Ann Allergy Asthma Immunol 118 (2017) 489e499

Contents lists available at ScienceDirect

Efficacy and safety of budesonide/formoterol pMDI vs budesonide

pMDI in asthmatic children (6e<12 years)
David S. Pearlman, MD *; Göran Eckerwall, MD, PhD y; Julie McLaren, MD z; Rosa Lamarca, PhD x;
Margareta Puu, PhD y; Ileen Gilbert, MD k; Carin Jorup, MD y; Kristina Sandin, DDS y; Miguel J. Lanz, MD {
* Colorado Allergy & Asthma Centers, P.C., Denver, Colorado
y
AstraZeneca R&D, Gothenburg, Sweden
z
AstraZeneca, Gaithersburg, Maryland
x
AstraZeneca, Barcelona, Spain
k
AstraZeneca, Wilmington, Delaware
{
Allergy, Asthma & Immunology, AAADRS Clinical Research Center, Coral Gables, Florida

A R T I C L E I N F O A B S T R A C T

Article history:
Received for publication October 21, 2016.
Received in revised form January 18, 2017.
Accepted for publication January 22, 2017.
Background: The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI)
have been demonstrated in patients with asthma at least 12 years old.
Objective: To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs
budesonide alone in children 6 to younger than 12 years with asthma.
Methods: This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3)
included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled
corticosteroid (ICS) or an ICS plus a long-acting b2-agonist. Children symptomatic during a 7e28-day run-in on
low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 mg twice daily (BID), were randomized to
receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 mg (160/9 mg) BID (n ¼ 92), budesonide/formoterol
pMDI 80/2.25 mg (160/4.5 mg) BID (n ¼ 95), or budesonide pMDI 80 mg (160 mg) BID (n ¼ 92) for 12 weeks.
Results: Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end
point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour
after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 mg vs budesonide
(P  .015 for all comparisons), but not for budesonide/formoterol 160/4.5 mg vs budesonide. Bronchodilator
effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined
asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar
across treatments. There were no notable safety differences among treatments.
Conclusion: Budesonide/formoterol pMDI 160/9 mg showed statistically significant and clinically meaningful
lung function improvements vs budesonide pMDI 160 mg, demonstrating appropriateness as a therapeutic
option for children 6 to younger than 12 years with asthma symptomatic on ICS alone.
Trial Registration: ClinicalTrials.gov Identifier: NCT02091986.
Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction addition of a long-acting b2-agonist (LABA) to a low-dose inhaled

It is estimated that approximately 3 million (10.6%) children in
the United States currently have asthma.1 Guidelines from the
National Asthma Education and Prevention Program identify the
Reprints: David S. Pearlman, MD, Colorado Allergy & Asthma Center, P.C., 125
Rampart Way, Suite 150, Denver, CO 80230; E-mail: ds.pearlman@colorado
allergy.com.
Disclosures: Dr Pearlman has received research funding and consultancy fees from
AstraZeneca, LP; Dr Lanz has received research funding from Stallergenes Greer,
Merck, and Genentech and consultancy fees from AstraZeneca, LP; and Drs
Eckerwall, McLaren, Lamarca, Puu, Gilbert, Jorup, and Sandin are employees of
AstraZeneca, LP, with stock ownership.
Funding Sources: This study was supported by AstraZeneca, LP.
corticosteroid (ICS) in a fixed-dose combination as a recom-
mended step 3 treatment option for patients 5 to 11 years old with
asthma to manage symptoms not adequately controlled by a
low-dose ICS alone.2
Previous studies have provided evidence that budesonide/
formoterol pressurized metered-dose inhaler (pMDI) has greater
efficacy and a similar safety profile compared with budesonide
alone in patients at least 12 years old with asthma3,4 and children
6 to younger than 12 years old with symptomatic asthma
previously treated with an ICS alone.5,6 Morice et al5 reported
a statistically significant improvement in morning peak expira-
tory flow (PEF; primary end point) budesonide/formoterol pMDI

