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Search #ABSTRACT#
AccuNeb is indicated for the relief of bronchospasm in patients 2 to 12
years of age with asthma (reversible obstructive airway disease). The use of AccuNeb in these age groups is supported by evidence from adequate and
well-controlled studies of AccuNeb in children ages 6 to 12 and published
reports of albuterol sulfate trials in pediatric patients 3 years of age and older. The safety and effectiveness of AccuNeb in children below 2 years of age has not been established.
A randomized 4-week study demonstrated that albuterol inhalation solutions of 1.25 mg (0.042%) and 0.62 mg (0.021%) produce significantly greater improvements in pulmonary functions than placebo produces in asthmatic children between the ages of 6 and 12 years. For more details on the study, click on the links below:
Reduced Doses of Nebulized Albuterol are Effective for Maintenance Treatment of Children with Asthma
Authors
James Kemp, MD
Dept. of Pediatrics, University of California, San Diego, San Diego, CA
Anjuli Seth Nayak, MD
Dept. of Pediatrics, University of Illinois College of Medicine, Peoria, IL
Michael Noonan, MD
Dept. of Pediatrics, Oregon Health Sciences University, Portland, OR
Joseph Oren, MD
Clinicom: Clinical Communications & Research Consultancy San Francisco, CA
Allan Kaplan, PhD
PDCS, Inc., Boca Raton, FL
Paul Covington, MD
PPD Development, Inc., Wilmington, NC
Corresponding Author:
James Kemp, MD,
9610 Granite Ridge Dr., San Diego, CA 92123;
Business Phone #: 619 292-1144, Fax #: 619 292-0681
List of Abbreviations and Definitions of Terms
| ANOVA |
analysis of variance |
| %- AUC FEV1 |
area under the FEV1 percent change from pre-dose versus time curve |
| FEV1 |
forced expiratory volume in one second |
| MAX FEV1 |
maximum percent change from the predose FEV1 |
Date :
November 2001
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Abstract
Objective
To determine the safety and efficacy of half
and quarter-strength unit doses of albuterol sulfate
inhalation solution in the treatment of moderately
severe asthma in children.
Study Design
In this prospective, multicenter, randomized,
double-blind, placebo-controlled, parallel-group
study, 349 children with moderately severe asthma,
ages 6 to 12 years of age, were randomly assigned
to receive a unit dose of either 1.25 mg (0.042%)
or 0.62* mg (0.021%) nebulized albuterol inhalation
solution or placebo 3 times a day (TID) for 4 weeks.
Spirometry and various safety endpoints were
measured pre-dose and for 6 hours post-dose on
Day 1 and Day 28 of the 4-week trial.
Results
At baseline, the mean forced expiratory volume in
1 second (FEV1) was 69% (range 50% to 90%) of the
predicted value. Comparing each dose to placebo,
both the 1.25 mg and 0.62 mg unit doses of albuterol
produced significant relief of asthma symptoms as
demonstrated by the areas under the FEV1 percent
change from pre-dose versus time curves (%? AUC
FEV1) after the initial dose (p < 0.001) and after
4 weeks TID treatment (p < 0.001). No significant
overall difference in efficacy was seen between the
0.62 mg and 1.25 mg treatments. Both doses
produced significant improvement in FEV1 following
initial dose for all age and weight groups. After the
initial dose, the maximum percent change from
pre-dose FEV1 (MAX FEV1) was on average 29.3%
for the 1.25 mg albuterol dose and 32.0% for the
0.62 mg dose. Within 30 minutes post-dose, 61.6% of
subjects in the 1.25 mg group demonstrated a ‡ 15%
increase from pre-dose FEV1 as did 74.3% of those
receiving 0.62 mg. The mean duration of response
was 160.4 and 147.3 minutes for the 1.25 mg dose and
0.62 mg doses, respectively.
Comparing efficacy after the initial treatment with
the post-dose measurements taken after 4 weeks TID
treatment, the MAX FEV1 increase was similar for
both doses (28.6% and 26.3% for 1.25 mg and 0.62 mg
groups, respectively). The percentage of individuals
having a ‡ 15% increase in FEV1 within 30 minutes
of dosing was slightly lower (56.4% and 59.8%,
respectively) and the response duration was shorter
(116.8 and 115.9 minutes for 1.25 and 0.62 mg doses,
respectively). For both visits, all comparisons of
means to placebo were statistically significant
(p † 0.001). In subgroup analysis, the 1.25 mg dose
was more beneficial than the 0.62 mg dose for subjects
with baseline FEV1 < 60% predicted, aged 11 - 12
years, or weighing > 40 kg at baseline.
