Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05819541 |
| Other study ID # |
R34HL168301 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
October 20, 2023 |
| Est. completion date |
October 31, 2025 |
Study information
| Verified date |
May 2024 |
| Source |
Vanderbilt University Medical Center |
| Contact |
Donald H Arnold, MD, MPH |
| Phone |
16155790516 |
| Email |
don.arnold[@]vumc.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This research will establish a mg/kg dose for a future RCT to determine the efficacy of
high-dose oral montelukast for children with moderate and severe acute asthma exacerbations.
Aim: Perform an adaptive, double-masked randomized controlled trial (RCT) of high-dose oral
montelukast, with escalating mg/kg dose levels determined by PK-guided dose modeling, added
to standard treatment versus standard treatment alone, in children with exacerbations that
are moderate or severe after initial treatment with inhaled albuterol.
Hypothesis 1: High-dose oral montelukast achieves peak plasma concentration (Cmax) >1,700
ng/ml in >86% of at least one of three sequential participant groups with escalating
weight-based (milligram/kilogram or mg/kg) doses between groups.
Hypothesis 2: Participants randomized to high-dose oral montelukast have a 2 point or greater
improvement of the validated Acute Asthma Intensity Research Score (AAIRS) at 4 hours
post-treatment in comparison with control group participants.
Hypothesis 3: Among montelukast recipients, Cmax correlates with change of the AAIRS at 4
hours, after adjustment for pre-treatment exacerbation severity and systemic leukotriene
stress measured using urinary leukotriene E4 (LTE4).
Description:
Study design parameters Design: 2-arm, phase 3 double-blind RCT Intervention: Oral
montelukast sprinkles or identical placebo Dose escalation: Doses between 2 mg/kg and 3 mg/kg
based on pharmacokinetic modeling after each group of 5 participants.
Montelukast is a potent LT-receptor antagonist and is FDA approved at a daily oral dose of
4-5 mg for chronic asthma and allergic rhinitis in children. It is also a potent
bronchodilator. In randomized controlled trials (RCT) of adults with moderate and severe
exacerbations and inadequate response to inhaled albuterol, intravenous (IV) montelukast
caused rapid (within 10 minutes) and sustained improvement of lung function in all subjects,
without selecting for CCS non-responsiveness. This underscores the potential clinical impact
of reducing LT-mediated inflammation during exacerbations. However, the standard 5 mg oral
dose does not achieve peak plasma levels (Cmax) comparable to the IV doses used in these
RCTs, and IV montelukast is not available.
The investigators' preliminary pharmacokinetic (PK) study in children with acute
exacerbations demonstrated that 30 mg oral montelukast (mean 1.0 mg/kg) achieves Cmax >1,700
ng/ml in 40% of participants. This is a Cmax expected after doses used in the adult RCTs
above. The primary hypothesis for this research is that the investigators will identify a
weight-based oral montelukast dose that reliably achieves Cmax >1,700 ng/ml by examining 3
escalating dose levels between 2 and 3 mg/kg. Dose escalation will be optimized using
computerized, PK-guided dose modeling that will be updated after each group of 5 participants
among 45 randomized to receive montelukast. The investigators further hypothesize that
high-dose montelukast meaningfully decreases exacerbation severity, measured using the
validated Acute Asthma Intensity Research Score (AAIRS).
Participants will be randomized to receive montelukast powder USP in ora-sure suspending
agent or identical placebo. Montelukast (MK) dose will begin at 2 mg/kg. Peak MK plasma
concentration (Cmax) will be measured after each group of 5 participants randomized to MK. MK
dose for subsequent participant groups will be escalated if Cmax is <1,700 ng/ml for >14% of
participants at current mg/kg dose level.
INCLUSION CRITERIA
- Child aged 4 - 12 years with doctor-diagnosed asthma
- Presents to the Vanderbilt Children's Hospital (VCH) with an acute asthma exacerbation
that is moderate or severe (AAIRS >= 7) after initial treatment with inhaled albuterol
o Per emergency department (ED) protocol, patients with AAIRS >= 7 have an IV catheter
placed, enabling blood draws.