http://dx.doi.org/10.1016/j.anai.2017.01.020
1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
490 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499
80/4.5 mg  2 inhalations (160/9 mg) twice daily (BID) versus
budesonide pMDI 200 mg BID over 12 weeks, with similar safety
profiles reported for the 2 treatments. In a 26-week safety study,
Berger et al6 found no differences in the number or severity of
adverse events (AEs) or clinically important safety variables
(eg, serum glucose and potassium, heart rate, and electrocardio-
graphic measurements) between budesonide/formoterol pMDI
320/9 mg BID versus budesonide 400 mg BID via dry powder
inhaler (DPI). Secondary efficacy end points in the study showed
greater benefit for pulmonary function and health-related qual-
ity-of-life (HRQoL) outcomes with the combination vs budesonide
alone.6
The Childhood Asthma Safety and Efficacy (CHASE) program
was developed in conjunction with the Food and Drug Adminis-
tration (FDA). The objective of the program was to study the efficacy
and safety of budesonide and formoterol as single agents and in
combination in children 6 to younger than 12 years with asthma. A
6-week budesonide dose-confirmatory study (CHASE 1;
NCT01136382) demonstrated statistically significant improvements
in lung function (ie, morning PEF [primary outcome], forced expi-
ratory volume in 1 second [FEV1], evening PEF, and forced expira-
tory flow between 25% and 75% of forced vital capacity
[FEF25%e75%]) and asthma symptom variables (ie, reliever medica-
tion use, nighttime awakenings, and awakenings with reliever use)
with budesonide pMDI 160 mg BID vs placebo.7 CHASE 2
(NCT01136655) was a formoterol dose-finding study, which
compared the bronchodilatory effect of 3 single doses of formoterol
pMDI (2.25, 4.5, and 9 mg), formoterol DPI (12 mg), and placebo in
children with asthma.8 All formoterol pMDI doses and the DPI
formulation showed significantly higher average 12-hour FEV1
(area under curve) vs placebo (primary outcome); the 2 higher
pMDI dosages were statistically superior to the lowest formoterol
pMDI dose and not significantly different from the 12-mg DPI dose.
In addition, formoterol 4.5 mg and 9 mg, but not 2.25 mg, resulted in
significant improvement in FEV1 at 12 hours after dosing vs
placebo. The incidence of AEs was low in each formoterol dose
group, and no serious AEs were reported.8
Based on the results of the budesonide dose-confirming CHASE
1 trial and the formoterol dose-finding CHASE 2 study and FDA
feedback at an end-of-phase 2 meeting, this study, CHASE 3, eval-
uated the efficacy and safety of 2 fixed-dose combinations of
budesonide/formoterol pMDI 160/9 mg or 160/4.5 mg BID compared
with budesonide pMDI 160 mg BID alone in children 6 to younger
than 12 years with persistent asthma symptoms when on low-dose
ICS.
Methods
Patient Population and Eligibility
This study included patients 6 to younger than 12 years with a
documented clinical diagnosis of asthma as defined by the Amer-
ican Thoracic Society9 for at least 6 months before the run-in visit
(visit 2). Patients were required to have used medium-dose ICS or,
alternatively, fixed-dose ICS plus LABA for at least 4 weeks before
enrollment (visit 1). Patients on fixed-dose ICS plus LABA were
switched to a comparable dose of ICS without LABA for at least 48
hours before the run-in visit.
During the run-in visit or before randomization (visit 3), FEV1
reversibility of at least 12% from pre-bronchodilator levels within
15 to 30 minutes after administration of a standard and equivalent
dose of 2 to 4 inhalations of albuterol (90 mg per inhalation, labeled
to reflect the dose delivered by the actuator mouthpiece; in the
United States) or salbutamol (100 mg per inhalation, labeled to
reflect the dose delivered from the canister valve; outside the
United States) with or without a spacer or either drug given by
nebulizer (2.5 mg) was required. At the run-in visit, patients were
required to have a morning pre-bronchodilator clinic FEV1 value of
60% to 100% of predicted normal (measured 6 hours after the
last dose of a short-acting b2-agonist [SABA] and 48 hours
after the last dose of a LABA). Eligible patients demonstrated the
ability to use a DPI for the run-in period and pMDI for the post-
randomization period.
Exclusion criteria for the study included hospitalization or
emergency treatment for asthma within 6 months before enroll-
ment, treatment, for any reason, with systemic corticosteroids
within 6 weeks before enrollment or during the run-in period, or
with a b-blocker (including eye drops), or omalizumab, or other
monoclonal or polyclonal antibody therapy within 6 months
before the run-in visit. The eSupplement (available online) pro-
vides additional exclusion criteria and adjunct medication
information.
This study was performed in accordance with ethical principles
based on the Declaration of Helsinki and its conduct was consistent
with International Conference on Harmonization and Good Clinical
Practice guidelines and all applicable regulatory requirements. The
final study protocol, protocol amendments, and informed consent
and assent forms were approved by institutional review boards in
each country or region or at each center in accordance with
national regulations. After an informed consent and assent process,
patients provided written informed consent or assent before
enrollment and any study-related activities.
Study Design
This was a phase 3, randomized, double-blinded, parallel-group,
multicenter study (registered at www.clinicaltrials.gov as
NCT02091986) performed from April 2014 through April 2016 at 88
sites in the United States, Mexico, Panama, and Slovakia.
The study consisted of an enrollment visit; a run-in visit
followed by a single-blinded 7- to 28-day run-in period on
low-dose ICS (budesonide DPI 90 mg  1 inhalation BID [80 mg
delivered dose]); and a randomization visit followed by a 12-week,
randomized, double-blinded treatment period, including clinic
visits at weeks 2, 4, 8, and 12. A follow-up telephone call approxi-
mately 2 weeks after the final study visit was conducted to record
information about ongoing AEs at the end of study treatment and to
document any new AEs and concomitant medications after the end
of study treatment.
Patients and parents or guardians were instructed on how to use
the DPI (at the run-in visit) and the pMDI (at the randomization
visit); inhaler technique was assessed, and further training was
given as needed. To be eligible for randomization, patients were
required, during the run-in, to have a total combined nighttime and
daytime asthma symptom score of at least 1 (0, no symptoms; 1,
mild symptoms; 2, moderate symptoms; 3, severe symptoms) or
use of rescue medication on at least 4 of 7 consecutive days
immediately preceding randomization. Patients also were required
to have a predose morning clinic FEV1 of at least 55% (6 hours
after the last dose of the SABA) at randomization and to not have an
absolute increase of at least 5% of the absolute value between the
run-in and randomization visits.
Eligible patients were stratified by age group (6e<9 or 9e<12
years) and randomly assigned within their stratum to receive 1 of
the following 3 treatments for 12 weeks: budesonide/formoterol
pMDI 80/4.5 mg  2 inhalations (160/9 mg) BID; budesonide/for-
moterol pMDI 80/2.25 mg  2 inhalations (160/4.5 mg) BID; or
budesonide pMDI, 80 mg  2 inhalations (160 mg) BID. Randomi-
zation was performed using an Interactive Voice Response System/
Interactive Web Response System to ensure an even distribution
between age groups.
To maintain blinding, no member of the study team at the study
sites or contract research organizations had access to the
 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499
Figure 1. Flowchart of patient disposition. aInformed consent was received. BID, twice daily.
randomization scheme during the study except those related to the
drug supply chain. The randomization scheme was not disclosed
until after the database lock.
Concomitant Medications
During the study, patients could use study-provided albuterol or
salbutamol as needed. Prophylactic use of SABA for exercise-
induced bronchoconstriction was permitted up to 2 times per
week, if part of a regular exercise regimen.
Efficacy and Safety Evaluations
The primary objective was to demonstrate the efficacy of each
budesonide/formoterol combination dose compared with bude-
sonide alone in children 6 to younger than 12 years with asthma;
the secondary efficacy objective was to compare the efficacy
between the 2 doses of budesonide/formoterol. To determine
the contribution of formoterol to the budesonide/formoterol
491
combination compared with budesonide alone, the primary effi-
cacy variable was the change from baseline predose clinic FEV1
(value at randomization, week 0) to the 1-hour postdose clinic
FEV1 at week 12.
Secondary efficacy variables included other clinic lung func-
tion parameters (predose and 15-minute postdose FEV1, predose
and 1-hour postdose forced vital capacity [FVC], predose and
1-hour postdose FEF25%e75%, and predose and 1-hour postdose
PEF); Pediatric Asthma Quality of Life Questionnaire with Stan-
dardized Activities (PAQLQ[S]) scores (23-item patient-reported
questionnaire in which each item is measured on a 7-point
scale [eg, 1, extremely bothered/all of the time; 7, not bothered/
none of the time]; overall score [mean of responses to each
question]; and each of 3 domain scores [activity limitations, 5
items; symptoms, 10 items; emotional function, 8 items] are
evaluated10); electronic diary (eDiary) variables; time to
discontinuation of study drug; and time to occurrence of first
protocol-defined asthma exacerbation.
492 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499

Table 1
Patient Demographics and Baseline Characteristics

Budesonide/formoterol Budesonide/formoterol Budesonide pMDI Total (N ¼ 279)

pMDI 160/9 mg BID (n ¼ 92) pMDI 160/4.5 mg BID (n ¼ 95) 160 mg BID (n ¼ 92)

