1013_ET_murphy 6/29/07 9:49 AM Page 1013
Clinical Therapeutics/Volume 29, Number 6, 2007
A 12-Week, Multicenter, Randomized, Partially Blinded,
Active-Controlled, Parallel-Group Study of Budesonide
Inhalation Suspension in Adolescents and Adults with Moderate
to Severe Persistent Asthma Previously Receiving Inhaled
Corticosteroids with a Metered-Dose or Dry Powder Inhaler
Kevin Murphy, MD1; Michael Noonan, MD2; Philip E. Silkoff, MD3; and
Thomas Uryniak, MS3
1Midwest Children’s Chest Physicians, Omaha, Nebraska; 2Portland Allergy Associates Research,
Portland, Oregon; and 3AstraZeneca LP, Wilmington, Delaware
ABSTRACT
Background: Nebulized budesonide inhalation sus-
pension (BIS) is approved in the United States for chil-
dren with asthma aged 1 to 8 years.
Objective: The primary objective of this study was
to compare the efficacy of BIS 0.5 mg QD and 2.0 mg
BID in terms of the mean change from baseline to end
of treatment in predose forced expiratory volume in
1 second (FEV1).
Methods: In this 12-week, partially blinded, ran-
domized study, subjects aged ≥12 years with moderate
to severe persistent asthma previously receiving in-
haled corticosteroids (ICSs) by dry powder inhaler
(DPI) or metered-dose inhaler (MDI) continued thera-
py during a 2- to 3-week run-in period and then
switched to BIS 0.5 mg QD, 1.0 mg QD, 1.0 mg BID,
or 2.0 mg BID, or budesonide DPI 400 µg BID (active
reference arm). Besides FEV1 (the primary variable),
other outcome variables included changes in forced
vital capacity (FVC) from baseline to weeks 4, 8, and
12 and to the average over the treatment period; as
well as changes from baseline to the end of treatment
in diary-collected daytime and nighttime asthma symp-
tom scores, rescue medication use, nighttime awaken-
ings due to asthma, morning and evening peak
expiratory flow (PEF), percentages of symptom-free
and medication–free periods, and the incidence of pre-
defined asthma events. Adverse events were recorded
by subjects. Steady-state pharmacokinetics of budes-
onide were assessed in all treatment arms. Efficacy
analyses included data in a modified intent-to-treat ap-
proach. Differences in the change from baseline to end
of treatment in FEV1 were assessed using analysis of
covariance (ANCOVA). For secondary variables,
June 2007
changes from baseline to each visit or to the treatment-
period average were compared among groups using an
ANCOVA model. P ≤ 0.05 was considered statistical-
ly significant.
Results: The randomized population consisted of
758 subjects: 57 (7.5%) aged 12 to <17 years, 667
(88.0%) aged 17 to <65 years, and 34 (4.5%) aged
≥65 years. There was no significant difference in mean
change in predose FEV1 between BIS 0.5 mg QD and
BIS 2.0 mg BID (0.02 vs 0.01 L). On average, mean
values for the BIS dosage groups did not indicate any
deterioration from baseline to the treatment period
for variables associated with asthma control such as
FEV1, FVC, daytime and nighttime asthma symptom
scores, rescue medication use, nighttime awakenings,
morning and evening PEF, percentages of symptom-
free and rescue medication–free periods, and prede-
fined asthma events. The BIS 1.0-mg BID treatment
appeared to be closest to budesonide DPI in plasma
budesonide concentrations and improvement in pre-
dose FEV1 (0.08 vs 0.12 L). All treatments were well
tolerated.
Conclusions: In this study, no difference in efficacy
between BIS 2.0 mg BID and 0.5 mg QD was found in
adolescents and adults with persistent asthma when
transitioned from ICSs delivered with a DPI or MDI.
Subjects taking all BIS dosages experienced similar re-
Accepted for publication April 12, 2007.
Express Track online publication June 14, 2007.
doi:10.1016/j.clinthera.2007.06.005
0149-2918/$32.00
Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2007 Excerpta Medica, Inc.
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Clinical Therapeutics
sponses for variables associated with asthma control.
(Clin Ther. 2007;29:1013–1026) Copyright © 2007
Excerpta Medica, Inc.
Key words: budesonide inhalation suspension, in-
haled corticosteroids, asthma, adolescents, adults, DPI,
pMDI, nebulizer.
INTRODUCTION
Inhaled corticosteroids (ICSs) are the preferred long-
term maintenance therapy for adults and children
with persistent asthma of all degrees of severity.1 De-
spite the proven efficacy of ICSs in the treatment of
asthma, some patients cannot use inhaler devices
properly and therefore fail to respond optimally to
treatment administered with an inhaler.2,3 Several fac-
tors, such as the inhalation device, formulation, in-
haler technique, patient compliance, and comorbid
conditions, play a role in the amount of drug that
reaches the airways.2 Although spacer devices or hold-
ing chambers minimize the need for coordinated in-
halation and actuation of the pressurized metered-
dose inhaler (pMDI), some patients still find use of
these devices complex.2 Children,3 the elderly,4,5 and
subjects with comorbid conditions3,6 may not have
the ability or coordination required to properly use
pMDIs and dry powder inhalers (DPIs) and may bene-
fit from the use of a nebulized drug that is adminis-
tered during tidal breathing.3
Budesonide inhalation suspension (BIS)* is the only
nebulized ICS available in the United States and is
approved by the US Food and Drug Administration
(FDA) for the prevention and maintenance treatment
of asthma in children aged 1 to 8 years. Data for ap-
proval were derived from 3 pivotal trials in 1018 pe-
diatric subjects.7–10 BIS is approved in 71 countries
worldwide for the maintenance treatment of bronchial
asthma in pediatric and adult subjects.11 In the United
States, BIS is not FDA approved for use in children
>8 years or adults with asthma; however, no differ-
ences in tolerability have been reported with the use of
BIS in geriatric subjects and younger subjects.9 More-
over, several studies in subjects aged 18 to 75 years
with severe persistent asthma demonstrated that switch-
ing from ICS inhalers to nebulized BIS (1–8 mg/d) al-
lowed discontinuation or reduction of oral corticoster-
*Trademark: Pulmicort Respules® (AstraZeneca LP, Wilming-
ton, Delaware).
1014
oid therapy.12–15 BIS was also effective in case studies
of adults with persistent asthma who did not have an
optimal response to other ICS preparations16 and in
26 adults with moderately severe unstable asthma.17
BIS may be a viable therapeutic alternative for sub-
jects with asthma whose physical and cognitive capa-
bilities preclude them from properly using a pMDI or
DPI, who prefer nebulized therapy, or who have se-
vere persistent asthma that does not respond to other
therapies.11 To evaluate the clinical utility of nebulized
BIS in adolescents and adults, the objectives of the
present study were to compare the efficacy, safety, and
pharmacokinetics of 4 dose levels of BIS in subjects
