an equivalent volume of taste- and texture-matched placebo.  This will be 
labeled with the patient’s name and MRN as well as administration instructions.  The pharmacy will 
maintain records of group allocation in a locked and sealed location, which will be broken only in the event 
of a significant adverse event, for planned interim analysis and after enrollment has been completed.   
  
In the event that a caregiver loses the medication prior to administration, or the child vomits it at home, 
they will be instructed to call the ED, further management will be at the discretion of the provider present 
at that time, and the patient data will analyzed with their initial group under the intention-to-treat principle.  
 

New York Methodist Hospital 
 
Patients will also be given a letter to take to their primary care physician, or any other follow-up provider, 
explaining their participation in the study and a request to contact the study coordinator if any of the events 
defining treatment failure is identified at the follow-up visit. 
 
At the time of discharge families will be given a symptom questionnaire (Patient Self Assessment Score, 
PSAS) to complete every 24 hours.  They will be asked to return to Emergency Department on day 5 for re-
examination.  They will be seen by a study investigator; a repeat PIS will be calculated at that time.  A brief 
structured questionnaire will be administered asking about presence of any primary outcomes.  If the family 
does not return for 5 day follow-up, they will be contacted by preferred means - phone, text message or e-
mail the same questionnaire will be administered.  
 
VI. STATISTICAL ANALYSIS 
 
● 
Primary Outcome:  
○ 
Treatment failure as defined by any of the following: unplanned hospitalization for 
asthma symptoms; unplanned return to emergency department, urgent care or clinic for 
asthma symptoms; or prescription of additional course of steroids within 5 days of 
enrollment. 
  
●.○.1. 
Relative Risk of treatment failure between the experimental and control groups  
 
●.○.2. 
Relative risk of treatment failure in each of the predefined subgroups (mild and 
moderate) 
●.○.3. 
Time to treatment failure will be compared between the two groups using the 
Kaplan Meier analysis 
 
● 
Secondary Outcomes: 
● 
Change in PIS between initial and follow-up visit  
● 
Change in PSAS over time -   
● 
Presence of adverse events including vomiting in the ED or at home, symptomatic 
hyperglycemia, subjective behavior change or subjective insomnia -  
● 
Caregiver preference for treatment regimen compared to prior steroid treatments.  
 
Categorical variables will be analyzed with the Chi-squared test.  
Continuous variables will be analyzed with the Mann-Whitney-U test 
Survival curves will be analyzed with the Kaplan-Meier test 
 
● 
Sample Size and Power Analysis 
○ 
We estimate a sample size of 220 will give us a power of 0.9 to detect a 9% difference in 
treatment failure at a significance of 0.05, inferring effect size from prior published 
studies comparing various dosing regimen of dexamethasone to prednisolone.   
 
● 
VII 
RISKS & DISCOMFORTS  
○ 
Significant side effects of single or multiple doses of dexamethasone are rare, and do not 
vary significantly from those experienced with prednisolone, with the exception of 
vomiting which is less common with dexamethasone.8 
 
 
 
VIII.     BENEFITS & RISKS 
Potential benefits to study participants include potentially decreased exposure to steroids, decreased 
caregiver burden, increased ease of medication compliance.  Potential risks to participants include toxicities 
associated with dexamethasone, potentially increased risk of treatment failure, potential need for unplanned 
or emergent return to ED or hospitalization.   

New York Methodist Hospital 
 
 
The potential benefit to society determination of the optimal dosing strategy for dexamethasone in acute 
asthma exacerbation.  The ideal regimen would be that which involves the fewest doses of medication and 
least burden on caregivers in terms of having to fill prescriptions and administer medications to often-
recalcitrant patients without an increased risk of relapse or treatment failure.   
 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
a. 
Independent monitoring of source data 
- Not applicable 
b. 
Safety monitoring (e.g., Data Safety Monitoring Board, etc.) 
- A Data Safety Monitoring Board will be composed of the Principle Investigator, 
Departmental Research Coordinator and Pediatric Emergency Medicine physicians to 
investigate any serious side effects that occur during the study.  
c. 
Outcomes monitoring 
- Preliminary statistics will be computed when we have enrolled 50% of the expected number 
of participants, if a significant difference ( RR > 4)  in favor of the control group is found 
in terms of the primary endpoint, the study will be ended at that point..  
d. 
Adverse event reporting guidelines 
- Any unexpected or serious adverse events will be reported to the IRB, any security breaches 
will be reported to Hospital Security.  
 
X 
REFERENCES 
 
                                                          
i Hames, H., et al. "A palatability study of a flavored dexamethasone preparation versus prednisolone liquid 
in children." The Canadian journal of clinical pharmacology= Journal canadien de pharmacologie 
clinique 15.1 (2007): e95-8. 
 
ii Gordon, Stephen, Tameko Tompkins, and Peter S. Dayan. "Randomized trial of single-dose intramuscular 
dexamethasone compared with prednisolone for children with acute asthma." Pediatric emergency care 
23.8 (2007): 521-527. 
 
iii Greenberg, Richard A., Gwen Kerby, and Genie E. Roosevelt. "A comparison of oral dexamethasone 
with oral prednisone in pediatric asthma exacerbations treated in the emergency department." Clinical 
pediatrics 47.8 (2008): 817-823 
iv Gries, Delores M., et al. "A single dose of intramuscularly administered dexamethasone acetate is as 
effective as oral prednisone to treat asthma exacerbations in young children." The Journal of pediatrics 
136.3 (2000): 298-303 
v Klig, Jean E., Dee Hodge, and Mary W. Rutherford. "Symptomatic improvement following emergency 
department management of asthma: a pilot study of intramuscular dexamethasone versus oral prednisone." 
Journal of Asthma 34.5 (1997): 419-425. 
 
vi Qureshi, Faiqa, Arno Zaritsky, and Michael P. Poirier. "Comparative efficacy of oral dexamethasone 
versus oral prednisone in acute pediatric asthma." The Journal of pediatrics 139.1 (2001): 20-26. 
 
vii Scarfone, Richard J., et al. "Nebulized dexamethasone versus oral prednisone in the emergency treatment 
of asthmatic children." Annals of emergency medicine 26.4 (1995): 480-486. 
 
viii Altamimi, Saleh, et al. "Single-dose oral dexamethasone in the emergency management of children with 
exacerbations of mild to moderate asthma."Pediatric emergency care 22.12 (2006): 786-793. 
 
ix Keeney, Grant E., et al. "Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analysis." 
Pediatrics 133.3 (2014): 493-499. 
 

New York Methodist Hospital 
 
                                                                                                                                                                             
x Cross, Keith P., Ronald I. Paul, and Ran D. Goldman. "Single-dose dexamethasone for mild-to-moderate 
asthma exacerbations Effective, easy, and acceptable." Canadian Family Physician 57.10 (2011): 1134-
1136. 
xi https://aap.confex.com/aap/2010/webprogram/Paper11632.html accessed 1/23/2015 
xii Schuh, Suzanne, et al. "A single versus multiple doses of dexamethasone in infants wheezing for the first 
time." Pediatric pulmonology 43.9 (2008): 844-850. 
 
xiii Ralston, Shawn L., et al. "Clinical practice guideline: the diagnosis, management, and prevention of 
bronchiolitis." Pediatrics 134.5 (2014): e1474-e1502.