Age (y)
Mean (SD) 9 (1.6) 9 (1.6) 9 (1.4) 9 (1.5)
Median 9 9 9 9
Range 6e11 6e11 6e11 6e11
Age group, n (%)
6e<9 y 30 (32.6) 36 (37.9) 32 (34.8) 98 (35.1)
9e<12 y 62 (67.4) 59 (62.1) 60 (65.2) 181 (64.9)
Sex, n (%)
Boys 50 (54.3) 61 (64.2) 55 (59.8) 166 (59.5)
Girls 42 (45.7) 34 (35.8) 37 (40.2) 113 (40.5)
Race, n (%)
White 61 (66.3) 60 (63.2) 53 (57.6) 174 (62.4)
Black or African American 24 (26.1) 26 (27.4) 26 (28.3) 76 (27.2)
Asian 0 0 2 (2.2) 2 (0.7)
Native Hawaiian or other Pacific Islander 1 (1.1) 0 0 1 (0.4)
American Indian or Alaska Native 2 (2.2) 3 (3.2) 3 (3.3) 8 (2.9)
Other 4 (4.3) 4 (4.2) 7 (7.6) 15 (5.4)
Unknown 0 2 (2.1) 1 (1.1) 3 (1.1)
Ethnicity, n (%)
Hispanic or Latino 38 (41.3) 36 (37.9) 32 (34.8) 106 (38.0)
Not Hispanic or Latino 54 (58.7) 59 (62.1) 60 (65.2) 173 (62.0)
Weight (kg), mean (SD) 38 (12.9) 38 (12.9) 40 (13.6) 39 (13.1)
Height (cm), mean (SD) 139 (11.1) 138 (10.9) 141 (10.5) 139 (10.8)
Asthma duration (y), mean (SD) 5.8 (3.0) 5.9 (3.2) 6.2 (3.1) 5.9 (3.1)
Baseline ICS dose level,a n (%)
Low 4 (4.3) 5 (5.3) 4 (4.3) 13 (4.7)
Medium 82 (89.1) 88 (92.6) 82 (89.1) 252 (90.3)
High 5 (5.4) 1 (1.1) 1 (1.1) 7 (2.5)
Not classified 1 (1.1) 1 (1.1) 5 (5.4) 7 (2.5)
Patients receiving ICS/LABA (previous medication), n (%) 27 (30.0) 25 (26.9) 19 (21.1) 71 (26.0)
Symptom-related variables at baseline, mean (SD)
Total asthma symptom scoreb,c 1.1 (0.51) 1.0 (0.68) 1.0 (0.58)
Nighttime awakenings due to asthma symptoms (%)d 18.9 (26.70) 21.0 (28.44) 16.5 (25.16)
Total daily reliever medication use (inhalations/d)c 1.2 (1.43) 1.8 (2.46) 1.2 (1.52)
Lung function variables at baseline
n 85 90 88 263
Predose FEV1 (L) at randomization, mean (SD) 1.58 (0.42) 1.57 (0.33) 1.62 (0.36) 1.59 (0.37)
n 85 90 88 263
Predose percentage predicted FEV1 at randomization, mean (SD) 74.5 (12.2) 75.5 (12.2) 73.8 (10.3) 74.6 (11.6)
n 89 93 90 272
Reversibility at run-in visit (%), mean (SD) 23.1 (18.5) 23.5 (14.9) 22.4 (13.1) 23.0 (15.6)
PAQLQ(S) score at baseline, mean (SD)e 5.36 (1.117) 5.61 (1.035) 5.53 (1.144)

Abbreviations: BID, twice daily; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting b2-agonist; PAQLQ(S), Pediatric Asthma Quality of
Life Questionnaire with Standardized Activities; pMDI, pressurized metered-dose inhaler.
a
Post hoc classification.
b
Asthma symptom scores range from 0 to 3 (0, no symptoms; 1, mild symptoms; 2, moderate symptoms; 3, severe symptoms).
c
Baseline defined as the mean from the morning record of 7 days before, up to, and including the day before randomization.
d
Baseline defined as the percentage of nighttime awakenings from asthma symptoms experienced of all available data recorded from the morning record of the last 6 days
before, up to, and including the morning record at randomization.
e
Overall score (mean of all domain scores); 23 items, each item reported on a 7-point scale (eg, 1, extremely bothered/all of the time; 7, not bothered/none of the time).
Baseline defined as the overall score taken at randomization.
One patient was randomized twice; data from the first occurrence in the study were used.

An eDiary was completed by the patient with the help of the
parent or guardian each morning and evening to capture morning
and evening PEF, FEV1, reliever medication use, asthma symptom
scores, and nighttime awakenings from asthma symptoms from the
start of the single-blinded run-in period until the patient’s last
study visit.
Asthma exacerbations were defined as emergency department
treatment, inpatient hospitalization, use of systemic steroids, or a
change in symptoms requiring an alteration in maintenance
asthma therapy.
The safety objective was to compare the safety of the 2 doses of
budesonide/formoterol with that of budesonide alone. Safety var-
iables included treatment-emergent AEs, serious AEs, and discon-
tinuations because of AEs. Vital signs were assessed at each visit;
physical examination, electrocardiogram, and laboratory analyses
(blood) were evaluated at the run-in visit and end-of-study
assessment visit or withdrawal from the study.
During the study, eDiary data were monitored for asthma
worsening; patients were contacted for clinical evaluation if any
of the following predefined criteria for asthma worsening were
met on 2 days within any consecutive 7-day period: decrease in
morning PEF of at least 15% from baseline (defined as the mean
of all values during the 7-day run-in period immediately
preceding the randomization visit); or nighttime awakening
from asthma requiring reliever medication use; or at least 6
inhalations of albuterol or salbutamol per day for relief of
asthma symptoms.
Statistical Analyses
A sample size of 93 patients in each treatment group was
estimated to provide 90% power to detect a difference of 0.12 L in
1-hour postdose FEV1 with a common SD of 0.25 L using a
2-sided test at the 5% significance level. The study was not
 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499 493

Mean change from baseline predose FEV1

0.35

to 1-hour postdose FEV1 at week 12 (L)

0.3

0.25

0.2

0.15

0.1

0.05

0
Budesonide/formoterol Budesonide/formoterol Budesonide
160/9 μg 160/4.5 μg 160 μg

Budesonide/formoterol Budesonide/formoterol Budesonide pMDI

pMDI 160/9 μg BID pMDI 160/4.5 μg BID 160 μg BID
(n = 90) (n = 93) (n = 90)
Change from baseline predose
FEV1 to 1-hour postdose FEV1
at week 12 (primary end point)
0.28 0.24 0.17
LS mean, L (95% CI) (0.22, 0.34) (0.18, 0.31) (0.10, 0.23)
Treatment difference between
groups
Vs budesonide 160 μg, 0.12 0.08
L (95% CI) (0.03, 0.20) (0.00, 0.16) --
P value 0.006 0.063 --
Vs budesonide/formoterol 0.04
160/4.5 μg, L (95% CI) (–0.05, 0.12) -- --