Conclusions
This study demonstrates efficacy of albuterol sulfate
solution at doses 75% - 50% lower than currently
available unit doses. Findings from this study show
that a 0.62 mg unit dose of albuterol sulfate inhalation
solution is efficacious in children † 10 years of age,
older children weighing † 40 kg or in children with
less severe asthma. The 1.25 mg unit dose was effective
in all subgroups. Both dose levels are safe in children
6-12 years of age.
Introduction
Asthma is the most common chronic lung disease
in children.1 During the years 1980 to 1994, asthma
prevalence has reportedly increased in the United
States by 75% overall and by 160% in young children.2
Asthma hospitalization rates are also higher in young
children due, in part, to difficulties in using currently
available drug delivery devices and failure to use
optimal doses of asthma therapies.
Short-acting inhaled beta2-agonists, such as
albuterol, are the first-choice treatment for relief of
symptoms of acute asthma in both adults and children.1
Albuterol is currently available as a 2.5 mg unit dose
(0.083%) inhalation solution for use in nebulizers.
Although this dose was originally approved for use by
adults, the FDA has recently expanded labeling
guidelines to include pediatric asthmatic patients as
young as age 2 years, an action based on published
studies of albuterol treatment in severe acute asthmatic
episodes. However, given on a regular basis, the
2.5 mg formulation may provide more albuterol than
needed in children, thereby increasing the risk
of adverse drug effects. In the recently revised
guidelines for asthma treatment, the National
Institutes of Health cautions patients to use the lowest
beta2-agonist dose needed to control symptoms.1
Indeed, in current clinical practice, using lower doses
of albuterol for patients under age 12 to reduce the
risk of side effects necessitates routine dilution of the
currently marketed products. Parents, day-care givers,
teachers and others may not have adequate experience
diluting the available dose, resulting potentially in
contamination or inappropriate dosing.
The purpose of this study, therefore, was to assess
safety and efficacy of sterile-filled unit doses of 1.25 mg
(0.042%) and 0.62 mg (0.021%) albuterol sulfate in
children with moderate to severe asthma. For new
albuterol products, the Food and Drug Administration
routinely requires data to be collected for 4 weeks.
Therefore, this study investigated the effects over a
4 week tid treatment period.
Methods
Subjects
Pediatric patients were eligible if they had a
documented history (‡ 6 months) of moderately
severe persistent asthma confirmed by a physician
and requiring daily asthma medication, but were in
otherwise good health. Patients were required to have
spirometrically documented FEV1 between 50% and
80% of predicted values (Polgar3) at baseline and at
the beginning of the double-blind treatment phase.
In addition, patients were required to demonstrate
during the screening visit at least 15% reversibility
in FEV1 following the administration of inhaled
nebulized albuterol (2.5 mg dose). Patients must have
exhibited symptomatic asthma requiring the use
of beta2-agonists on at least 6 of the 14 – 3 days of
observation during the placebo-controlled run-in
period. All study patients and their caregivers
provided informed written consent approved by the
Institutional Review Board with jurisdiction over
the site.
Patients were excluded from the study if one,
or more, of the following conditions or situations
were present: severe asthma or any serious medical
condition; use of prescription medication for which
albuterol sulfate is contraindicated; hypersensitivity
to albuterol or similar agents; active pulmonary
disease other than bronchial asthma; upper respiratory
tract infection within 4 weeks of the start of the
placebo phase; any other chronic condition that could
have interfered with successful completion of the
study or confounded its interpretation; acute use of
corticosteroids or other treatments which might
interfere with the study within 4 weeks of the screening
visit; and/or inability or unwillingness to perform the
requirements of this protocol.
Allowed Concomitant Medications
Patients who met the inclusion criteria while on
regularly prescribed asthma medications could continue
on those medications (inhaled corticosteroids,
cromolyn sodium, or nedocromil) during the course
of the study if the doses remained stable. Patients
were required to withhold their morning dose before
each study visit and during the entire study session.
