Clinical trial NCT03900624
Conditions: Asthma Childhood
Sponsor: Johns Hopkins All Children's Hospital
Start date: 2019-04-21; Completion date: 2022-05-15
Enrollment: 92 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Determine if differences in (1) pediatric intensive care unit length of stay, (2) continuous nebulized albuterol duration, and (3) a composite outcome of advanced asthma therapy incidence including use of non-invasive ventilation (NIV), terbutaline, inhaled helium and mechanical ventilation between cohorts of children admitted with status asthmaticus to the PICU treated with either IV dexamethasone (DM) or methylprednisolone (MP).

Detailed description:
As the pathophysiology of an acute asthma exacerbation is dysregulated inflammatory pathways, standard treatment includes the prompt initiation of intravenous systemic corticosteroids. Corticosteroids reduce the production of many mediators involved in the inflammatory process and inhibit macrophages, monocytes, T-lymphocytes, eosinophils, and basophils, which are activated during this process. Furthermore, corticosteroids improve the efficacy of beta-2 agonists, such as albuterol, a nebulized medication used for bronchodilation in acute asthma exacerbations. There remains an ongoing dialogue among the expert medical community regarding the superiority of specific IV corticosteroid, dosing, route and delivery. This debate continues secondary to a lack of definitive comparative data in the literature. While the benefits of receiving systemic corticosteroids has been demonstrated in multiple studies, to date, no head-to-head trials have been conducted comparing IV systemic corticosteroids in the PICU setting (DM vs. MP).

While several systemic corticosteroids are FDA approved for the treatment of asthma exacerbation including prednisone, prednisolone, MP and DM, the standard practice in PICU-level care is IV MP every 6 hours until enteral medications can be safely tolerated. Recent data from emergency room literature would suggest there is equipoise in use of dexamethasone as an alternative for methylprednisolone due to its increased glucocorticoid (anti-inflammatory) potency. Steroid agents are chosen at the discretion of clinical providers based upon a child's capacity to tolerate enteral medications and the specific clinical setting (outpatient vs. general inpatient vs. critical inpatient).

The investigators have performed a retrospective study over a 2-year period to assess if differences in clinical outcomes or adverse events exist in cohorts defined by DM exposure in the ER. Their data revealed no differences, but most children were switched to MP during their PICU stay making data analyses severely confounded by exposure to the defining characteristics of the comparative cohort. The investigators seek to first prospectively consent individuals to receive DM during their PICU asthma treatment and compare outcomes to PICU asthmatics concurrently admitted to the PICU receiving local standard care (MP). Johns Hopkins All Children's Hospital (JHACH) admits approximately 150 asthmatics per year in the PICU and the investigators hope to enroll up to 50 subjects into a DM only arm. The comparative standard care arm will be assessed at the end of the study period. Primary outcomes include (1) PICU Length of Stay, (2) Continuous nebulized albuterol duration, and (3) a composite outcome including use of non-invasive ventilation (NIV), terbutaline, inhaled helium, inhaled anesthetic gas, mechanical ventilation, and extracorporeal life support. This research will provide the needed epidemiologic and basic comparative data required to power and conduct a definitive, head-to-head trial of DM vs. MP.

Arms: arm 1: Non-randomized, prospective, observational arm of children receiving standard care for status asthmaticus in the PICU with intravenous methylprednisolone. arm 2: Non-randomized, open-label, prospective use of intravenous dexamethasone for children admitted to the PICU with status asthmaticus.
Interventions: intervention 1: Dexamethasone
Intervention descriptions: intervention 1: Non-randomized, open-label, prospective use of intravenous dexamethasone for children admitted to the PICU with status asthmaticus

Protocol documents:
Prot_SAP_000.pdf: 
 
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Protocol Title: Ideal STeroids for Asthma Treatment in the PICU (iSTAT PICU): A prospective, 
comparative, single-arm study assessing dexamethasone versus methylprednisolone in severe status 
asthmaticus admitted to the pediatric intensive care unit. 
 