P value 0.373 -- --

Figure 2. Primary efficacy end point: mean change from baseline predose FEV1 (value at randomization, taken at week 0) to the 1-hour postdose FEV1 at week 12. Values are LS
means from mixed model for repeat measurements. Lines indicate 95% CI. CI, confidence interval; FEV1, forced expiratory volume in 1 second; LS, least squares; pMDI,
pressurized metered-dose inhaler.

powered to detect a difference between the 2 budesonide/
formoterol pMDI doses.
The efficacy analysis set included all randomized patients who
received at least 1 dose of study medication and contributed post-
baseline data for at least 1 efficacy end point. The safety analysis set
included all randomized patients who took at least 1 dose of study
medication and for whom data were collected after randomization.
Patients who discontinued treatment were encouraged to remain
in the study and attend scheduled visits. Primary analysis was
based on all available data, regardless of whether patients had
discontinued study treatment.
The primary efficacy end point was analyzed by a mixed model
for repeated measures. All data collected for patients who remained
in the study were included in the model with terms for treatment,
age group, visit, and geographic region as factors and baseline FEV1
as a covariate. Treatment-by-visit interaction also was included in
the model. Sensitivity analyses were performed on the primary
variable to further assess effects of treatment under several
scenarios (additional information in the eSupplement).
Secondary outcomes of predose and 1-hour postdose lung
function variables evaluating change from baseline to week 12 were
analyzed using a mixed model for repeated measures similar to that
for the primary efficacy end point. For 15-minute postdose clinic
FEV1, the change in FEV1 from predose at baseline to 15 minutes
postdose at week 12 was compared between treatment groups
using an analysis of covariance model with treatment, age group,
and geographical region as factors and with baseline FEV1 as a
covariate. Summary statistics were performed for eDiary variables.
The PAQLQ(S) total and domain scores were analyzed by analysis
of covariance for change from baseline to study period average.
A responder analysis also was performed using the Cochran-
Mantel-Haenszel test adjusting for region and age group, based
on the proportions of patients with clinically relevant improve-
ments (0.5 point) from baseline to the end of the study in
PAQLQ(S) total scores. Time to discontinuation of study drug and
time to occurrence of first protocol-defined asthma exacerbation
were analyzed using log-rank test and Cox regression analysis.
All statistical comparisons were 2-sided using a significance
level of 5%. A hierarchical testing procedure was implemented
to address multiplicity for the primary variable. Budesonide/
formoterol 160/9 mg was tested first; if significant at the 5%
significance level, then budesonide/formoterol 160/4.5 mg was
tested. Comparison between the 2 budesonide/formoterol
doses was not part of the testing procedure. No adjustments for
multiplicity were made for secondary variables.
Results
Patients
A total of 881 patients were screened and 279 patients were
randomized, of whom 253 (90.7%) completed the study (Fig 1). Of
the 26 patients (9.3%) who were withdrawn, the most frequent
cause of treatment discontinuation was the patient’s decision.
The demographic and key baseline characteristics are presented
in Table 1. The 3 treatment groups were generally well balanced and
the randomized patient population was in line with the intended
494 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499

Table 2
Change from Baselinea Predose at Randomization to Week 12 in Secondary Lung Function Variables, and Baseline to End-of-study Average for Asthma Symptomsb, Awak-
eningsc, and Reliever Medication Useb by Treatment Group

Budesonide/formoterol pMDI Budesonide/formoterol pMDI Budesonide pMDI

160/9 mg BID (n ¼ 90) 160/4.5 mg BID (n ¼ 93) 160 mg BID (n ¼ 90)

Change from baseline FEV1 to 15-min postdose FEV1 at week 12

LS (L), mean (95% CI) 0.25 (0.18e0.31) 0.19 (0.12e0.25) 0.15 (0.08e0.21)
Treatment difference between groups (L), mean (95% CI)
Vs budesonide 160 mg 0.10 (0.02e0.18) 0.04 (0.04 to 0.12) d
P value .015 .342 d
Vs budesonide/formoterol 160/4.5 mg 0.06 (0.02 to 0.15) d d
P value .138 d d
Change from baseline predose FEF25%e75%, to 1-hour postdose clinic FEF25%e75%
at week 12
LS (L/s), mean (95% CI) 0.55 (0.43e0.67) 0.47 (0.35e0.59) 0.23 (0.11e0.35)
Treatment difference between groups (L/s), mean (95% CI)
Vs budesonide 160 mg 0.32 (0.15e0.48) 0.23 (0.07e0.40) d
P value <.001 .005 d
Vs budesonide/formoterol 160/4.5 mg 0.08 (0.08 to 0.25) d d
P value .326 d d
Change from baseline predose PEF to 1-hour postdose clinic PEF at week 12
LS (L/min), mean (95% CI) 57.04 (46.12e67.97) 41.14 (30.26e52.01) 31.57 (20.78e42.36)
Treatment difference between groups (L/min), mean (95% CI)
Vs budesonide 160 mg 25.47 (10.94e40.00) 9.56 (4.92 to 24.05) d
P value .001 .195 d
Vs budesonide/formoterol 160/4.5 mg 15.90 (1.34e30.47) d d
P value .032 d d
Change from baseline predose FVC to 1-hour postdose clinic FVC at week 12
LS (L), mean (95% CI) 0.22 (0.15e0.30) 0.16 (0.09e0.23) 0.17 (0.10e0.24)
Treatment difference between groups (L), mean (95% CI)
Vs budesonide 160 mg 0.05 (0.04 to 0.15) 0.01 (0.11 to 0.08) d
P value .276 .759 d
Vs budesonide/formoterol 160/4.5 mg 0.07 (0.03 to 0.16) d d
P value .165 d d
Change from baseline predose to end-of-study average
Total asthma symptom score, mean (SD) 0.5 (0.73) 0.6 (0.73) 0.4 (0.55)
Nighttime awakenings due to asthma symptoms (%), mean (SD) 14.0 (29.2) 17.3 (33.2) 13.0 (21.9)
Total daily reliever medication use (inhalations/d), mean (SD) 0.7 (1.75) 1.1 (2.37) 0.7 (1.37)

Abbreviations: BID, twice daily; CI, confidence interval; FEF25%e75%, forced expiratory flow between 25% and 75% of forced vital capacity; FEV1, forced expiratory volume in 1
second; FVC, forced vital capacity; LS, least squares; PEF, peak expiratory flow; pMDI, pressurized metered-dose inhaler.
a
Baseline defined as the value recorded on day 0 (randomization) of the study.
b
Baseline defined as the mean from the morning record of 7 days before, up to, and including the day before randomization. End-of-study average defined as the average of
available records from 7 days before, up to, and including the day before withdrawal from study or week 12.
c
Baseline defined as the percentage of nighttime awakenings due to asthma symptoms experienced of all available data recorded from the morning record of the last 6 days
before, up to, and including the morning record at randomization. End-of-study average is the percentage of nighttime awakenings due to asthma symptoms from 6 days
before, up to, and including the morning of withdrawal from study or week 12.