After the patient completed the study session, the
regularly scheduled dosing resumed for that day. All
medication used to treat chronic conditions, including
immunotherapy, had to be initiated at least 30 days
prior to study start, and the dosing regimen had to
be stabilized by Visit 1. The supplemental use of
beta2-agonists was limited to "rescue" use of studysupplied
albuterol [Dey MDI or Dey Albuterol
Sulfate Inhalation Solution, 2.5 mg (0.083%)].
Study Design
In this multi-center, randomized, double-blind,
placebo-controlled, 3-way parallel group study,
qualifying children ages 6 to 12 years were
randomized to receive 1 of the 3 treatments TID for
4 weeks, each in 3.0 mL volume: 1.25 mg albuterol
sulfate inhalation solution (0.042% nebulizer
solution), 0.62 mg albuterol sulfate inhalation
solution (0.021% nebulizer solution) or placebo
(saline). Each patient was provided with a personal
compressor-driven PARI LC PLUS “ nebulizer
(Pari Respiratory Equipment, Inc., Richmond, VA)
for the duration of the study.
A screening visit was followed by a 2-week
placebo run-in phase to confirm the need for regular
symptomatic beta2-agonist therapy and to give
patients experience with daily diaries and peak flow
measurements, as well as to demonstrate compliance.
The 4-week study period began with the initial
morning dose of the study drug at the study
site followed by pulmonary function tests (PFTs)
30 minutes after the end of nebulization and hourly
thereafter for 6 hours; pre-dose PFTs were also done.
Patients returned after 14–3 days for exchange of
study medication and diaries and PFTs before and
30 minutes after the morning dosing. After completing
28–3 days of treatment, patients returned to the test
site for a repeat of the 6-hour evaluation of safety and
efficacy following administration of study medication.
Diary cards were used to record asthma symptoms,
night awakenings, peak flow measurements,
supplemental albuterol use, change in medications
and adverse events.
Vital signs (heart rate, blood pressure, respiration
rate and body temperature) were collected at
screening, pre-dose, 30 minutes post dose and then
hourly for 6 hours at Visits 2 and 4, and pre-dose and
30 minutes post dose at Visit 3. Electrocardiograms
(ECGs) were done at screening, pre-dose and
30 minutes post dose at Visits 2 — 4 and at the
termination visit, if the subject discontinued
prematurely from the study, and also at 60 minutes
post dose at Visits 2 and 4. To standardize the
interpretations of the ECG, the rhythm strips were
faxed to a central institution for reading by a pediatric
cardiologist. The investigator, who had first-hand
knowledge of the patient s medical history and health
status, re-assessed any abnormal interpretations
for their clinical relevance.
Pulmonary Function Tests
All spirometry measurements were standardized
with the Pulmonary Data Service (PDS, Boulder, CO)
KOKO“ Spirometry and linked to a computer using
specialized software incorporating American
Thoracic Society guidelines and Polgar prediction
equations for pediatric pulmonary function testing.3
The primary efficacy endpoint was the area under
the percent change from pre-dose FEV1 versus time
curve (%¢ AUC FEV1) for the initial dosing visit
(Day 1) and the final dosing visit (Week 4).
Secondary efficacy endpoints included MAX FEV1;
’percentage with response’ defined as the percentage
of subjects with a >15% increase from pre-dose FEV1
at various time points; and the ’duration of the
response’ defined as the duration of a >15% increase
from pre-dose FEV1 (in minutes).
Data Analysis
Efficacy could have been demonstrated in a
relatively small number of patients for each drug
treatment group (30 children); however, in order
to accumulate sufficient safety data for each of the
2 unit-doses, a greater number of children was needed.
The recruitment goal was to randomize at least 100
pediatric patients per treatment arm with a minimum
of 80 children in each group completing the
testing phase.
All analyses and reporting of data were performed
using SAS¤ version 6.09 on a VAX Alpha platform
(SAS Institute, Cary, NC). All statistical tests were
two-sided. Continuous demographic variables were
tested for baseline comparability between treatments
using analysis of variance (ANOVA); the categorical
variables, race and gender, were tested using Fisher s
Exact Test. Non-parametric methods (Kruskal-Wallis
and Wilcoxon Rank Sum Tests) were used to test
for overall treatment effect and pairwise treatment
differences. The result of a test was considered
statistically significant if p † 0.05.