aged ≥12 years with moderate to severe persistent
asthma previously maintained on an ICS delivered
with a DPI or pMDI. To provide a reference for tran-
sitioning budesonide from a DPI to nebulized thera-
py, we determined which BIS dosage was comparable
(based on efficacy and pharmacokinetics) to budeso-
nide DPI.† The adult population in this trial is a sur-
rogate for the population of subjects who would most
likely prefer nebulized therapy because of an inability
to use MDI or DPI devices due to factors such as
arthritis or impaired comprehension.
METHODS
Study Design and Subjects
This randomized, partially blinded, multicenter,
parallel-group study (no. SD-004-0764) in adolescents
and adults with moderate to severe persistent asthma
included a 2- to 3-week run-in period followed by a
12-week treatment phase and a 2-week tolerability
follow-up period. The study included 5 visits: screen-
ing visit (2–3 weeks before randomization), randomi-
zation visit (day 1), on-treatment visits (weeks 4 and 8),
and an end-of-treatment visit (week 12 or last visit).
Electronic diaries (Logpad, PHT Corporation, Charles-
town, Massachusetts) and Mini-Wright Peak Flow
Meters (Clement Clarke International Ltd., Essex,
United Kingdom) were provided to subjects at the
screening visit. Diaries were used to collect data on
peak expiratory flow (PEF), study drug use, asthma
symptom scores (scale, 0 = no symptoms to 3 =
severe symptoms), nighttime awakenings due to asth-
ma symptoms, and rescue medication use. Subjects
were instructed to record the highest of 3 PEF mea-
†Trademark: Pulmicort Turbuhaler® (AstraZeneca LP).
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1013_ET_murphy 6/29/07 9:49 AM Page 1015
surements that were performed twice daily, upon ris-
ing in the morning before use of albuterol and in the
evening ~12 hours later. Subjects downloaded their
diary data daily to a central site; these data were re-
viewed by study personnel at least 3 times weekly.
Males and females aged ≥12 years with a diagnosis
of moderate to severe persistent asthma, as defined
by the American Thoracic Society (ATS)18 and deter-
mined by prestudy daily ICS requirements, were quali-
fied to participate. Subjects met the screening eligi-
bility requirements if they had a forced expiratory
volume in 1 second (FEV1) between 45% and 90% of
predicted normal; postbronchodilator reversibility of
FEV1 of ≥12% (this criterion could be met at the ran-
domization visit if not met at the screening visit); and
had received treatment with beclomethasone dipropi-
onate, budesonide, fluticasone propionate, flunisolide,
or triamcinolone acetonide maintained at a constant
level with a medium daily dose, as defined by the
2002 National Asthma Education and Prevention
Program (NAEPP) guidelines,1 or higher, for ≥30 days
before study entry. Women of childbearing potential
were required to have been using acceptable birth con-
trol. Key exclusion criteria included the following:
≥1 hospitalization or >1 emergency treatment for
asthma within the previous 6 months; smoking within
90 days before screening or a >10–pack-year history of
smoking; any life-threatening or severe persistent asth-
ma (eg, intubation, respiratory arrest) as a result of asth-
ma exacerbation within the previous 10 years; or any
other disease, disorder, or medical condition that might
place the subject at risk or influence the study’s results.
During the run-in period, subjects were to discon-
tinue use of all asthma therapies other than their usual
ICS and rescue medication (eg, leukotriene modifiers).
Those who were receiving combination therapy with
an ICS and a long-acting β2-adrenergic agonist (LABA)
were switched to a comparable dose of an ICS alone
(eg, fluticasone propionate 500 µg/salmeterol 50 µg
1 inhalation BID to fluticasone 220 µg 2 inhalations
BID) during the run-in period. No effort was made to
titrate to the maximal effective ICS dose during the
run-in period. After the run-in period, subjects who
met the initial screening criteria were eligible for ran-
domization if they met the following requirements: an
FEV1 between 45% and 85% of predicted normal,
postbronchodilator FEV1 reversibility of ≥12% (if not
met at the screening visit), and documented daytime
or nighttime asthma symptom scores >0 on at least
June 2007
K. Murphy et al.
3 of 7 consecutive days before randomization. Subjects
with unstable asthma at the randomization visit were
discontinued from the study. Unstable asthma was de-
fined as a decrease in FEV1 of ≥20% from the screen-
ing visit or to <45% of predicted normal; the use of
≥6 doses of albuterol per day on ≥3 days within 7 con-
secutive days; ≥3 consecutive night awakenings due
to asthma that required the use of rescue medication
within a period of 7 consecutive days; or any clinical
exacerbation of asthma requiring emergency treat-
ment, hospitalization, or use of an asthma medication
not allowed by study protocol.
The study was approved by the investigational re-
view board at each participating site and was con-
ducted in accordance with guidelines for the ethical
treatment of human subjects that have their origin in
the Declaration of Helsinki and are consistent with
the International Conference on Harmonisation/Good
Clinical Practice and applicable local regulatory re-
quirements. Before the study was conducted, written
informed consent was provided by the parents or
guardians of subjects aged 12 to <18 years and by all
subjects aged ≥18 years; subjects aged <18 years were
required to provide signed informed assent.
Treatment
Eligible subjects were randomly assigned by site to
1 of 4 BIS treatment groups or to the budesonide DPI
reference arm using a computer-generated allocation
schedule produced in advance with the use of bal-
anced blocks of 5 (Figure 1). The study was consid-
ered partially blinded because investigators were
blinded to the treatment (ie, study medication visit
kits were similar in appearance), but subjects may
have been aware of differences in doses (ie, subjects in
the 0.5-mg and 1.0-mg QD groups received 2 Respules
(small vial) BID, whereas subjects in the 1.0-mg and
2.0-mg BID groups received 4 Respules BID). The BIS
0.5-mg QD dosage was selected as a surrogate for a
placebo because of the ethical issues and anticipated
high placebo withdrawal rate in subjects with moder-
ate to severe persistent asthma. This 0.5-mg dose is
the lowest BIS dosage available and was considered to
be subtherapeutic for this population based on the
2002 NAEPP guidelines, which recommend the use of
medium to high doses of ICS alone in adults with
moderate to severe asthma and consider BIS 0.5 mg
QD to be a low dosage in children (data are unavail-
able in adults).1 Thus, we expected that subjects ran-
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Clinical Therapeutics