Short Title: Ideal STeroids for Asthma Treatment in the PICU [Acronym: iSTAT PICU] 
 
Protocol / Johns Hopkins All Children’s Hospital (JHACH) IRB Number: IRB00187813 
 
National Clinical Trial (NCT) Identified Number:  NCT03900624    
 
Amendment Number: n/a 
 
Date of  Protocol Approval: 3/28/2019 
 
Study Summary: 
Title 
Ideal STeroids for Asthma Treatment in the PICU (iSTAT PICU): a 
prospective, single center, open-label, parallel-group, nonrandomized clinical 
trial. 
Short Title 
Ideal STeroids for Asthma Treatment in the PICU [Acronym: iSTAT PICU] 
IND 
N/A 
Phase 
4 
Design 
Prospective, open-label, parallel-group, nonrandomized clinical trial 
Study Duration 
24 months 
Study Center(s) 
Single-center 
Objectives 
Determine if differences in (1) length of stay, (2) continuous nebulized 
albuterol duration, (3) a composite outcome of rate of advanced asthma 
pharmacologic and respiratory adjunctive therapies, and (4) corticosteroid-
related adverse event rate for children hospitalized with critical asthma 
enrolled to receive IV dexamethasone (Intervention Arm) or 
methylprednisolone (Standard Care Arm). 
Number of Participants 
Minimum of 90 subjects will be enrolled allocated 2:1 to standard care to 
interventional arms  
Diagnosis and Main Eligibility 
Criteria 
Critical Asthma Admission (Status Asthmaticus / Acute Asthma 
Exacerbation) hospitalized in the pediatric intensive care unit (PICU). 
Study Product, Dose, Route, Regimen 
Dexamethasone, 0.25mg/kg/dose (Max 15 mg) every 6 hours, intravenous 
Duration of Administration 
Maximum of 48 hours  
Statistical Methodology 
Descriptive statistics, comparative statistics (Wilcoxon rank sum, Fisher’s 
exact, and student’s t tests). Type I error will be set at 0.05. All data will be 
analyzed using Stata v15.1 (Statacorp©, College station, TX). 
 


 
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STUDY PROTOCOL 
1. Study Team Members: 
a. Senior Investigator:  
i. Anthony A. Sochet, MD, MS (JHU, JH-ACH, Critical Care Medicine) 
b. Principal Investigator:  
i. Meghan Roddy, PharmD (JH-ACH, Critical Care Medicine) 
c. Coinvestigators / Collaborators: 
i. Kristina K. Darville, ARNP; (JH-ACH, Critical Care Medicine)  
ii. Neil Goldenberg, MD; (JHU, JH-ACH, Director of Research) 
iii. Meghan Martin, MD; (JH-ACH, Pediatric Emergency Medicine) 
iv. Scott McKinley, MD; (JH-ACH, Pulmonology and Sleep Medicine) 
v. Thomas A. Nakagawa, MD; (University of Florida, Critical Care Medicine) 
vi. Austin Sellers, MD; (JH-ACH, Institute for Clinical and Translational Research) 
vii. Beatriz Teppa, MD; (JH-ACH, Critical Care Medicine) 
 
2. Abstract 
Critical asthma is disease of immune dysregulation that is acutely treated with inhaled beta-agonists 
and systemic corticosteroids. Steroid agents are chosen at the discretion of clinical providers based upon a 
child's capacity to tolerate enteral medications and the specific clinical setting (outpatient vs. general 
inpatient vs. critical inpatient). Intravenous methylprednisolone (MP) is unanimously used in the critical 
care (PICU) literature and populations but little data exists comparing MP to other potent intravenous 
corticosteroids such as dexamethasone (DM). Both drugs have been FDA approved for the acute treatment 
of inflammatory disorders including asthma, but no superiority trials have been conducted in the inpatient 
setting for this specific population. 
 