Efficacy data were calculated from the patients
who, as a minimum, had the following PFT data
points (pre-dose and 30 minutes, 1 hour, 2 hours, and
6 hours post-dose) at Visit 2 (the initial dose visit)
and/or Visit 4 (the final visit post 4-weeks of
study drug).
This study tested the null hypothesis that the %¢
AUC FEV1 at Visit 4 was equal across all treatment
groups. Descriptive statistics for %¢ AUC FEV1 were
summarized by treatment for the efficacy population.
Non-parametric analyses of variance were used for
the ranks of %¢ AUC FEV1 and MAX FEV1. The
duration of response (in minutes) was analyzed with
univariate statistics; the other duration variable
(in time groups) was described by frequency
distributions.
Subgroup analyses were done by age (6 - 8, 9 - 10,
and 11 - 12 year olds), weight ( < 30kg, 30 - 40 kg,
40 kg), concomitant corticosteroids and disease
severity (dichotomized at FEV1 60% of predicted).
Summaries of safety data were based on the intentto-
treat population, which included all patients who
received at least one dose of study drug. Chi-square
testing was done on the incidence of adverse events.
In addition, changes from baseline (defined as
pre-dose at Visit 2, the start of the treatment phase)
and normal/abnormal shifts were summarized for the
laboratory values at Visit 4. Vital signs and ECG data
were summarized by treatment and by time using
descriptive statistics.
Results
Subjects
Atotal of 349 children (220 males and 129 females)
were randomized and 288 (82.5%) completed the
double-blind 4-week treatment period. Demographic
and other baseline characteristics were comparable
between the 3 treatment groups (Table 1). Patients in
all 3 groups had comparable mean percentages of predicted
FEV1 (69%; range: 50% - 90%). Forty-five
(74%) of the 61 patients who discontinued prior to the
end of the study did so due to adverse events. Only 1
of the 61 patients who discontinued the study did so
due to lack of efficacy; an 11 year-old African
American male weighing 38 kg discontinued after 15
days on 0.62 mg albuterol. There were no betweengroup
differences in the number of patients discontinuing
due to adverse events.
Change in FEV1:
Compared to placebo, both the 1.25 mg and the
0.62 mg albuterol unit doses produced significant
improvement in FEV1 following both the initial dose
and the dose given at Visit 4 after 4 weeks of TID
treatment (Figures 1 and 2).
As depicted in Tables 2 and 3, the means of the
primary efficacy parameter, %¢ AUC FEV1, and
secondary efficacy parameters, MAX FEV1 and
duration of response, are all significantly different
from placebo; this is true for both doses and for both
visits, although there were no statistically significant
differences between the 1.25 mg and the 0.62 mg
albuterol doses at either visit. The %. AUC FEV1 and
the MAX FEV1 were both higher at the 0.62 mg dose
than at the 1.25 mg dose. Comparing the efficacy
endpoints after the initial visit (Table 2) and after
4 weeks of treatment (Table 3), note that the means
and percentages for each treatment arm, including
placebo, are higher at the beginning of the study than
at the end. Following the initial dose the mean
%. AUC FEV1 values were 99.5 % ¥ hr, 104.5 % ¥ hr
and 43.6 % ¥ hr for 1.25 mg albuterol, 0.62 mg
albuterol and placebo, respectively (p < 0.001). The
mean MAX FEV1 increases were 29.3%, 32.0% and
15.5%, respectively.
A 15% improvement in FEV1 was defined as a
therapeutic bronchodilator response. The percentage
of individuals having a ‡ 15% increase in FEV1 within
30 minutes of dosing was 61.6% for the 1.25 mg dose
and 74.3% for the 0.62 mg dose compared
with 19.0% for placebo. These responses showed
statistically significant improvement over placebo
(p < 0.001). After the initial study dose the response
duration was 160.4 minutes for the 1.25 mg albuterol
dose and 147.3 minutes for the 0.62 mg dose versus
60.7 minutes for placebo.