- The parent agrees to phone and/or mail follow-up at 2-3 weeks for completion of Screen
for Anxiety Related Disorders (SCARED) and side-effect questionnaires.
EXCLUSION CRITERIA
Any of the following preclude enrollment of a child for this protocol:
- Gestational age < 34 weeks
- acute or chronic liver disease
- allergy to montelukast
- female with any evidence of Tanner stage 2 or greater breast development
- gastroesophageal reflux requiring acid-blocking medication
- history of anxiety disorder, depression and/or other neuropsychiatric disorder except
attention-deficit/hyperactivity disorder (ADHD)
- positive on question 1 or 2 of the Columbia Suicide Severity Rating Scale (CSSR-S)
- score >25 on the 82-point Screen for Child Anxiety Related Disorders (SCARED)
questionnaire
- Patients currently receiving daily montelukast (4 or 5 mg) will not be excluded from
study participation.
Blood sampling, scoring the Acute Asthma Intensity Research Score(AAIRS), and measurement of
airway resistance by impulse oscillometry (IOS, below) will be performed before (time 0) and
at approximately 2, 3, 4, 6, 12-18, and 18- 24 hours after drug administration, if the
participant is available. Reasons for non-availability include but are not limited to
discharge from ED or hospital and participant sleeping, performing another procedure, eating,
or being rounded upon by the clinical team. If a participant is to be discharged from the
hospital before the final time point, the investigators will attempt to perform the above
studies immediately prior to discharge.
With the variability of plasma levels at each mg/kg dose in mind, the investigators will use
plasma level distribution as the primary statistical measure for this aim. Plasma montelukast
assays will be performed after each Group of 5 participants are randomized to receive MK,
with a Futility Criterion determining whether subsequent Groups at a Dose Level will be
enrolled at that Dose Level or moved to the next one. Interim analyses will be conducted
after each Dose Level has been studied.
Testing Hypothesis 1:
The investigators are primarily interested in estimating the change in plasma concentrations
of montelukast over time and will report summary statistics at each time point numerically
and graphically. They will also summarize the longitudinal measurements by the Cmax, the
proportion of subjects achieving a Cmax of at least 1,700 ng/ml, the time (Tmax) to reaching
Cmax, and the time to reaching 1,700 ng/ml (T1700). While the investigators anticipate being
able to monitor all subjects for 24 hours, the primary analysis will consider subjects who
have at least 4 hours of blood draws to allow minimally sufficient time to achieve Cmax.
Power calculation for Hypothesis 1: This research is powered for to test hypothesis 1 and may
not be sufficiently powered to test hypotheses 2 and 3. PK studies of oral montelukast at
daily doses (4 - 5 mg) used for control of childhood asthma and allergic rhinitis included
12-32 participants. Investigators established sample size for these studies without formal
power and sample-size calculations. With these considerations in mind, and in collaboration
with the FDA, the sample size for this research has been set at 45 for each arm of this RCT.
For this power calculation the investigators consider the probability of successfully finding
a dose at which at least 86% of Dose level participants achieve a Cmax >1,700 ng/ml.
The first consideration is the scenario in which at least 13 of the 15 (86.7%) group
participants successfully achieves a Cmax >= 1,700 ng/ml. The probability of successfully
identifying this dose will depend on p, the true probability a dose will lead to a Cmax above
1,700 ng/ml. If p=0.90, there is 82% power that the investigators will observe 13 or more
successes in 15 subjects; if p=0.95, there is a 96% power that the investigators will observe
13 or more successes. These calculations are based on a one-tailed cumulative binomial
distribution function with N=15, but there is the possibility of carryover leading to a Dose
Level N of 20, 25, or 30. For N=25 and p=.9, there is a 76% power that the investigators will
observe 22 or more successes; if p=0.95, there is 97% probability of observing 22 or more
successes.