Our research group has conducted a retrospective study over a 2-year period to assess if differences 
in clinical outcomes or adverse events exist in cohorts defined by DM exposure in the ER. Our data 
revealed none, but most children were switched to MP during their PICU stay making data analyses 
severely confounded by exposure to the defining characteristics of the comparative cohort. As both agents 
are FDA approved and in an effort to appropriate power sample size calculations for a prospective non-
blinded clinical trial of DM vs MP in status asthmaticus, we seek to first prospectively study individuals 
enrolled into an interventional arm (DM) during their PICU asthma treatment and compare outcomes to 
PICU asthmatics concurrently admitted to the PICU enrolled into a parallel group, standard care arm (MP). 
This research will provide much needed epidemiologic and basic comparative data required to power and 
conduct a definitive, trials of DM vs. MP assessing other clinical efficacy endpoints 
 
3. Study Endpoints: 
Primary endpoints include (1) length of stay, (2) continuous albuterol duration, (3) a composite 
outcome including frequency of critical asthma adjunctive pharmacologic and respiratory-based 
interventions, and (4) corticosteroid-related adverse events 
 
4. Background  
As the pathophysiology of an critical asthma is dysregulated inflammatory pathways, standard 
treatment includes the prompt initiation of intravenous systemic corticosteroids. Glucocorticoids are the 
mainstay of therapy for children treated for critical asthma (Taylor, 1993). Furthermore, corticosteroids 


 
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improve the efficacy of beta-2 agonists, such as albuterol (Svedmyr, 1990), a nebulized medication used for 
bronchodilation in acute asthma exacerbations. There remains an ongoing dialogue among the expert 
medical community regarding the superiority of specific IV corticosteroid, dosing, route and delivery. This 
debate continues secondary to a lack of definitive comparative data in the literature. While the benefits of 
receiving systemic corticosteroids has been demonstrated in multiple studies (Scarfone, 1993; Ho, 1994; 
Connett, 1994; Storr, 1987; Younger 1987; Gleeson, 1990; Kattan, 1980), to date, no superiority trials have 
been conducted comparing IV systemic corticosteroids in the PICU setting.  
While many systemic corticosteroids are FDA approved for the treatment of asthma exacerbation 
including prednisone, prednisolone, MP and DM, standard care in management of critical asthma is IV MP 
1mg/kg/dose (max 60mg) every 6 hours for a 5-day course. Recent data from emergency room literature 
would suggest there is equipoise in use of dexamethasone as an alternative for methylprednisolone due to 
its increased glucocorticoid (anti-inflammatory) potency and long elimination half-life (Keeney, 2014; 
Paniagua, 2017). Steroids are chosen at the discretion of clinical providers based upon a child's capacity to 
tolerate enteral medications and clinical setting (outpatient vs. general inpatient vs. critical inpatient).  
Our research group has conducted a retrospective study over a 2-year period to assess if differences 
in clinical efficacy endpoints or safety endpoints exist in cohorts defined by DM exposure in the ER. Our 
data revealed no differences, but many children were switched to MP during their PICU stay making data 
analyses severely confounded by exposure to the defining characteristics of the comparative cohort. We 
seek to prospectively consent individuals to receive DM (intervention arm) during their PICU stay and 
compare outcomes to a standard care arm (MP). The JH-ACH admits approximately 150 asthmatics per 
year in the PICU and we aim to enroll 90 subjects (30 intervention and 60 standard care) to detect a 1-day 
change in length of stay with a power of 0.8 and alpha set at 0.05. Primary outcomes include (1) length of 
stay, (2) continuous nebulized albuterol duration, (3) a composite outcome including rate of critical asthma 
adjunctive pharmacologic and respiratory interventions, and (4) rates for corticosteroid-related adverse 
events. We plan to use the findings of our study to inform the methodology of upcoming superiority trials 
to better understand how choice of corticosteroid may impact clinical, molecular, physiology efficacy 
endpoints.  
 