BIS 0.5 mg QD
1 BIS 0.5-mg/mL Respule and 1 placebo Respule AM
2 Placebo Respules PM

BIS 1.0 mg QD
2 BIS 0.5-mg/mL Respules AM
2 Placebo Respules PM

2- to 3-Week Run-In BIS 1.0 mg BID

2 BIS 0.5-mg/mL Respules and 2 placebo Respules AM
2 BIS 0.5-mg/mL Respules and 2 placebo Respules PM

BIS 2.0 mg BID

4 BIS 0.5-mg/mL Respules AM

4 BIS 0.5-mg/mL Respules PM

BUD DPI 400 µg BID (Reference)

BUD DPI 200 µg/inhalation × 2 inhalations AM

BUD DPI 200 µg/inhalation × 2 inhalations PM

12-Week Treatment Period

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Adverse Event

Day –14/–21 Day 1 Week 4 Week 8 Week 12 Follow-up
(Screening) (Randomization)

Figure 1. Study design. BIS = budesonide inhalation suspension; BUD DPI = budesonide dry powder inhaler.

domized to this treatment arm would experience worse
outcomes. Both BIS and placebo Respules were ad-
ministered using a PARI LC-Jet Plus nebulizer con-
nected to a PARI Master compressor (PARI Respiratory
Equipment Inc., Midlothian, Virginia). Nebulization
of each Respule takes 5 to 10 minutes. Doses were
administered in pairs each morning and evening.
Budesonide DPI was included as an unblinded active
reference to provide a comparison to the responses to
the BIS doses in this population. Study medication
compliance was captured in the electronic diary,
where subjects were asked twice daily if they had
taken their study medication. Medication compliance
was calculated by comparing the number of “yes” re-
sponses to the total number of actual responses (“yes”
and “no”).
Albuterol inhalers were provided for rescue medi-
cation as needed for subjects in all 5 groups; nebulized
albuterol also could be used if required. Prohibited
medications included the following: systemic cortico-

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steroids or high-potency topical corticosteroids (topi-
cal hydrocortisone ≤1% permitted) from 30 days
before randomization through week 12; cetirizine or
hydroxyzine from 3 days before randomization through
week 12; omalizumab within 6 months before randomi-
zation; and leukotriene modifiers, inhaled LABAs,
combination ICS/LABA, theophylline, anticholiner-
gics, cromolyn, nedocromil, and β-blocker therapies
(including ophthalmic preparations) from screening
through week 12. Subjects undergoing the pharmaco-
kinetic evaluation were not allowed to use any medi-
cations known to affect the activity of the cytochrome
P450 3A4 enzyme (inhibitors or inducers) or other
budesonide preparations (eg, budesonide intranasal
spray).
Efficacy Variables
The primary variable was the mean change in pre-
dose FEV1 from baseline to the end of treatment. The
primary treatment comparison was between BIS
0.5 mg QD and BIS 2.0 mg BID. Secondary spiromet-
ric outcome variables were changes in FEV1 and
forced vital capacity (FVC) from baseline to weeks 4,
8, and 12 and to the average over the treatment peri-
od. All pulmonary function tests were conducted in
the clinic using a calibrated spirometer that met ATS
standards,18 and site staff were instructed to use the
same spirometer at each visit. Measurements were
performed in triplicate before the morning dose of
study medication and ~6 hours after the last dose of
short-acting β2-adrenergic agonist. The largest of the
triplicate FEV1 measurements was recorded.
Secondary outcome variables also included the mean
changes from baseline to the end of treatment (last
2 weeks of the treatment period) in daytime and night-
time asthma symptom scores, study rescue medication
use, nighttime awakenings due to asthma requiring
rescue medication use, and morning and evening PEF.
Additional variables derived from these diary record-
ings were the percentages of symptom-free days, nights,
and 24-hour periods; awakening-free nights; rescue
medication–free days, nights, and 24-hour periods;
and asthma-control days (defined as no asthma symp-
toms and no rescue medication use).
The incidence of predefined asthma events for
which subjects were withdrawn from the trial for
worsening asthma and the time to first predefined
asthma event during the treatment period were addi-
tional secondary variables. A predefined asthma event
June 2007
K. Murphy et al.
was defined as any of the following: a decrease in
morning predose FEV1 of ≥20% from randomization
or to <35% of the predicted normal value; use of
≥6 doses of albuterol per day on ≥3 days within 7 con-
secutive days; a decrease in morning PEF of ≥20%
from baseline on ≥3 days within 7 consecutive days;
≥3 consecutive nighttime awakenings due to asthma
that required the use of rescue medication within
7 consecutive days; and a clinical exacerbation of
asthma requiring emergency treatment, hospitaliza-
tion, or use of an asthma medication not allowed by
study protocol.
Safety Variables
Adverse events (AEs) were recorded by subjects (or
parents/guardians) in notebooks and reviewed at each
study visit. The final AE assessment was completed at
the end of the posttreatment follow-up period. Serious
AEs were those that resulted in death, were immedi-
ately life-threatening, required or prolonged hospitali-
zation, resulted in significant disability, or were con-
genital abnormalities.
Pharmacokinetic Assessments
An additional secondary objective of the study was
to assess the steady-state pharmacokinetics of budeso-
nide in all treatment arms. The analysis of budesonide
in plasma was conducted by TNO Nutrition and
Food Research (Zeist, The Netherlands). The assay of
(22RS)-budesonide uses solid-phase extraction and
liquid chromatography–atmospheric pressure chemi-
cal ionization–tandem mass spectrometry. At the
week-4 visit, subjects who agreed to participate in the
analysis provided blood samples that were used to de-
termine budesonide AUC, AUC0–t, t1/2, Cmax, Tmax,
and mean residence time. Blood samples for this
analysis were obtained within 30 minutes before study
drug inhalation and at 10, 30, 45, 60, 120, 240, 360,
540, and 720 minutes after the start of study drug
inhalation. Blood samples (7 mL) were drawn into
sodium-heparin–treated Vacutainer tubes (Becton,
Dickinson and Company, Franklin Lakes, New Jersey)
from an indwelling catheter inserted into an arm vein
or taken by venipuncture. For all catheter-drawn sam-
ples, the first milliliter was discarded. Specimens were
centrifuged for 10 minutes at room temperature, and
plasma was transferred into a 7-mL polypropylene
tube by pipette and stored frozen at –20°C until
analysis.
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Clinical Therapeutics
Statistical Analysis
A sample size of 150 subjects per treatment group
at 90% power was chosen to compare the BIS 0.5-mg
QD group with the BIS 2.0-mg BID group to detect a
0.2-L improvement in change from baseline FEV1, as-
suming an SD of 0.5 L for the change from baseline in
FEV1 and allowing for a 10% dropout rate and a sig-
nificance level of 0.05.
Efficacy analyses included data from all random-
ized subjects who received ≥1 dose of study medica-
tion and contributed sufficient data for the calculation
of ≥1 efficacy end point (modified intent-to-treat ap-
proach). For the primary variable, differences in the
change from baseline to end of treatment in FEV1
were analyzed using analysis of covariance (ANCOVA),
with treatment and center as study factors and base-
line FEV1 as a covariate, using the last-observation-
carried-forward (LOCF) approach but not carrying
forward baseline values.19 For all other secondary
variables, changes from baseline to each visit (LOCF)
(or to the average value over the last 2 weeks of treat-
ment for diary variables) and from baseline to the
treatment-period average across visits were compared
among groups using an ANCOVA model, with change
from baseline as the dependent variable, treatment
and center as main effects, and the baseline value as
the covariate.19
All hypothesis testing was conducted as 2-tailed
tests, with prespecified P values ≤0.05 considered sta-
tistically significant. Inferential statistical comparisons
were performed between the BIS 0.5-mg QD and BIS
2.0-mg BID groups. For comparisons between the BIS
groups and the reference budesonide DPI group, no
inferential statistical testing was conducted. The only
prespecified comparison for inferential purposes was
between the BIS 0.5-mg QD and BIS 2.0-mg BID
groups. For treatment comparisons involving the
budesonide DPI group, the aim of the study was to es-
timate relative treatment effects without accounting for
multiplicity. Hence, uncorrected 2-sided 95% CIs were
provided to describe these between-group differences.
The proportion of subjects meeting predefined
asthma-event criteria was compared between treat-
ments using the Fisher exact test, and the time from
randomization to the first predefined asthma event
was described using a Kaplan-Meier plot and ana-
lyzed using a log-rank test for treatment pairs.
Pharmacokinetic parameters were compared be-
tween groups using a multiplicative analysis of vari-
1018
ance model with single factor treatment, and 90%
2-sided CIs were provided for the differences between
the 2 BIS BID groups, the 2 BIS QD groups, and the
BIS 1.0-mg BID and budesonide DPI groups. Budeso-
nide AUC was calculated after administration of a
single dose for specific dose intervals, that is, 12 hours
for BID treatments and 24 hours for QD treatments,
using the trapezoidal method.
RESULTS
Subjects
A total of 760 subjects from 69 centers were ran-
domly assigned to treatment between May 2003 and
September 2004. Data from 1 subject who knowingly
and willingly enrolled at 2 separate study sites and
completed the study were omitted; thus the random-
ized population consisted of 758 subjects. Of the ran-
domized subjects, 70% (529/758) completed the study.
The BIS 2.0-mg BID group demonstrated the highest
incidence of early study discontinuation (39.5%
[58/147]), driven by the highest number of subjects
unwilling to continue (Figure 2).
Demographics and baseline asthma characteristics
of the randomized subjects were generally comparable
among groups (Table I). Mean baseline daytime and
nighttime symptom scores were low in all treatment
groups.
Treatment Compliance
Most (91.8% [696/758]) randomized subjects re-
ported taking their study medication on ≥80% of the
days during the randomized treatment period. The pro-
portion of subjects who reported using their study
medication on <80% of the days during the random-
ized treatment period was highest in the BIS 2.0-mg
BID group (Table II). The mean duration of treatment
was lower in the BIS 2.0-mg BID group (64.5 days)
than in the other BIS groups (range, 68.1–71.5 days)
and the budesonide DPI reference arm (75.9 days).
Thirty-two subjects (4.2%) received a disallowed
asthma medication after randomization that led to
study discontinuation and censoring of the data. The
most commonly used disallowed medications across all
groups were corticosteroids (3.2% [24/758] of subjects).
Efficacy
Spirometry Variables
The difference in adjusted mean change in predose
FEV1 from baseline to the end of treatment (primary
Volume 29 Number 6