study population. The mean age of patients was 9 years (range 6e11
years); 35.1% of patients were 6 to younger than 9 years. The mean
asthma duration was 5.9 years (range 0.50e11.96 years). Most pa-
tients in each treatment group (89%e93%) were receiving medium-
dose ICS at baseline; one fourth of all patients were receiving ICS
plus LABA at baseline. Some small differences in demographic and
disease characteristics were noted among treatment groups. In
particular, there was a smaller percentage of white and Hispanic or
Latino patients in the budesonide group and a larger percentage of
boys in the budesonide/formoterol 160/4.5 mg BID group.
Efficacy
Lung function
Budesonide/formoterol 160/9 mg BID resulted in a statistically
significantly greater change from baseline predose FEV1 (value at
randomization, taken at week 0) to the 1-hour postdose FEV1 at
week 12 (primary end point) vs budesonide 160 mg BID (treatment
difference 0.12 L, 95% confidence interval [CI] 0.03e0.20, P ¼ .006;
Fig 2). There also was a numerical difference between the bude-
sonide/formoterol 160/4.5 mg BID and budesonide 160 mg BID
groups (treatment difference 0.08, 95% CI 0.00e0.16, P ¼ .063) and
between the 2 different budesonide/formoterol groups (treatment
difference 0.04 L, 95% CI 0.05 to 0.12, P ¼ .373), but neither
reached statistical significance. The results of the sensitivity
analyses supported the findings of the primary analysis.
Most secondary lung function variables supported the findings
of the primary end point. In patients treated with budesonide/for-
moterol 160/9 mg BID, bronchodilatory effects were evident from
the first assessment at 15 minutes on day 1 and were maintained at
week 12. The change from baseline predose FEV1 to 15-minute
postdose clinic FEV1 at week 12 with budesonide/formoterol
160/9 mg BID was statistically significantly greater than with
budesonide 160 mg BID (estimated difference 0.10 L, 95% CI
0.02e0.18, P ¼ .015; Table 2, Fig 3).
Improvements from baseline predose FEF25%e75% at randomi-
zation to 1-hour postdose clinic FEF25%e75% at week 12 were sta-
tistically significantly higher with budesonide/formoterol 160/9 mg
BID and budesonide/formoterol 160/4.5 mg BID compared with
budesonide alone (P  .005 for the 2 comparisons; Table 2, Fig 4).
Similarly, for change from baseline predose PEF at randomization to
1-hour postdose clinic PEF at week 12, a statistically significantly
greater improvement was observed for patients receiving budeso-
nide/formoterol 160/9 mg BID than for those receiving budesonide
(estimated difference 25.47 L/min, 95% CI 10.94e40.00, P ¼ .001),
whereas the improvement observed for budesonide/formoterol
160/4.5 mg BID was not statistically significantly different from
budesonide. The improvement in 1-hour postdose clinic PEF
observed with budesonide/formoterol 160/9 mg BID also was
 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499 495

treatment groups in the change from baseline predose at

Mean change in FEV1 from predose at
baseline to 15-minutes postdose on

randomization to predose values at week 12 for FEV1, FEF25%e75%,

day 1 and at end of study (Liters)

PEF, or FVC (Table 4).

Symptom-Related Variables and Asthma Exacerbations

Figure 3. Mean change from baseline predose FEV1 (value at randomization, taken
at week 0) to the 15-minute postdose FEV1 at day 1 and end of study. aDay 1 rep-
resents the 15-minute postdose clinic FEV1 data collected at randomization; values
shown are descriptive mean change. bEnd of study represents the 15-minute post-
dose clinic FEV1 data collected at the end of the study (withdrawal from study or
week 12); values shown are least squares means. FEV1, forced expiratory volume in 1
second.
statistically significantly greater than that observed with budeso-
nide/formoterol 160/4.5 mg BID (estimated treatment difference
15.90 L/min, 95% CI 1.34e30.47, P ¼ .032; Table 2, Fig 4). The mean
changes from baseline to end-of-study average for eDiary FEV1 and
PEF (morning and evening) were generally consistent with the
findings observed for their corresponding clinic values (Table 3).
There were no statistically significant differences in baseline
predose FVC at randomization to 1-hour postdose FVC at week 12
between the budesonide/formoterol groups and budesonide alone
or between the 2 budesonide/formoterol groups (Table 2). In
addition, there were no statistically significant differences between
As presented in Table 2, for all symptom-related variables, a
similar pattern was observed, with an improvement from baseline
in all treatment groups and with a tendency for a greater
improvement in the budesonide/formoterol 160/4.5 mg BID group.
The percentage of patients with protocol-defined asthma
exacerbations was similar across treatment groups (Fig 5).
Thirty-three patients (12.1%) had 34 protocol-defined asthma
exacerbations from the first dose of study drug to the end of the
study. Most of these patients required a change to maintenance
medication (ie, increased or additional asthma maintenance
medications) or systemic steroids. The percentage of patients
who required a change to maintenance medication was smallest
in the budesonide/formoterol 160/9 mg BID group and the pro-
portion requiring systemic steroids was largest in the budesonide
group. No statistically significant differences were observed
between treatment groups for the time to first protocol-defined
asthma exacerbation or time to discontinuation of study drug,
although the probability of discontinuation was numerically
lower for the budesonide/formoterol 160/9 mg BID group at any
single time point.
Health-Related Quality of Life
The change from baseline to the mean during the study period
in PAQLQ(S) total and subdomain scores indicated a general
improvement in HRQoL for the study period, regardless of treat-
ment group; no statistically significant difference among treatment
groups was observed (Fig 6). There also were no statistically sig-
nificant differences between treatment groups in the proportion of
patients with a clinically relevant improvement.