Responses to study drug following 4 weeks of TID
treatment were qualitatively similar to the initial
response. The MAX FEV1 increase was 28.6% for the
1.25 mg albuterol dose and 26.3% for the 0.62 mg
dose compared to 13.4% for placebo. The percentage
of individuals having a ‡ 15% increase in FEV1 within
30 minutes of dosing was 56.4% for the 1.25 mg dose
and 59.8% for the 0.62 mg dose compared to 10.1%
for placebo. These responses showed statistically
significant improvements over placebo (p < 0.001).
The mean response duration was shorter after 4 weeks
exposure (116.8 minutes for the 1.25 mg albuterol
dose and 115.9 minutes for the 0.62 mg dose vs
39.2 minutes for placebo).
The mean duration of the response to albuterol at
the initial exposure was approximately 2.5 hours,
which dropped to 2 hours after 4 weeks of treatment;
however, 53% - 58% of the patients receiving
albuterol had a duration of response > 2 hours
following the initial exposure compared to 19% of
the placebo patients, and 27% - 33% had a duration of
response > 4 hours compared to 12% with placebo.
After 4 weeks of treatment, the percentages of
patients with > 2 hours response were 40% - 42% for
both albuterol groups and the percentages of patients
with > 4 hours response were 21% - 22% for the
albuterol groups.
Use of Rescue Medication:
Patients subsequently randomized to each of the
treatment groups used comparable amounts of rescue
medication during the placebo run-in period as shown
in Table 1. During Week 1 of active treatment, the
mean use of rescue medication decreased in both
albuterol groups while remaining the same for the
placebo group (1.6 puffs/day, 1.7 puffs/day and 2.1
puffs/day for the 1.5 mg albuterol group, 0.75 mg
albuterol group and placebo, respectively). During
Week 4 of active treatment, both the albuterol groups
were using a mean of 1.4 puffs/day compared to a
mean of 2.1 puffs/day for the placebo group.
Subgroup Analyses:
In all age groups, both active treatment groups
produced significant improvement in the FEV1
following the initial dose and the 4 weeks of treatment.
All improvements were statistically significant
at p < 0.05, except for the 11 - 12 year olds following
4 weeks of exposure to the 0.62 mg albuterol dose.
Analyzing the durations of response by age resulted
in no identifiable differences across age groups.
In all weight categories, both active treatment
groups produced significant improvement in the
FEV1 over time following the initial exposure and
following 4 weeks of treatment with one exception,
heavier children (> 40 kg) receiving the lower dose of
0.62 mg for 4 weeks who had a mean %. AUC FEV1
of 58.9 % ¥ hr (72.0 sd.) compared to 30.9 % ¥ hr
(38.1 sd.) for the placebo group (p = 0.101). In
the 1.25 mg albuterol group, the same subset had
a mean %. AUC FEV1 of 109.7 % ¥ hr (122.3 sd.;
p = < 0.001). Analyzing the durations of response by
weight subset resulted in no identifiable differences
across weight groups.
We also conducted subgroup analysis by disease
severity; i.e., for patients above and below the
cutpoint of FEV1 < 60% predicted at the start of the
treatment phase of the study. There were 56 patients
in this more severe category for the initial exposure
and 38 patients at the end of the 4 week treatment.
Both the 1.25 mg and the 0.62 mg albuterol doses
produced significant improvements in the %. AUC
FEV1 for this more severe group following the initial
dose. After 4 weeks of treatment, the response to the
0.62 mg dose, while still better than placebo, was not
statistically different than placebo (p = 0.141) while
the response to 1.25 mg albuterol remained significantly
different than placebo (p = 0.049). The mean
MAX FEV1, however, was significantly increased
in that population at 4 weeks (45.1%; p = 0.034 for
1.25 mg unit dose and 36.6%; p = 0.024 for the
0.62 mg unit dose)
The percentages of patients using concomitant
inhaled corticosteroids during the study were similar
across the treatment groups (52%, 56% and 50% for
1.25 mg, 0.62 mg albuterol and placebo, respectively).
For both active doses at both the initial and 4-week
exposure, patients with concomitant steroid use
consistently had higher values for the %¢ AUC FEV1
than did patients without concomitant inhaled steroid
use. However, the mean %¢ AUC FEV1 following
4 weeks of treatment with the 0.62 mg dose did not
reach statistical significance (p = 0.151).
Safety:
During this study, 164 (47%) of 349 patients reported
350 adverse effects (AEs); asthma exacerbation and
rhinitis were the most frequently reported. The
majority (92%) of the AEs were considered by the
investigators to be unrelated to the study medication.