June 2007
BIS 0.5 mg QD
(n = 149)
Discontinued Study (n = 39)
Met study-specific d/c
criteria (n = 25)
Not willing to continue
(n = 8)
Eligibility criteria not
fulfilled (n = 1)
Adverse event (n = 3)
Lost to follow-up (n = 1)
Other (n = 1)
Completed Study
(n = 110)
Figure 2. Disposition of subjects. d/c = discontinuation; BIS = budesonide inhalation suspension; BUD DPI = budesonide dry powder inhaler.
*The number of subjects randomized excludes 1 subject who was enrolled twice and counted as 2 subjects.
1019
Screened (N = 1361)
Randomized (n = 758)*
BIS 1.0 mg QD
(n = 147)
Discontinued Study (n = 47)
Met study-specific d/c
criteria (n = 27)
Not willing to continue
(n = 7)
Eligibility criteria not
fulfilled (n = 2)
Adverse event (n = 6)
Lost to follow-up (n = 4)
Other (n = 1)
Completed Study
(n = 100)
BIS 1.0 mg BID
(n = 160)
Discontinued Study (n = 52)
Met study-specific d/c
criteria (n = 24)
Not willing to continue
(n = 15)
Eligibility criteria not
fulfilled (n = 3)
Adverse event (n = 7)
Lost to follow-up (n = 2)
Other (n = 1)
Completed Study
(n = 108)
1013_ET_murphy
6/29/07
Failed Screening (n = 601)
Eligibility criteria not fulfilled (n = 441)
Met study-specified d/c criteria (n = 68)
Subject not willing to continue study (n = 67)
9:49 AM
Lost to follow-up (n = 15)
Other (n = 8)
Adverse event (n = 2)
Page 1019
BIS 2.0 mg BID BUD DPI 400 µg BID
(n = 147) (n = 155) (reference)
Discontinued Study (n = 58) Discontinued Study (n = 33)
Met study-specific d/c Met study-specific d/c
criteria (n = 24) criteria (n = 23)
Not willing to continue Not willing to continue
(n = 23) (n = 3)
Eligibility criteria not Eligibility criteria not
fulfilled (n = 2) fulfilled (n = 3)
Adverse event (n = 6) Adverse event (n = 0)
Lost to follow-up (n = 3) Lost to follow-up (n = 1)
Other (n = 0) Other (n = 3)
Completed Study Completed Study
(n = 89) (n = 122)
K. Murphy et al.
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Clinical Therapeutics

Table I. Baseline demographic and clinical characteristics of the study population.