Clinic FEF25%–75% (L/sec)

Budesonide/formoterol 160/9 μg (n = 89)

vs budesonide 160 μg (n = 90)

Budesonide/formoterol 160/4.5 μg (n = 93)

vs budesonide 160 μg (n = 90)

Budesonide/formoterol 160/9 μg (n = 89)

vs budesonide/formoterol 160/4.5 μg (n = 93)

-0.1 0.0 0.1 0.2 0.3 0.4 0.5

Clinic PEF (L/min)

Budesonide/formoterol 160/9 μg (n = 89)
vs budesonide 160 μg (n = 90)

Budesonide/formoterol 160/4.5 μg (n = 93)

vs budesonide 160 μg (n = 90)

Budesonide/formoterol 160/9 μg (n = 89)

vs budesonide/formoterol 160/4.5 μg (n = 93)

-10 0 10 20 30 40
Mean difference (95% CI)

Figure 4. Treatment differences in mean change (95% CI) from baseline predose at randomization to 1-hour postdose lung function variables at week 12. CI, confidence
interval; FEF25%e75%, forced expiratory flow between 25% and 75% of the forced vital capacity; PEF, peak expiratory flow.
496 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499

Table 3
Mean Change from Baseline Predose to End-of-study Average in eDiary FEV1 and PEF (Morning and Evening)a

Budesonide/formoterol pMDI 160/9 mg BID Budesonide/formoterol pMDI 160/4.5 mg BID Budesonide pMDI 160 mg BID

Morning FEV1 (L)

Baseline mean (SD), n
Mean change (SD), n
Evening FEV1 (L)
Baseline mean (SD), n
Mean change (SD), n
Morning PEF (L/min)
Baseline mean (SD), n
Mean change (SD), n
Evening PEF (L/min)
Baseline mean (SD), n
Mean change (SD), n
1.637 (0.5091), 82 1.593 (0.4566), 87 1.634 (0.4495), 84
0.137 (0.4006), 72 0.150 (0.3951), 77 0.082 (0.4238), 72
1.708 (0.5150), 80 1.668 (0.4978), 87 1.729 (0.4316), 85
0.084 (0.3769), 69 0.067 (0.4150), 72 0.014 (0.3977), 68
211 (65.7), 82 208 (63.2), 87 215 (64.2), 84
28 (48.5), 72 16 (58.4), 77 19 (51.6), 72
229 (61.2), 80 219 (64.7), 87 225 (65.2), 85
18 (46.7), 69 6 (59.8), 72 7 (50.3), 68

Abbreviations: BID, twice daily; FEV1, forced expiratory volume in 1 second; PEF, peak expiratory flow; pMDI, pressurized metered-dose inhaler.
a
Baseline is the mean from the morning record of 6 days before and including the morning record at the randomization visit for morning entries and the mean from the
evening record of 7 days before and including the day before randomization for evening entries. End-of-study average is defined as the mean from 6 days before, up to, and
including withdrawal from study or week 12 for morning entries and the mean from 7 days, up to, and including the day before withdrawal from study or week 12 for
evening entries.

Safety and Asthma Worsening
Overall, the study did not show any notable differences in safety
profiles between the budesonide/formoterol doses compared with
budesonide or between the 2 budesonide/formoterol doses. No
deaths were reported during the study. The proportion of patients
with at least 1 on-treatment AE was similar across treatment
groups (Table 5). Serious AEs occurred in 2 patients (2.2%) receiving
budesonide (acute lymphocytic leukemia [n ¼ 1], asthma exacer-
bation [n ¼ 1]); none were reported in the budesonide/formoterol
groups. In total, 5 patients discontinued treatment because of an AE
during the study: 1 patient (1.1%) in each budesonide/formoterol
group (both with asthma) and 3 patients (3.3%) in the budesonide
160 mg group (asthma [n ¼ 2]; acute lymphocytic leukemia [n ¼ 1]).
Among the most commonly reported AEs (3% in any group),
upper respiratory tract infection, pharyngitis, headache, and
vomiting were reported more frequently in the budesonide/for-
moterol treatment groups compared with budesonide alone
(Table 5).
Adverse events relating to potential ICS class effects were re-
ported in 2 patients (2.2%) in the budesonide/formoterol 160/4.5 mg
BID group (dysgeusia and candida infection) and 2 patients (2.2%)
in the budesonide 160 mg BID group (oral candidiasis and upper
limb fracture; Table 5). The only reported AE related to potential
b2-agonist class effects was headache (4 patients reported in each
budesonide/formoterol group and 0 in the budesonide 160 mg BID
group; Table 5).

Table 4
Change from Baseline Predose Secondary Lung Function Variables to Predose Values at Week 12a

Budesonide/formoterol pMDI Budesonide/formoterol pMDI Budesonide pMDI

160/9 mg BID (n ¼ 90) 160/4.5 mg BID (n ¼ 93) 160 mg BID (n ¼ 90)

Mean change from baseline predose FEV1 to predose FEV1 at week 12

LS (L), mean (95% CI) 0.11 (0.04e0.17) 0.10 (0.03e0.16) 0.09 (0.03e0.15)
Treatment difference between groups (L), mean (95% CI)
Vs budesonide 160 mg 0.02 (0.07 to 0.10) 0.00 (0.08 to 0.09) d
P value .724 .909 d
Vs budesonide/formoterol 160/4.5 mg 0.01 (0.07 to 0.09) d d
P value .811 d d
Mean change from baseline predose clinic FEF25%e75% to predose FEF25%e75%
at week 12
LS (L/s), mean (95% CI) 0.12 (0.01e0.24) 0.13 (0.01e0.25) 0.09 (0.03 to 0.21)
Treatment difference between groups (L/s), mean (95% CI)
Vs budesonide 160 mg 0.03 (0.12 to 0.19) 0.04 (0.12 to 0.20) d
P value .684 .621 d
Vs budesonide/formoterol 160/4.5 mg 0.01 (0.16 to 0.15) d d
P value .929 d d
Mean change from baseline predose clinic PEF to predose clinic PEF at week 12
LS (L/min), mean (95% CI) 27.73 (16.37e39.08) 15.86 (4.39e27.33) 16.01 (4.50e27.52)
Treatment difference between groups (L/min), mean (95% CI)
Vs budesonide 160 mg 11.72 (3.63 to 27.06) 0.15 (15.58 to 15.28) d
P value .134 .985 d
Vs budesonide/formoterol 160/4.5 mg 11.87 (3.43 to 27.16) d d
P value .128 d d
Mean change from baseline predose clinic FVC to predose clinic FVC at week 12
LS (L), mean (95% CI) 0.11 (0.03e0.18) 0.11 (0.04e0.19) 0.13 (0.05e0.20)
Treatment difference between groups (L), mean (95% CI)
Vs budesonide 160 mg 0.02 (0.12 to 0.08) 0.02 (0.12 to 0.08) d
P value .664 .747 d
Vs budesonide/formoterol 160/4.5 mg 0.01 (0.11 to 0.09) d d
P value .913 d d

Abbreviations: BID, twice daily; CI, confidence interval; FEF25%e75%, forced expiratory flow between 25% and 75% of forced vital capacity; FEV1, forced expiratory volume in 1
second; FVC, forced vital capacity; LS, least squares; PEF, peak expiratory flow; pMDI, pressurized metered-dose inhaler.
a
Baseline is the most recent non-missing predose assessment before the first dose of study drug (typically at randomization).
 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499 497

14 13.3
12.9
(n = 12)
(n = 12)
12
Percentage of patients 10.0 10.0 10.0
10 (n = 9) (n = 9)
(n = 9)
8.6
7.8 7.5 (n = 8)
8
(n = 7)
(n = 7)

6
4.4
4 3.3 (n = 4)

(n = 3) 2.2 2.2
2 (n = 2) (n = 2)
1.1
0 0 (n = 1)
0
With ≥1 Systemic Additional/increased ED treatment Hospitalization
protocol-defined steroids maintenance medication
asthma exacerbation

Budesonide/formoterol 160/9 μg (n = 90) Budesonide/formoterol 160/4.5 μg (n = 93) Budesonide 160 μg (n = 90)

Figure 5. Incidence of protocol-defined asthma exacerbations during the study period, which were those that required emergency department, hospitalization, systemic
steroids, or increased or additional maintenance medication. Number of events is presented within parentheses within the bars. ED, emergency department.

