Christine Conageski, Heather Hoch, Britni Sanchez, Amy Tyler

Bios 6648 Fall 2015

Christine Conageski, Heather Hoch, Britni Sanchez, Amy Tyler

Comparing Dexamethasone to Prednisone for Pediatric Asthma Exacerbations Requiring Hospital Admission

Background and setting:

Asthma is rising in prevalence, currently affecting over 7 million children ages 0-17 in the United States1. Asthma is a multifaceted disorder with a variety of complex phenotypes. It is characterized by chronic airflow obstruction, manifested as wheeze, shortness of breath, cough and/or chest tightness2. Asthma in childhood can be predicted by a number of factors, including passive smoke exposure, diagnosis in older siblings, and moderate to severe respiratory illnesses during infancy, especially rhinovirus, 3, though the true interaction between early viruses and the development of asthma remains unclear4. Systemic corticosteroids are the mainstay of treatment for asthma. The traditional standard of care for acute asthma exacerbations has been oral prednisone; however, dexamethasone, another oral corticosteroid, has been gaining popularity.

Dexamethasone, compared to prednisone, is superior in palatability, length of half-life and cost-effectiveness. Prednisone has a half-life of 12-36 hours. It is administered orally two times per day fortotal treatment duration of five days. Prednisone has a number of side effects including vomiting due to its bitter taste. This results in decreased patient compliance to full duration of drug treatment. In comparison to prednisone, dexamethasone has a greater affinity for the glucocorticoid receptor and thus a longer half-life of 36-72 hours. Dexamethasoneis can therefore be given orally every twelve to thirty-six hours. Given these factors, there has been a strong push to determine if dexamethasone is as effective for the treatment acute asthma exacerbations as prednisone. Early literature from emergency departments (ED)has shown that they are equivalent. While the use of dexamethasone has been well validated in the emergency setting, it has not been as well studied in the inpatient asthmatic population.

Previous studies comparing dexamethasone treatment to standard care for patients in ED with exacerbated asthma symptoms:

A meta-analysis of six studies in pediatric patients compared prednisone to dexamethasone in emergency departments found that not only was dexamethasone not inferior to prednisone in terms of several asthma related outcomes, but dexamethasone offered several advantages to prednisone in terms of adherence to medications, cost and palatability5. Another large meta-analysis of pediatric studies found that there was no difference in the relative risk of relapse between children receiving prednisone and dexamethasone at any time point between 5-30 days, and dexamethasone was associated with significantly less vomiting6. Andrews et al found patients discharged from the emergency department with dexamethasone vs. prednisone reduced return visits to the ED as well as return hospitalizations after the sentinel ED visit resulting in a cost savings of up to $7000 per 100 patients7. The only inpatient study, a retrospective cohort study utilizing the Pediatric Health Information System (PHIS) database of 42 Children’s hospitals, compared 1166 hospitalizations where only dexamethasone was received to 1284 propensity-matched hospitalizations. They found that the proportion of patients staying less than three days was significantly higher in the dexamethasone group compared with the prednisone group. The dexamethasone group had a significantly lower cost of index admission and episode of care. There was not significant difference between the two groups for readmission rate or escalation of care8. Clearly, dexamethasone has been evaluated extensively in the ED setting. Aside from one retrospective cohort study, it has not been sufficiently prospectively evaluated in the inpatient pediatric population.

Questions to be addressed in the study being designed for this project:

We propose a phase III trial to study the efficacyand safety of dexamethasone for the treatment of pediatric asthma exacerbations in the inpatient setting. The key question to answer is whether dexamethasone is non-inferior to prednisone in the inpatient setting in terms of length of stay. Some secondary outcomes will include: return to care after discharge, escalation of care following admission, rate of occurrence of secondary infections, rate of adverse events such as dosing errors, provider satisfaction, patient satisfaction, cost of index admission and cost of episode of care. We will utilize a prospective, randomized, double blinded, placebo controlled parallel group trial design to evaluate this question. The study setting will be a large, tertiary care children’s hospital.

Synopsis of proposed study

Study population:Patients aged 2-17 years admitted to Children’s Hospital Colorado from the Emergency Department (ED) with a primary diagnosis of acute asthma exacerbation during the study period. Patients must receive their first dose of dexamethasone in the ED to be eligible for the study. Patients with co-morbid medical conditions, co-diagnoses such as pneumonia and patients initially admitted to the intensive care unit rather than the floor will be excluded.

Study treatment(s):Patients will be randomized to receive 2mg/kg (max dose 40mg) of prednisone twice daily or 0.6mg/kg (max dose 8 mg) at 48 hours from their first dose administered in the ED. All patients will receive either placebo or study drug at 12-hour intervals following admission and at 48 hours following admission. Patients discharged before 48 hours will remain in the study and receive study drugs and placebo at discharge.

Statistical design:

We propose a single center,prospective, randomized, double blinded, placebo controlled parallel group trial design to evaluate this question.