The safety profiles (e.g., vital signs, ECG, etc.) of the
higher dose of albuterol (1.25 mg) and the lower dose
(0.62 mg) were comparable and similar to placebo.
Beta2-agonist related events, such as tremors, were
higher in the albuterol groups than in the placebo
group with each type of adverse event being reported
by † 1.3% of the patients in both albuterol groups. No
deleterious systemic effects, measured by changes in
vital signs and ECG parameters, were detected. Acute
effects of albuterol on laboratory parameters were not
examined in this study.
Six serious adverse events (SAEs) were reported
during the study. Two patients in the 1.25 mg
albuterol sulfate treatment group experienced asthma
exacerbations that required emergency treatment.
Four patients in the 0.62 mg albuterol sulfate
treatment group experienced SAEs: three related to
the respiratory system (an asthma exacerbation, a
pneumonia, and a flu-like syndrome), and one related
to a pre-existing condition (fever associated with
sickle-cell anemia). Based on the investigator’s
judgment at each site, all SAEs were considered
unrelated to study medication. No SAEs were reported
by placebo patients.
Discussion
Findings from this study support the use of
lower unit doses of albuterol sulfate than is currently
available by prescription in the United States. This
study demonstrates that nebulized unit doses of
0.042% (1.25 mg) and 0.021% (0.62 mg) albuterol
inhalation solutions are effective in producing
significant improvements in the pulmonary functions
of asthmatic children.
The 1997 National Asthma Education and
Prevention Program Expert Panel recommended the
use of 0.05 mg/kg (minimum of 1.25 mg, maximum
of 2.5 mg) nebulized albuterol for children.1 The only
albuterol unit dose inhalation solution currently
marketed has 2.5 mg (0.083%) in 3 mL. This study
demonstrates that nebulized unit doses of 0.042%
(1.25 mg ) and 0.021% (0.62 mg) albuterol inhalation
solutions are effective in producing significant
improvements in the pulmonary functions of asthmatic
children.
Other published studies support the effectiveness of
doses of albuterol nebulized solution lower than the
currently available product. A small randomized
2-week TID study showed that the 1.25 mg albuterol
base dose was effective in treating severe asthma in
children.4 The study was conducted in 28 children,
ages 5 - 14 years, with acute asthma characterized by
intense coughing, dyspnea and wheezing and all had
FEV1 that was † 66% of predicted. The 1.25 mg
albuterol dose was found to be equally effective in
significantly improving pulmonary functions with
or without the concomitant use of another drug
under study.
In a study comparing heated versus room temperature
nebulized salbutamol (albuterol), 40 asthmatic
children ranging in ages from 5 - 12 years (mean age:
8.5 years) were randomized to the 2 treatment groups
and then exposed in a crossover design to either
the manufacturer s recommended dose (0.15 mg/kg,
to a maximum of 5 mg) or half the recommended
dose (0.075 mg/kg).5 The 2 doses gave equivalent
improvements in pulmonary function. Salbutamol
(albuterol) 0.075 mg/kg (at standard temperature)
produced 55% increase in FEV1 versus 43% for the
0.15 mg/kg dose.
The response durations seen with the 2 lower dose
albuterol solutions were comparable to the duration of
response reported for an albuterol metered dose
inhaler (MDI);6 furthermore, the percentage of
patients continuing to demonstrate a response at 2 and
4 hours post treatment were similar to those reported
in the Ventolin¤ package insert.7
The potential for the development of drug tolerance
to beta-agonists (or, alternatively, tachyphylaxis) has
been debated for more than 20 years.8-12 The apparent
decrease in efficacy over time seen with the 0.62 mg
albuterol unit dose in this study is consistent with
other findings from clinical trials examining higher
doses.10-12 Although we detected a decrease in efficacy
over time with the 0.62 mg unit dose, the response
was still clinically significant (i.e., > 15% increase
in FEV1).