BIS BUD DPI

400 µg BID
0.5 mg QD 1.0 mg QD 1.0 mg BID 2.0 mg BID (n = 155)
Characteristic (n = 149) (n = 147) (n = 160) (n = 147) (Reference)

Age, y
Mean (SD) 42.2 (13.2) 38.7 (14.8) 41.1 (15.1) 41.3 (15.7) 39.7 (14.3)
Range 12–77 12–67 12–77 12–74 12–73
Age strata, no. (%)*
12–<17 y 4 (2.7) 15 (10.2) 11 (6.9) 14 (9.5) 13 (8.4)
17–<65 y 140 (94.0) 128 (87.1) 140 (87.5) 122 (83.0) 137 (88.4)
≥65 y 5 (3.4) 4 (2.7) 9 (5.6) 11 (7.5) 5 (3.2)

Sex, no. (%)

Female 87 (58.4) 97 (66.0) 100 (62.5) 92 (62.6) 94 (60.6)
Male 62 (41.6) 50 (34.0) 60 (37.5) 55 (37.4) 61 (39.4)

Race, no. (%)*

White 123 (82.6) 115 (78.2) 131 (81.9) 118 (80.3) 129 (83.2)
Black 23 (15.4) 26 (17.7) 25 (15.6) 26 (17.7) 25 (16.1)
Asian 2 (1.3) 2 (1.4) 3 (1.9) 2 (1.4) 0
Other 1 (0.7) 4 (2.7) 1 (0.6) 1 (0.7) 1 (0.6)

Weight, mean (SD), kg† 87.8 (21.2) 83.2 (23.5)‡ 81.0 (19.4)§ 84.7 (23.2) 82.9 (21.7)

Duration of asthma,
mean (SD), y 21.3 (14.0) 21.4 (14.7) 21.1 (14.2) 23.2 (15.6) 19.9 (13.3)

Total ICS dose at visit 1,

mean (SD), µg/d 624.1 (239.1) 615.3 (236.4) 594.4 (258.1) 643.8 (258.8) 608.1 (222.1)

LABA use at visit 1, no. (%) 64 (43.0) 71 (48.3) 67 (41.9) 76 (51.7) 78 (50.3)

FEV1
No. of subjects 148 146 159 147 154
% Predicted, mean (range) 70.0 (30–101) 70.4 (37–101) 71.2 (44–109) 69.6 (35–97) 70.3 (34–91)

Daytime symptom score㛳

No. of subjects 149 147 160 146 154
Mean (SD) 1.11 (0.46) 1.03 (0.41) 1.06 (0.42) 1.02 (0.46) 1.07 (0.46)

Nighttime symptom score㛳

No. of subjects 149 147 160 147 154
Mean (SD) 0.92 (0.44) 0.85 (0.43) 0.88 (0.47) 0.82 (0.49) 0.89 (0.48)

BIS = budesonide inhalation suspension; BUD DPI = budesonide dry powder inhaler; ICS = inhaled corticosteroid; LABA = long-
acting β2-adrenergic agonist; FEV1 = forced expiratory volume in 1 second.
*Percentages may not total 100 due to rounding.
† Weight at screening.
‡ n = 146.
§ n = 162.
㛳 Scale: 0 = none to 3 = severe.

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Table II. Treatment compliance in adolescents and adults with moderate to severe persistent asthma receiving
budesonide inhalation suspension (BIS) or budesonide dry powder inhaler (BUD DPI).

BIS BUD DPI

400 µg BID
0.5 mg QD 1.0 mg QD 1.0 mg BID 2.0 mg BID (n = 155)
Compliance (n = 148) (n = 145) (n = 158) (n = 146) (Reference)
Mean (SD) 94.8 (7.9) 93.7 (11.8) 93.4 (12.4) 90.4 (16.4) 95.6 (13.0)
<80%, no. (%) 6 (4.1) 11 (7.6) 12 (7.6) 21 (14.4) 6 (3.9)
≥80%, no. (%) 142 (95.9) 134 (92.4) 146 (92.4) 125 (85.6) 149 (96.1)

variable) between the BIS 0.5-mg QD group and the
BIS 2.0-mg BID group (primary comparison) was not
statistically significant (Table III). Further compari-
sons of the mean change in FEV1 from baseline to the
end of treatment between the BIS 1.0-mg QD and BIS
1.0-mg BID groups with the BIS 0.5-mg QD group
also were not statistically significant. Mean improve-
ments from baseline in predose FEV1 were similar be-
tween the budesonide DPI 400-µg BID reference arm
(0.12 L) and the BIS 1.0-mg BID group (0.08 L) as
compared with the other BIS dosage groups (range,
0.01–0.02 L).
No significant differences in the adjusted mean
changes in FEV1 or FVC from baseline to weeks 4,
8, and 12 and averaged across the treatment period
(secondary variables) were observed between the BIS
0.5-mg QD group and the other BIS dosage groups.
However, improvements in FEV1 at each time point
were higher in the budesonide DPI reference arm
(range, 0.11–0.12 L) and the BIS 1.0-mg BID group

Table III. Changes from baseline to end of treatment (last observation carried forward) in predose forced expira-
tory volume in 1 second (FEV1) in adolescents and adults with moderate to severe persistent asthma re-
ceiving budesonide inhalation suspension (BIS) or budesonide dry powder inhaler (BUD DPI). Values
are mean (SE) liters unless otherwise indicated.

BIS BUD DPI

400 µg BID
0.5 mg QD 1.0 mg QD 1.0 mg BID 2.0 mg BID (n = 151)
Parameter (n = 140) (n = 135) (n = 145) (n = 129) (Reference)

Baseline FEV1 2.37 (0.05) 2.30 (0.05) 2.32 (0.05) 2.30 (0.06) 2.35 (0.05)
Adjusted change from baseline 0.02 (0.03) 0.01 (0.03) 0.08 (0.03) 0.01 (0.03) 0.12 (0.03)
Adjusted change from baseline
vs BIS 0.5 mg QD
Difference in adjusted means NA –0.01 (0.04) 0.06 (0.04) –0.01 (0.04) NA
95% CI NA –0.09 to 0.08 –0.02 to 0.14 –0.09 to 0.07 NA
P value* NA 0.899 0.122 0.834 NA
Adjusted change from baseline
vs reference†
Difference in adjusted means 0.11 (0.04) –0.11 (0.04) –0.04 (0.04) –0.11 (0.04) NA
95% CI of the difference 0.03 to 0.18 –0.19 to –0.03 –0.12 to 0.03 –0.19 to –0.03 NA

*Analysis of covariance.
† No inferential statistical comparisons were planned between the BIS groups and the reference group.