Primary outcome: Proportion of patients with length of stay >2 days

Secondary outcomes: Return to care after discharge, escalation of care following admission, provider satisfaction, patient satisfaction, cost of index admission and cost of episode of care

Exploratory outcomes: Rate of occurrence of secondary infections, rate of adverse events such as dosing errors

Sample size: The primary outcome variable is length of stay greater than or equal to two days. Taken from the Parikh data, the percentage of patients staying 2 days or longer is 54.6%. We specified a clinically relevant non-inferiority margin of 60%, which would be an absolute risk increase of 5.4%. We, therefore, selected a sample size of 1757 children in each treatment arm to have 90% power to detect the specified clinically important difference at a 2-sided significance level of 0.05. We anticipate very little if any dropouts or losses to follow up due to the nature of the study.

Analysis plan: Baseline and demographic characteristics will be characterized by use of means and standard deviations for continuous variables and percentages for categorical variables. Our primary outcome variable will be summarized as a percentage of patients staying two days or greater. Secondary outcomes will be summarized for each treatment arm using means and SDs where appropriate. Comparisons of means will be done by a Student’s t test and comparisons of proportions by Pearson Chi-square (Χ2). Statistical significance will be set at p<0.05 for all comparisons; 95% confidence intervals will be reported.

Study implementation and conduct

Study Recruitment:

The transfer center nurses will notify study personnel of planned ED to floor admissions for patients with a primary diagnosis of asthma exacerbation. A research assistant will approach the ED treatment team to determine whether patients meet eligibility criteria. The research assistant will then approach all patients meeting inclusion criteria within 8 hours of their dexamethasone administration time in the ED. Informed consent to participate in the study will be obtained from the caregiver.

Our primary outcome of length of stay will be obtained from the medical record. Time of admission and time discharge are already reliably recorded in each patient’s electronic health record. Time of “discharge order” will also be collected and analyzed for comparison, but will not be used for our primary outcome.

Randomization procedures:

Participants will be randomly allocated at time of recruitment to treatment or placebo using random blocks sizes of 6-12. Sequence will be determined prior to the start of the study and the list will be kept at the study pharmacy. All study participants, caregivers, treatment team members and study personnel will be blinded to the treatment arm. Placebo drugs will not differ from study drugs in taste or smell. The study pharmacy personnel will be aware of treatment arm and will dispense all study drugs and placebos. The study pharmacy personnel will not be part of the treatment team or interact with the study participants or study personnel unless unbinding is requested by the treatment team.

Blinding:

Explain blinding procedures: How will in-patient care be blinded, and how will out-patient care be blinded?

Missing data:

There is no concern for missing data in regards to the primary outcome for this study (length of stay). There is similarly no concern that data will be missing for the secondary outcomes of escalation of care following admission, cost of index admission and cost of episode.

Surveys will be used to collect data on patient satisfaction during the hospital stay and following discharge. Missing data for the inpatient portion of the survey will only be a concern if research assistants are not able to approach families prior to discharge due to process limitations. This will be minimized by ensuring adequate study personnel staffing.

Following discharge all families will be contacted to collect additional satisfaction measures by survey and also to collect data on unexpected returns to care following discharge. To minimize missing data at this stage, at time of enrollment, families will be asked for primary and secondary contact information. We will also ask families to identify the best time of day and best day of week for this follow-up phone call. Study personnel will also inform families at time of enrollment that the follow-up phone call will be brief (less than 5 minutes) to minimize the burden on families.

References

1.Akinbami LJ, Moorman JE, Garbe PL, Sondik EJ. Status of childhood asthma in

the United States, 1980-2007. Pediatrics. 2009 Mar;123 Suppl 3:S131-45. doi:

10.1542/peds.2008-2233C. PubMed PMID: 19221156.

2.Global Strategy for Ashtma Management and Prevention-Updated 2015. Accessed 5/26/15. 2015.

3. Lemanske RF, Jr., Jackson DJ, Gangnon RE, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. The Journal of allergy and clinical immunology 2005;116:571-7.

4.Gern JE, Busse WW. Relationship of viral infections to wheezing illnesses and asthma. Nat Rev Immunol 2002;2:132-8.

5. Meyer JS, Riese J, Biondi E. Is dexamethasone an effective alternative to oralprednisone in the treatment of pediatric asthma exacerbations? HospPediatr. 2014May;4(3):172-80. doi: 10.1542/hpeds.2013-0088. PubMed PMID: 24785562.

6.Keeney GE, Gray MP, Morrison AK, et al. Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analysis.Pediatrics. 2014;133(3):493-499. doi:10.1542/peds.2013-2273.

7. Andrews AL, Wong KA, Heine D, Scott Russell W. A cost-effectiveness analysis

of dexamethasone versus prednisone in pediatric acute asthma exacerbations. AcadEmerg Med. 2012 Aug;19(8):943-8. doi: 10.1111/j.1553-2712.2012.01418.x. Epub 2012 Jul 31. PubMed PMID: 22849379.

8.Parikh K, Hall M, Mittal V, Montalbano A, Gold J, Mahant S, Wilson KM, Shah

SS. Comparative Effectiveness of Dexamethasone versus Prednisone inChildren

Hospitalized with Asthma. J Pediatr. 2015 Sep;167(3):639-644.e1. doi:

10.1016/j.jpeds.2015.06.038. PubMed PMID: 26319919.