Asthma- and potentially asthma-related events were least 7 events in 6 patients (2 in each treatment group) required
common in the budesonide/formoterol 160/9 mg BID group clinical evaluation.
(Table 5). Almost two thirds of patients met predefined Laboratory, vital signs, electrocardiograms, and physical
worsening criteria on at least 1 occasion during the study: 54 examination findings did not raise any safety concerns. Mean
(60.0%), 61 (65.6%), and 62 (68.9%) in the budesonide/formoterol changes from baseline for glucose were 0.4, 0.3, and 0.2
160/9 mg BID, budesonide/formoterol 160/4.5 mg BID, and mmol/L for the budesonide/formoterol 160/9 mg BID, budesonide/
budesonide 160 mg BID groups, respectively. Most of these formoterol 160/4.5 mg BID, and budesonide 160 mg BID groups,
patients (52.4% across all treatment groups) met the criterion for respectively. Mean potassium levels increased during the study by
a decrease from baseline in morning PEF of at least 15%. Only 0.3 mmol/L for the budesonide/formoterol 160/9 mg BID group and

Overall
Budesonide/formoterol 160/9 μg (n = 79)
Budesonide/formoterol 160/4.5 μg (n = 80)
Budesonide 160 μg (n = 82)

0.0 0.2 0.4 0.6 0.8 1.0

Symptoms
Budesonide/formoterol 160/9 μg (n = 79)
Budesonide/formoterol 160/4.5 μg (n = 80)
Budesonide 160 μg (n = 82)

0.0 0.2 0.4 0.6 0.8 1.0

Activity Limitation
Budesonide/formoterol 160/9 μg (n = 79)
Budesonide/formoterol 160/4.5 μg (n = 80)
Budesonide 160 μg (n = 82)

0.0 0.2 0.4 0.6 0.8 1.0

Emotional Function
Budesonide/formoterol 160/9 μg (n = 79)

Budesonide/formoterol 160/4.5 μg (n = 80)

Budesonide 160 μg (n = 82)

0.0 0.2 0.4 0.6 0.8 1.0

Mean change (95% CI)

Figure 6. Mean change (95% CI) in Pediatric Asthma Quality of Life Questionnaire with Standardized Activities scores from predose baseline at randomization to study period
average for subdomain and overall scores. Study period average is the mean value of the post-baseline values during the study taken after first dose of study drug (typically at
randomization) up to and including withdrawal from study or week 12. CI, confidence interval.
498 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499

Table 5
Safety Outcomes by Treatment Arma

Patients, n (%) Budesonide/formoterol pMDI Budesonide/formoterol pMDI Budesonide pMDI

160/9 mg BID (n ¼ 90) 160/4.5 mg BID (n ¼ 93) 160 mg BID (n ¼ 90)

Reporting 1 on-treatment AE 42 (46.7) 41 (44.1) 40 (44.4)

Most common on-treatment AEs (3%) by PT
Asthma 7 (7.8) 11 (11.8) 10 (11.1)
Upper respiratory tract infection 9 (10.0) 12 (12.9) 4 (4.4)
Pyrexia 4 (4.4) 4 (4.3) 4 (4.4)
Nasopharyngitis 4 (4.4) 2 (2.2) 5 (5.6)
Rhinitis allergic 3 (3.3) 3 (3.2) 4 (4.4)
Cough 1 (1.1) 4 (4.3) 4 (4.4)
Pharyngitis 5 (5.6) 3 (3.2) 1 (1.1)
Headache 4 (4.4) 4 (4.3) 0
Rhinitis 3 (3.3) 2 (2.2) 2 (2.2)
Vomiting 2 (2.2) 3 (3.2) 0
AEs related to potential ICS class effectsb 0 2 (2.2) 2 (2.2)
AEs related to potential b2-agonist class effectsc 4 (4.4) 4 (4.3) 0
Asthma- and potentially asthma-related eventsd 10 (11.1) 15 (16.1) 14 (15.6)

Abbreviations: AE, adverse event; BID, twice daily; ICS, inhaled corticosteroid; pMDI, pressurized metered-dose inhaler; PT, preferred term.
a
All AEs were coded according to terminology used in the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
b
Dysgeusia and Candida infection were each reported in 1 patient in the budesonide/formoterol 160/4.5 mg group; oral candidiasis and upper limb fracture were each reported
in 1 patient in the budesonide group.
c
Headache was reported in 4 patients in each budesonide/formoterol group.
d
Asthma and potentially asthma-related AEs (budesonide/formoterol 160/9 mg, budesonide/formoterol 160/4.5 mg, and budesonide 160 mg groups, respectively) included
asthma (7, 11, and 10 patients), cough (1, 4, and 4 patients), wheezing (1, 0, and 2 patients), and chest discomfort (1, 0, and 0 patients).