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Clinical Therapeutics
(range, 0.07–0.09 L) than in the other BIS dosage
groups (range, 0.01–0.05 L).
Asthma Events Based on Predefined Criteria
The percentages of subjects experiencing a prede-
fined asthma event (see Methods) during the treat-
ment period were similar among all BIS groups (0.5 mg
QD, 18.8% [28/149]; 1.0 mg QD, 21.8% [32/147];
1.0 mg BID, 17.5% [28/160]; and 2.0 mg BID, 19.0%
[28/147]) and the budesonide DPI reference arm
(17.4% [27/155]). A decrease in morning PEF of >20%
from baseline was the most common predefined asth-
ma event, occurring in 7.8% (59/758) of subjects. No
statistically significant differences were found in the
time to first predefined event among any of the BIS
dosage groups or between any BIS group and the
budesonide DPI reference arm.
Diary Variables
All treatments resulted in small improvements from
baseline to end point (average over the last 2 weeks of
treatment) in all diary variables and diary-derived
variables (Table IV), with the exception of awakening-
free nights (≥95% of subjects in all treatment groups
reported awakening-free nights at baseline). None of
the treatment-group differences between the BIS 0.5-mg
QD group and the BIS 2.0-mg BID group were statis-
tically significant at the end of treatment. The differ-
ences in the changes of these diary values from baseline
to end of treatment also were not significant between
the BIS 1.0-mg QD group and the BIS 1.0-mg BID
group compared with the BIS 0.5-mg QD group.
Pharmacokinetics
The demographic characteristics of the 120 sub-
jects analyzed for pharmacokinetics were comparable
to those for all randomized subjects. Pharmacokinetic
parameters for the BIS dosage groups and the budeso-
nide DPI reference arm are described in Table V.
Increases in mean plasma budesonide concentra-
tions and AUC were dose dependent (increased with
increasing dosages) but were slightly less than dose
proportional (Figure 3). Thus, the ratio of the dose-
corrected mean values for AUC and Cmax indicated
that doubling of the dose in the BIS dosage groups
resulted in a <2-fold increase in systemic exposure to
budesonide. Pairwise comparison between BIS 1.0 mg
and 0.5 mg QD indicated that the ratio of the dose-
corrected mean values for AUC and Cmax were 83.6%
1022
(90% CI, 65.5%–106.7%) and 80.6% (90% CI,
59.5%–109.2%), respectively. For the comparison be-
tween BIS 2.0 mg and 1.0 mg BID, the AUC and Cmax
ratios of the mean values were 85.4% (90% CI,
64.5%–113.2%) and 88.1% (90% CI, 62.1%–
125.0%), respectively. Of all the BIS dosage groups,
the pharmacokinetic parameters for BIS 1.0 mg BID
were most similar to those for budesonide DPI 400 µg
BID. The AUC of BIS 1.0 mg BID was ~12% greater
and the Cmax was ~15% greater than those of budeso-
nide DPI 400 µg BID.
Mean Tmax was comparable among all BIS dosage
groups and greater than in the budesonide DPI refer-
ence arm. Mean t1/2 was comparable across all groups.
Safety
The percentages of subjects with ≥1 AE and the
severity of AEs were similar among all groups, and the
majority of AEs were mild to moderate in intensity
(91.8% [723/788] total events). The most common AE
was upper respiratory tract infection (6.9% [52/758])
(Table VI). Six subjects (2 in the BIS 1.0-mg BID
group and 1 in every other group) experienced a total
of 8 serious AEs; 2 of these serious AEs were judged
by the investigator to be related to study drug (1 re-
port of asthma in each of the BIS 1.0-mg QD and
1.0-mg BID groups). The incidence of discontinua-
tions due to AEs during the treatment period was gen-
erally comparable among the BIS groups (0.5 mg QD,
2.0% [3/149]; 1.0 mg QD, 3.4% [5/147]; 1.0 mg BID,
4.4% [7/160]; and 2.0 mg BID, 3.4% [5/147]). Such
discontinuations generally occurred within 28 days of
treatment initiation. One subject in the BIS 1.0-mg
QD group discontinued the study because of an AE
during the posttreatment period, and 1 subject in the
BIS 2.0-mg QD group discontinued because of an AE
that began during the run-in period.
DISCUSSION
On average, subjects in this study who were previous-
ly treated with moderate doses of ICSs delivered with
a pMDI or DPI and who received any of the nebulized
BIS doses evaluated showed little change from base-
line in variables that reflect asthma control, including
asthma symptoms, FEV1, PEF, and rescue medication
use. In addition, the incidence of asthma events based
on predefined criteria was low in all treatment arms,
further suggesting that subjects’ asthma remained well
controlled. These results suggest that the transition
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K. Murphy et al.

Table IV. Adjusted mean changes from baseline to end of treatment (EOT) (last 2 weeks of treatment) in diary-
derived variables in adolescents and adults with moderate to severe persistent asthma receiving budeso-
nide inhalation suspension (BIS) or budesonide dry powder inhaler (BUD DPI). Values are mean (SE)
unless otherwise indicated.

BIS BUD DPI

400 µg BID
0.5 mg QD 1.0 mg QD 1.0 mg BID 2.0 mg BID (n = 155)
Diary-Derived Variable (n = 149) (n = 147) (n = 160) (n = 147) (Reference)

Symptom-free days, %
No. of subjects 145 138 156 141 148
Baseline 12.3 (2.0) 14.5 (2.2) 13.8 (1.9) 17.6 (2.2) 14.1 (2.1)
Adjusted mean change at EOT 5.8 (2.5)* 3.6 (2.5) 6.6 (2.4) 10.2 (2.5) 4.6 (2.4)

Symptom-free nights, %
No. of subjects 145 140 156 142 148
Baseline 20.2 (2.7) 25.0 (3.0) 25.7 (2.8) 30.8 (3.1) 24.6 (2.8)
Adjusted mean change at EOT 3.5 (2.5)* –0.3 (2.5) 1.7 (2.4) 5.6 (2.5) 1.1 (2.5)

Symptom-free 24-h periods, %

No. of subjects 143 132 156 140 141
Baseline 8.6 (1.6) 9.1 (1.7) 9.6 (1.6) 12.6 (1.8) 9.9 (1.8)
Adjusted mean change at EOT 7.5 (2.4) 4.6 (2.5) 7.7 (2.3) 11.2 (2.4) 4.8 (2.4)

Rescue medication–free 24-h periods, %

No. of subjects 142 140 154 141 148
Baseline 47.6 (3.2) 45.6 (3.4) 46.4 (3.2) 44.4 (3.3) 43.1 (3.1)
Adjusted mean change at EOT 8.7 (2.6) 9.2 (2.7) 14.9 (2.5) 14.9 (2.7) 10.3 (2.6)