The Food and Drug Administration routinely
requires data for 4 weeks of treatment to demonstrate
efficacy and safety for albuterol products. In this
study, the efficacy measurements after 4 weeks were
lower than measurements after the initial dose,
including placebo. Since the effect was also seen
in the placebo group, the decrease may represent
weariness on the part of the patients and not a
reduction in efficacy (potentially resulting in less
effort with regard to spirometry and, perhaps, to dose
administration--both are effort-dependent). This was
a demanding study for children to undertake
considering the 4-week dosing regimen, PEF monitoring,
diaries, placebo, run-in, etc., as evidenced by the
drop-out rate. The study, nonetheless, has demonstrated
superiority over placebo for both doses after the
4 weeks of exposure.
Conclusions
This randomized, double-blind, placebo-controlled,
parallel-group, 4-week study demonstrated that
albuterol inhalation solutions of 1.25 mg (0.042%)
and 0.62 mg (0.021%) produce significantly greater
improvements in pulmonary functions than placebo
produces in asthmatic children between the ages of
6 and 12 years. This improvement occurred regardless
of whether or not the child was on concomitant
inhaled corticosteroids. No deleterious systemic
effects were seen with either the 1.25 mg or 0.62 mg
albuterol doses; therefore, both the 1.25 mg and
0.62 mg albuterol unit dose solutions are safe and
effective. The 0.62 mg unit dose of albuterol sulfate
inhalation solution is effective for children ages † 10
years and older children weighing † 40 kg or with
less severe asthma. The 1.25 mg unit dose of albuterol
is effective, in addition, for long-term use in children
ages 11 - 12 years, weighing > 40 kg or in those
who have more severe asthma. It would appear
inappropriate from these data to give higher doses
of albuterol nebulizing solution on a regular basis
to children.
Acknowledgements
Other principal investigators who participated in
the clinical trial were: Thomas D. Bell, MD,
Missoula, MT; Robert Berkowitz, MD, Atlanta, GA;
Jonathan Bernstein, MD, Cincinnati, OH; Eugene
Bleecker, MD, Baltimore, MD; Michael Z. Blumberg,
MD, Richmond, VA; Thomas Casale, MD, Papillion,
NE; Arther C. DeGraff Jr., MD, Hartford, CT;
Thomas B. Edwards, MD, Albany, NY; Albert Finn,
MD, Charleston, SC; Sandra M. Gawchik, DO,
Chester, PA; Sherwin A. Gillman, MD, Orange, CA;
Stanley Goldstein, MD, Rockville Center, NY; Jay
Grossman, MD, Tucson, AZ; Melvin Haysman, MD,
Savannah, GA; Robert Holzhauer, MD, Rochester,
NY; Roger Katz, MD, Los Angeles, CA; Phillip
Korenblat, MD, St. Louis, MO; Craig Fred LaForce,
MD, Raleigh, NC; Robert F. Lemanske, Jr., MD,
Madison, WI; Roger Menendez, MD, El Paso, TX;
S. David Miller, MD, Dartmouth, MA; David S.
Pearlman, MD, Aurora, CO; Paul Ratner, MD, San
Antonio, TX; Richard Rosenthal, MD, Fairfax, VA;
Michael E. Ruff, MD, Dallas, TX; Eric J. Schenkel,
MD, Easton, PA; Nathan D. Schultz, MD, Danville,
CA; Gail G. Shapiro, MD, Seattle, WA; Tommy C.
Sim, MD, Friendswood, TX; Loren Southern, MD,
Princeton, NJ; Joseph Spahn, MD, Denver, CO;
William W. Storms, MD, Colorado Springs, CO;
Robert G. Townley, MD, Omaha, NE; Mark L.
Vandewalker, MD, Rolla, MO; Suzanne Weakley,
MD, Houston, TX; Steven F. Weinstein, MD,
Huntington Beach, CA; Ned Whitcomb, MD,
Carmichael, CA; James D. Wolfe, MD, San Jose, CA;
and Jerold J. Yecis, MD, Stockton, CA.
In addition, the authors wish to acknowledge the
staff at PPD Development, Inc., especially Scott
Lamm, Pam Norton, Randy Anderson and Delores
Graham for the conduct and analysis of the clinical
trial and preparation of the study reports.
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Table 1: Demographics and Other Baseline Characteristics
Table 2: Efficacy Parameters after Initial Dose
Table 3: Efficacy Parameters After 4-Week TID Treatment
Figure 1. Albuterol sulfate-induced relative change in FEV1 over time following initial challenge.
Figure 2. Albuterol sulfate-induced relative change in FEV1 vs. time following 4-week TID treatment.
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