Second, consider the scenario of an inadequate dose that needs to be escalated. In this
scenario, the investigators would escalate to the next dose when more than 2 subjects have a
Cmax below 1,700 ng/ml after enrolling 5, 10, or 15 subjects. If a given dose is only 50%
effective (p=0.5) in achieving a Cmax above 1,700 ng/ml, then there is a 50%, 94%, or 99.6%
probability of escalating after 5, 10, or 15 subjects, respectively.
Testing Hypothesis 2:
The Acute Asthma Intensity Research Score (AAIRS) is a 0 - 16 point (16 most severe) bedside
severity score that incorporates multiple domains of exacerbation severity and predicts
%-predicted FEV1 across all levels of severity. Additionally, an AAIRS <3 predicts safe
discharge from the ED. The AAIRS is an optimal surrogate of need-for hospitalization and an
outcome measure for this research that the investigators can accurately measure before and at
precise time points after active drug or placebo dosing.
Descriptive analysis of key demographic and clinical variables by randomization group will be
performed to evaluate randomization. The primary analysis will be linear regression of change
of the AAIRS severity score 4-hours post dosing (outcome) with an indicator for treatment
group as the predictor of interest and controlling for baseline (pre-treatment) AAIRS and
urinary leukotriene E4 concentration (a measure of systemic leukotriene stress). This model
will allow the investigators to estimate the mean difference in the change in AAIRS score,
treatment versus control, with corresponding 95% confidence intervals. Controlling for
baseline severity using the pre-treatment AAIRS will improve the precision of the estimated
treatment effect. Secondary analyses will replace the binary indicator of treatment group
with the dose of montelukast received. If the investigators find that the assumptions of the
linear model are not appropriate, they will use the proportional odds ordinal regression
model with the same outcome and predictors. The proportional odds model generalizes the
Wilcoxon rank sum test to a regression setting to estimate an odds ratio corresponding to a
treatment effect.
Power and sample size considerations are based on a fixed sample size of 45 treatment and 45
control subjects. In prior studies, the investigators found that the standard deviation of
the change in AAIRS score after 4 hours of treatment was 2.97 points. If the true difference
in the change in AAIRS score between treatment and control groups is 2 points, there will be
89% power to detect a difference between groups. The test will use a two-sided significance
level of 0.05.
Testing Hypothesis 3:
Initial descriptive analysis will include summary statistics and bivariate correlations of
4-hour change of the AAIRS as outcome with Cmax, pre-treatment exacerbation severity, and
urinary LTE4 concentration. Bivariate associations will be flexibly fit using loess smooth
lines and Spearman's rank correlation. Hypothesis 3 will be tested in a multivariable linear
regression model using change of the AAIRS severity score as the outcome with Cmax,
pre-treatment AAIRS, and urinary leukotriene 4 concentration as predictors. Regression
splines will be included as needed to allow for non-linear associations between predictors
and the outcome as needed. As with hypothesis 2, if it is found that the assumptions of the
linear model are not appropriate, the investigators will use the proportional odds ordinal
regression model with the same outcome and predictors.
Power and sample size considerations are based on the 45 montelukast recipients. For
bivariate correlations, there will be 80% power to detect correlations of 0.40 or greater
(R-square of 0.16). For the multivariable model calculation, if it is assumed that
exacerbation severity and leukotriene stress explain 20% of the variability in AAIRS severity
score, then there will be 80% power to detect if Cmax explains an additional 12% of the
variability in AAIRS severity score (improvement in R-square of 0.12). If exacerbation
severity and leukotriene stress only explain 10% of the variability in AAIRS severity score,
then there will be 80% power to detect if Cmax explains an additional 14% of the variability
in AAIRS severity score (improvement in R2 of 0.14). Calculations are based on a two-sided
significance level of 0.05.