Awakening-free nights, %
No. of subjects 144 140 156 141 148
Baseline 96.5 (0.7) 96.6 (0.8) 95.1 (1.0) 96.9 (0.7) 95.9 (0.9)
Adjusted mean change at EOT –0.2 (0.7)* 0.6 (0.8) 1.2 (0.7) 1.1 (0.8) –0.3 (0.7)

Asthma control days, %

No. of subjects 143 132 156 140 141
Baseline 8.1 (1.5) 8.1 (1.7) 8.4 (1.5) 10.9 (1.7) 8.8 (1.6)
Adjusted mean change at EOT 7.8 (2.4)* 4.3 (2.5) 7.0 (2.2) 11.1 (2.4) 5.1 (2.4)

Morning PEF, L/min

No. of subjects 146 142 156 144 150
Baseline 356.8 (7.5) 360.7 (7.9) 351.8 (6.9) 346.2 (8.2) 360.8 (7.8)
Adjusted mean change at EOT 5.0 (3.1) 3.1 (3.2) 6.2 (3.0) 7.8 (3.2) 7.4 (3.1)

Evening PEF, L/min

No. of subjects 147 143 157 144 150
Baseline 366.5 (7.5) 369.6 (8.4) 362.5 (7.0) 360.2 (8.3) 371.0 (7.9)
Adjusted mean change at EOT 8.9 (3.3) 4.7 (3.3) 2.6 (3.1) 4.1 (3.3) 3.9 (3.2)

PEF = peak expiratory flow.

*No statistically significant differences between the BIS treatment groups were found.

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Clinical Therapeutics

Table V. Pharmacokinetic properties of budesonide inhalation suspension (BIS) and budesonide dry powder in-
haler (BUD DPI) in adolescents and adults with moderate to severe persistent asthma.

BIS BUD DPI

400 µg BID
0.5 mg QD 1.0 mg QD 1.0 mg BID 2.0 mg BID (n = 27)
Parameter (n = 28) (n = 25) (n = 22) (n = 18) (Reference)

AUC, mean (%CV), nmol 䡠 h/L* 2.64 (44.5) 4.42 (65.0) 5.98 (72.6) 10.22 (50.3) 5.36 (54.5)
Cmax, mean (%CV), nmol/L* 0.84 (60.5) 1.35 (100.8) 1.97 (70.9) 3.46 (51.7) 1.71 (80.3)
Tmax, mean (SD), min† 27.1 (16.0) 28.1 (12.9) 39.9 (13.9) 35.4 (26.0) 18.7 (13.3)
t1/2, mean (%CV), h* 3.91 (31.5) 3.96 (44.3) 3.89 (30.9) 3.50 (34.3) 4.00 (30.6)

*Geometric mean.
† Arithmetic mean.

BIS 0.5 mg QD (n = 28)

BIS 1.0 mg QD (n = 25)
4.0 BIS 1.0 mg BID (n = 22)
+ BIS 2.0 mg BID (n = 18)
BUD DPI 400 µg BID (reference) (n = 27)
+
3.2
+
Mean Plasma Budesonide
Concentration (nmol/L)

2.4 +

+
1.6

+
0.8
+ +
+ +
0
0 2 4 6 8 10 12
Time After Study Drug Administration (h)
Figure 3. Plasma budesonide concentrations at steady state. BIS = budesonide inhalation suspension; BUD DPI =
budesonide dry powder inhaler.

from ICS delivered with a pMDI or DPI to BIS was
successful. However, no difference in efficacy could be
detected between BIS 2.0 mg BID and BIS 0.5 mg QD
as assessed by predose FEV1, the primary variable.
Moreover, no differences in outcomes were found be-
tween the doses. Therefore, definitive conclusions re-
garding the efficacy of BIS in adolescents and adults
with moderate to severe persistent asthma cannot be
drawn from the results of this study.
A possible limitation of this study is that asthma
severity, which was based on prestudy ICS dose, may
have been overestimated, as evidenced by relatively
preserved lung function and mild symptoms among
subjects before randomization. Thus, it may have
been difficult to demonstrate differences between
groups in the primary comparison of FEV1 because of
the inclusion of subjects whose asthma would have
been controlled with lower ICS doses.20 Additionally,

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K. Murphy et al.

Table VI. Adverse events (AEs) reported by ≥3% of adolescents and adults with moderate to severe persistent
asthma in any budesonide inhalation suspension (BIS) and budesonide dry powder inhaler (BUD DPI)
treatment group (N = 758). Values are no. (%) of subjects.

BIS BUD DPI

400 µg BID
0.5 mg QD 1.0 mg QD 1.0 mg BID 2.0 mg BID (n = 155)
AE (n = 149) (n = 147) (n = 160) (n = 147) (Reference)
Any AE 67 (45.0) 79 (53.7) 88 (55.0) 66 (44.9) 79 (51.0)
Upper respiratory tract infection 9 (6.0) 12 (8.2) 14 (8.8) 10 (6.8) 7 (4.5)
Headache 8 (5.4) 9 (6.1) 12 (7.5) 3 (2.0) 14 (9.0)
Sinusitis 7 (4.7) 3 (2.0) 0 3 (2.0) 10 (6.5)
Diarrhea 5 (3.4) 2 (1.4) 3 (1.9) 1 (0.7) 2 (1.3)
Nasopharyngitis 4 (2.7) 6 (4.1) 12 (7.5) 7 (4.8) 12 (7.7)
Pharyngolaryngeal pain 4 (2.7) 6 (4.1) 9 (5.6) 4 (2.7) 4 (2.6)
Influenza 3 (2.0) 5 (3.4) 1 (0.6) 0 1 (0.6)
Oral candidiasis 2 (1.3) 1 (0.7) 3 (1.9) 6 (4.1) 3 (1.9)
Bronchitis 1 (0.7) 5 (3.4) 2 (1.3) 1 (0.7) 2 (1.3)
Nasal congestion 1 (0.7) 5 (3.4) 2 (1.3) 1 (0.7) 6 (3.9)