5. Study Procedures 
a. Study design: After IRB approval, we will conduct a prospective, parallel-arm, non-randomized, 
open label, single-center, cohort study in children 5 to 17 years of age admitted to the JH-ACH 
PICU with critical asthma. Children consented to the interventional arm will receive intravenous 
(IV) DM 0.25 mg/kg/dose (max dose 15 mg per dose) every 6 hours for up to 2 days and those 
enrolled into standard care arm will receive IV MP 1 mg/kg/dose (max dose 60mg per dose) 
every 6 hours for up to 5 days.  
b. Study duration: Up until 30-days after hospital discharge following study enrollment.  
c. Blinding: None. 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. DM has an FDA approved indication for asthma exacerbation management. The use of 
DM has been adopted in the emergency room and inpatient acute care setting as standard care. 
e. Definition of treatment failure or participant removal criteria.: As the half-life for DM is such 
that 2 days of dosing is the equivalent of 5 days of steroid exposure, at the completion of day 4, 
if a child is still severely ill (at the discretion of the clinical provider in consultation with 
pediatric Pulmonlogy as part of standard care) was defined as treatment failure. Standard care 
would dictate further steroid administration at this time with either IV or PO corticosteroids 
beyond 5 days with planned taper in the inpatient/outpatient setting. If treatment failure occurs 
and IV steroids are elected to be continued beyond the prespecified duration, the clinicians 
could choose the corticosteroid type at their discretion.  


 
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f. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely: After children receive up to 2 days of 
DM, no further corticosteroids are indicated as the elimination half-life is such that it is an 
equivalent of 5 days of treatment with MP. Standard care for children admitted to the PICU for 
critical asthma includes the route modification from IV to enteral largely dependent on 
respiratory and mental status improvements. At that time, a child may be transitioned to enteral 
prednisone or prednisolone during standard care management (MP). If a child enrolled into the 
intervention arm (DM) receives < 2 days of IV DM but are ready to initiate enteral medications, 
then they will be switch to enteral DM 0.5mg/kg/dose daily for a total duration of exposure not 
to exceed 2-days during protocolized treatment. 
g. Inclusion/Exclusion Criteria: Inclusion criteria are children 5 to 17 years of age with primary 
admission diagnoses of critical asthma (including both acute asthma exacerbation or status 
asthmaticus in the PICU setting). Exclusion criteria are children with existing tracheostomy, 
cystic fibrosis, malignancy, transplantation status, and pulmonary hypertension. 
 
6. Drugs/ Substances/ Devices 
 
ARM Name 
Intervention Arm 
Intervention Type 
Dexamethasone (Intervention) 
Dose Route 
Intravenous 
Dose Units 
mg/kg 
Dose Strength 
0.25/dose (Max 15mg) 
Dose Frequency 
Every 6 hours 
Sourcing 
Clinical pharmacy 
Packaging/Labeling Per clinical standard 
 
ARM Name 
Intervention Arm 
Intervention Type 
Dexamethasone (Intervention) 
Dose Route 
Enteral 
Dose Units 
mg/kg 
Dose Strength 
0.5/dose (Max 16mg) 
Dose Frequency 
Daily 
Sourcing 
Clinical pharmacy 
Packaging/Labeling Per clinical standard 
 
ARM Name 
Standard Care Arm 
Intervention Type 
Methylprednisolone 
Dose Route 
Intravenous 
Dose Units 
mg/kg 
Dose Strength 
1/dose (Max 60mg) 
Dose Frequency 
Every 6 hours 
Sourcing 
Clinical pharmacy 
Packaging/Labeling Per clinical standard 


 
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ARM Name 
Standard Care Arm 
Intervention Type 
Prednisone / Prednisolone 
Dose Route 
Enteral  
Dose Units 
mg/kg 
Dose Strength 
1/dose 
Dose Frequency 
Every 12 hours 
Sourcing 
Clinical pharmacy 
Packaging/Labeling Per clinical standard 
 
a. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed: Not applicable. 
b. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.: Not applicable 
 
7. Study Statistics 
a. Primary outcome variables: Primary outcomes include (1) length of stay, (2) continuous 
nebulized albuterol duration, (3) a composite outcome including rate of critical asthma 
adjunctive pharmacologic and respiratory interventions (i.e., magnesium, methylxanthines, 
terbutaline, ketamine, inhaled anesthetics, invasive mechanical ventilation, non-invasive 
ventilation, extracorporeal life support, and heliox), and (4) rates for corticosteroid-related 
adverse events (corticosteroids (i.e., clinically relevant gastrointestinal bleeding, gastritis, 
necrotizing enterocolitis, hypertension, hyperglycemia, altered mentation [hallucinations and 
delirium], and adrenal suppression) 
b. Other study data to be collected: anthropometrics, demographics, Pediatric Risk of Mortality-3 
score Probability of Mortality, Pediatric Asthma Severity Score, National Heart Lung and Blood 
asthma classification, Pediatric Index of Mortality-3 score Risk of Mortality, comorbidities, and 
unplanned same-cause hospital readmission within 30 days 
c. Statistical plan: Descriptive statistics such as proportions/frequencies, means ± standard 
deviation, and medians [interquartile range]. Comparative statistics will include Wilcoxon rank 
sum, Fisher’s exact, and student’s t tests where appropriate. Type I error will be set at 0.05. All 
data will be analyzed using Stata v15.1 (Statacorp©, College station, TX). 
  
8. Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency: 
i. There always exists a potential risk for data leak, loss of privacy and breach of 
confidentiality.  All measures (described below) will be taken to minimize these risks. 
b. Steps taken to minimize the risks: 
i. Patient data will be stored for research purposes as a HIPAA defined limited data set in a 
secure, password protected electronic database and analyzed with Stata v15.1.  Each 
patient will be assigned a unique Participant ID number in the system.  Access to the 
system will be restricted to research team members listed above.  Data extractions as 
well as modifications or edits to data will be logged. 


 
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ii. Serious adverse events will be followed throughout study, officially reported within 24-
hours, and adjudicated within the co-investigator and steering committee. In the event 
that > 5% of children have a serious adverse event during enrollment, trial enrollment 
will be halted to prevent potential harm.  
c. Plan for reporting unanticipated problems or study deviations: 
i. The principal investigator will meet on a monthly basis with study members either face-
to-face or via telecommunications to discuss study management, education / re-
education of team members and mentorship. This will include any discussion related to 
unanticipated problems or study deviations. This will not exclude team members from 
meeting with the principal investigator on other occasions to discuss matters as it relates 
to this study protocol. These meetings will be confidential and take place in a secure 
meeting room in the Johns Hopkins All Children’s Hospital Pediatric Critical Care 
Medicine office in the OCC Suite 702.  Any deviations from the study protocol will be 
logged and immediately reported to the local JH-ACH IRB for review. 
d. Legal risks such as the risks that would be associated with breach of confidentiality: see above. 
e. Financial risks to the participants: none 
 
9. Benefits 
a. This research will provide the needed epidemiologic and basic comparative data required to 
power and conduct a definitive, head-to-head trial of DM vs. MP. As a result of these data, 
definitive study with a randomized, RCT could be conducted to confirm superiority or non-
inferiority of DM vs MP as well as assessment of other relevant endpoints.  
b. We expect that given the shorter treatment duration and potent glucocorticoid activity, DM will 
offer potential advantages related to patient compliance. 
 
10. Payment and Remuneration: None  
 
11. Costs: None 
 
12. Discontinuation of Study Intervention and Participant Withdrawal: 
a. If a patient has a serious or non-serious adverse event thought to be associated with DM, then 
the IRB, subject, and family will be notified of any adverse events immediately.  
b. A participant may voluntarily withdraw from the study at any time at his/her own request (or 
consenting family member’s request).  
 
13. Regulatory and Ethical Considerations: 
a. The investigator will be responsible for the following: 
i. Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
ii. Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
iii. Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 


 
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14. Informed Consent Process: 
a. The investigator or his/her authorized designee will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study. 
b. Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
c. The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the informed consent form 
(ICF). 
d. Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
e. A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
 
15. Protocol Deviations 
a. A protocol deviation is any departure from the defined procedures and treatment plans as 
outlined in the protocol version submitted and previously approved by the IRB. Protocol 
deviations have the potential to place participants at risk and can also undermine the scientific 
integrity of the study thus jeopardizing the justification for the research.   
b. The JHM IRB requires the prompt reporting of protocol deviations which are: 
i. Emergency deviations (when immediate deviations are required to protect the life or 
physical well-being of a participant) 
ii. Major (representing a major change in the approved protocol), non-emergent deviation 
occurring without prior IRB approval  
c. Minor or administration deviations, which do not affect the scientific soundness of the research 
plan or the rights, safety, or welfare of human participants, are reported to the JHM IRB at the 
time of continuing review.