dose comparisons in this study may have been limited
by differences in compliance between BIS 2.0 mg BID
and BIS 0.5 mg QD. The substantially longer nebu-
lization time (10–20 minutes vs 20–30 minutes) may
have been a factor in the numerically lower compli-
ance and higher withdrawal rates in the 2.0-mg BID
group. Subjects treated with the 2.0-mg BID dose per-
formed less well than expected for FEV1 despite the
highest systemic exposure, whereas those treated with
BIS 0.5 mg QD, which is considered a low ICS dose
based on current asthma guidelines,1 performed better
than expected for a population with moderate to se-
vere persistent asthma. Because of these limitations,
further research is required to establish the efficacy
and safety of BIS in adult subjects with asthma who
require nebulized delivery of ICS. Finally, the findings
of this study cannot be extrapolated to other patient
populations because studies in children have clearly
demonstrated the efficacy of BIS dosages ranging from
0.25 mg QD to 1.0 mg BID, with the strongest evi-
dence for twice-daily dosing.7–10
Based on a review of the literature, this study is the
first to report pharmacodynamic and pharmacokinet-
ic similarity between nebulized BIS and budesonide
DPI. All BIS doses, including the QD doses, were simi-
lar to budesonide DPI 400 µg BID in maintaining asth-
ma symptoms, rescue medication use, and nighttime
awakenings at levels similar to those observed during
the run-in period on ICS inhaler therapy. All BIS doses
were comparable to budesonide DPI 400 µg BID in
controlling asthma during the 12-week treatment pe-
riod, as assessed by the frequency of asthma events
based on predefined criteria. Of all the BIS doses,
however, BIS 1.0 mg BID provided an improvement
in predose FEV1 and a systemic budesonide exposure
that were the same order of magnitude to those ob-
served with budesonide DPI 400 µg BID. Finally, all
BIS doses demonstrated an excellent safety profile
comparable to that observed in children treated with
nebulized budesonide and in adults treated with
budesonide DPI.9,21
CONCLUSIONS
The present study did not find a difference in efficacy
between BIS 0.5 mg QD and BIS 2.0 mg BID among
adolescents and adults with persistent moderate to se-
vere asthma. Asthma control was maintained in all
BIS treatment groups.
ACKNOWLEDGMENTS
This research was financially supported by AstraZeneca
LP, Wilmington, Delaware.
The authors acknowledge Marissa Buttaro, MPH,
and Amy Zannikos, PharmD, Scientific Connexions,

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Clinical Therapeutics
Newtown, Pennsylvania, for providing medical writing
support. Editorial support was funded by AstraZeneca
LP.
REFERENCES
1. National Asthma Education and Prevention Program.
Expert panel report: Guidelines for the diagnosis and
management of asthma—update on selected topics–2002
[published correction appears in J Allergy Clin Immunol.
2003;111:466]. J Allergy Clin Immunol. 2002;110(Suppl 5):
S141–S219.
2. Cochrane MG, Bala MV, Downs KE, et al. Inhaled corti-
costeroids for asthma therapy: Patient compliance, de-
vices, and inhalation technique. Chest. 2000;117:542–
550.
3. Dolovich MB, Ahrens RC, Hess DR, et al, for the American
College of Chest Physicians and the American College of
Asthma, Allergy, and Immunology. Device selection and
outcomes of aerosol therapy: Evidence-based guidelines:
American College of Chest Physicians/American College
of Asthma, Allergy, and Immunology. Chest. 2005;127:
335–371.
4. Allen SC, Prior A. What determines whether an elderly
patient can use a metered dose inhaler correctly? Br J Dis
Chest. 1986;80:45–49.
5. Connolly MJ. Inhaler technique of elderly patients:
Comparison of metered-dose inhalers and large volume
spacer devices. Age Ageing. 1995;24:190–192.
6. Allen SC. Competence thresholds for the use of inhalers in
people with dementia. Age Ageing. 1997;26:83–86.
7. Baker JW, Mellon M, Wald J, et al. A multiple-dosing,
placebo-controlled study of budesonide inhalation sus-
pension given once or twice daily for treatment of persis-
tent asthma in young children and infants. Pediatrics. 1999;
103:414–421.
8. Kemp JP, Skoner DP, Szefler SJ, et al. Once-daily budeso-
nide inhalation suspension for the treatment of persis-
tent asthma in infants and young children. Ann Allergy
Asthma Immunol. 1999;83:231–239.
9. Pulmicort Respules (budesonide inhalation suspension)
[prescribing information]. Wilmington, Del: AstraZeneca
LP; January 2007.
Address correspondence to: Kevin Murphy, MD, Midwest Children’s Chest
Physicians, 16945 Frances Street, Omaha, NE 68114. E-mail: murphknsc@
aol.com
1026
10. Shapiro G, Mendelson L, Kraemer MJ, et al. Efficacy and
safety of budesonide inhalation suspension (Pulmicort
Respules) in young children with inhaled steroid-dependent,
persistent asthma. J Allergy Clin Immunol. 1998;102:
789–796.
11. Marcus P. The role of nebulized inhaled corticosteroid
therapy in adult patients with asthma and chronic ob-
structive pulmonary disease. Adv Ther. 2005;22:407–418.
12. Higenbottam TW, Clark RA, Luksza AR, et al. The role of
nebulised budesonide in permitting a reduction in the
dose of oral steroid in persistent severe asthma. Eur J Clin
Res. 1994;5:1–10.
13. Otulana BA, Varma N, Bullock A, Higenbottam T. High
dose nebulized steroid in the treatment of chronic steroid-
dependent asthma. Respir Med. 1992;86:105–108.
14. O’Connor BJ, Basran GS, O’Connell F, O’Shaughnessy
KM. Oral steroid sparing effect of nebulized budesonide
in chronic severe asthma. Am J Respir Crit Care Med. 1996;
153:A341. Abstract.
15. Connolly KC, Peake MD, Halpin DMG, et al. Challenging
current asthma treatment guidelines: Improved control of
asthma symptoms with nebulised budesonide in patients
with severe asthma receiving continuous oral steroids. Dis
Manag Health Outcomes. 2000;7:217–225.
16. Bisgaard H, Nikander K, Munch E. Comparative study of
budesonide as a nebulized suspension vs pressurized
metered-dose inhaler in adult asthmatics. Respir Med.
1998;92:44–49.
17. Gawchik SM. Successful treatment of previously uncon-
trolled adult asthma with budesonide inhalation suspen-
sion (Pulmicort Respules™). Ann Allergy Asthma Immunol.
2002;88:97. Abstract.
18. American Thoracic Society. Standardization of spirometry,
1994 update. Am J Respir Crit Care Med. 1995;152:1107–1136.
19. Fleiss JL. Design and Analysis of Clinical Experiments. New
York, NY: John Wiley & Sons, Inc; 1986.
20. Smith AD, Cowan JO, Brassett KP, et al. Use of exhaled ni-
tric oxide measurements to guide treatment in chronic
asthma. N Engl J Med. 2005;352:2163–2173.
21. Pulmicort Turbuhaler (budesonide inhalation powder)
[prescribing information]. Wilmington, Del: AstraZeneca
LP; December 2003.
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