0.2 mmol/L for the budesonide/formoterol 160/4.5 and budeso-
nide 160 mg BID groups.
Discussion
The present study (CHASE 3) is the last of 3 clinical trials
designed in conjunction with the FDA constituting the CHASE pe-
diatric asthma program, which together provide a comprehensive
evaluation of the efficacy and safety of specific doses of budesonide
and formoterol administered by pMDI in children 6 to younger than
12 years with asthma. The CHASE 3 study evaluated the efficacy and
safety of 2 doses of formoterol in fixed combination with budeso-
nide (budesonide/formoterol pMDI, 160/9 mg or 160/4.5 mg BID),
compared with budesonide pMDI 160 mg BID over 12 weeks in
children 6 to younger than 12 years with symptomatic asthma,
despite low-dose ICS therapy.
This study met its primary end point, because budesonide/for-
moterol pMDI 160/9 mg BID resulted in a statistically significantly
greater change from baseline predose FEV1 at randomization to 1-hour
postdose FEV1 at week 12 vs budesonide 160 mg BID. There were no
statistically significant differences between budesonide/formoterol
160/4.5 mg BID and budesonide 160 mg BID or between budesonide/
formoterol 160/9 mg and 160/4.5 mg BID for the primary variable.
Several thresholds indicating a clinically relevant improvement
from baseline FEV1 have been reported for patients at least 6 years
old with asthma. These include at least 10%9 or at least 15%11
improvement from pre- to post-bronchodilator FEV1 (irrespective
of absolute volume change) and at least 12% plus at least 200 mL
difference in pre- and post-bronchodilator FEV1.11 In the CHASE 3
study, the 2 doses of budesonide/formoterol achieved improve-
ments from baseline predose to 1-hour postdose FEV1 at week 12
consistent with these suggested thresholds (160/9 mg BID, im-
provements of 18% and 280 mL; 160/4.5 mg BID, improvements of
15% and 240 mL), whereas budesonide 160 mg BID alone did not
meet all of these thresholds (improvements of 11% and 170 mL). The
criteria for a clinically important difference in FEV1 between
treatments also have been described (100 mL [per the National
Institutes of Health]11 and 5%12). Based on these thresholds, only
the budesonide/formoterol 160/9 mg BID dose showed clinically
meaningful improvements compared with budesonide alone (6%
and 120 mL increase in FEV1).
Response to step-up therapy in children with asthma not well
controlled on low-dose ICS alone has been shown to vary among
patients.12 Thus, it is important to have different treatment options.
Based on the results of the CHASE 3 study, budesonide/formoterol
pMDI 160/9 mg BID provides a safe treatment alternative demon-
strating statistically significant and clinically meaningful im-
provements in a core efficacy variable (ie, FEV1) vs medium-dose
ICS alone in children with asthma.
Similar to the 1-hour postdose FEV1 value at week 12, the in-
crease from baseline predose FEV1 at randomization to 15 minutes
postdose FEV1 at 12 weeks was statistically significantly larger in
the budesonide/formoterol 160/9 mg BID group than in the bude-
sonide 160 mg BID group, with an effect that was evident at the first
time point assessed after dosing on day 1 and maintained at week
12. These results support previous studies in adults and adoles-
cents3 and in children,8 which demonstrated a rapid and statisti-
cally significant bronchodilatory effect of formoterol 9 mg BID
administered with budesonide compared with budesonide
alone.3,8
The budesonide/formoterol 160/9 mg BID group showed supe-
riority over the budesonide/formoterol 160/4.5 mg BID and bude-
sonide 160 mg BID groups in change from baseline predose PEF to
1-hour postdose PEF at week 12. The 2 budesonide/formoterol
doses demonstrated a statistically significantly greater increase
from baseline predose to 1-hour postdose FEF25%e75% vs budeso-
nide 160 mg BID at week 12. eDiary lung function findings were
generally consistent with those from the clinic, further supporting a
greater treatment effect in the budesonide/formoterol 160/9 mg BID
group. For symptom-related variables, improvements from base-
line were observed in all treatment groups.
The present findings demonstrate a dose-response effect on
bronchodilation, with maximal benefit observed with budeso-
nide/formoterol 160/9 mg BID. This finding is in line with those
from the formoterol dose-finding CHASE 2 study, which showed
numerically greater bronchodilation with the single dose of for-
moterol 9 mg vs single doses of 4.5 and 2.25 mg in patients 6 to
younger than 12 years.8 The results also are consistent with
previous work demonstrating a numerical trend in favor of for-
moterol DPI 9 mg compared with 4.5 mg in morning PEF when
used as an add-on medication with ICS treatment in children.13 In
addition, the present results are in line with 2 studies that
 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499
showed significant improvements in PEF and FEV1 with budeso-
nide/formoterol DPI 160/9 mg vs budesonide alone in children
with asthma.14,15
Similar results might have been found by comparing twice-daily
SABA plus budesonide 160 mg with budesonide/formoterol 160/9
mg; however, it is currently not known what dose of SABA would be
comparable to formoterol 9 mg during 12 hours. Moreover, the FDA
recommends the use of a fixed-dose ICS/LABA combination to
ensure compliance with concomitant therapy in pediatric and
adolescent patients requiring the addition of a LABA to an ICS.16
Moreover, it has been shown that corticosteroids and b2-adren-
ergic agonists (long- and short-acting) target different aspects of
the inflammatory process of asthma, leading to complementary,
additive, and sometimes synergistic anti-inflammatory effects.17
However, a much longer presence of LABA than SABA in airway
tissue after inhalation and comparable airway residence time of
LABA and ICS ensure that an ICS/LABA combination provides
enhanced anti-inflammatory protection over 24 hours.
Improvements in HRQoL values and symptom-related variables
from baseline were detected in all groups. Overall, there was no
statistically significant difference in the change from baseline for
HRQoL measures between any of the treatment groups. Although
not compared statistically, a similar pattern was observed across
treatment groups for all symptom-related variables. These findings
are consistent with those previously observed after budesonide/
formoterol vs mono-component treatment, where statistically
significant improvements in lung function were observed in the
absence of changes in symptoms.5,14,15 Differences in sensitivity
between the 2 outcome measurements could be one potential
explanation for these findings.
There were no notable differences in the safety profile between
either budesonide/formoterol dose and budesonide alone or
between the 2 budesonide/formoterol groups. These results are
consistent with those from the CHASE 2 study, which showed no
difference in AE profiles in patients receiving the same dosage of
budesonide (160 mg BID), regardless of whether they received add-
on formoterol doses of 9 or 4.5 mg.8 There also were no new safety
signals in any of the treatment groups and relatively minor class
effects.
In conclusion, budesonide/formoterol pMDI 80/4.5 mg  2
inhalations (160/9 mg) BID treatment resulted in statistically sig-
nificant and clinically meaningful improvements in lung function
vs budesonide pMDI 80 mg  2 inhalations (160 mg) BID alone,
with no important safety differences. Findings from the CHASE 3
study, together with those from previous studies of budesonide/
formoterol pMDI in children with asthma, support the appropri-
ateness of adding LABA therapy in children 6 to younger than 12
years with asthma who are symptomatic on ICS alone.
Acknowledgments
We thank Dan Rigotti, PhD, and Devin S. Gary, PhD, of Scientific
Connexions, an Ashfield Company, part of UDG Healthcare plc
499
(Lyndhurst, New Jersey), for medical writing support funded by
AstraZeneca LP (Wilmington, Delaware).
Supplementary Data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.anai.2017.01.020.
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499.e1 D.S. Pearlman et al. / Ann Allergy Asthma Immunol 118 (2017) 489e499
eSupplement
Adjunct Medication
In addition to the requirement of medium-dose ICS or fixed-
dose ICS/LABA for at least 4 weeks before enrollment, patients
were allowed other nonsteroidal adjunct asthma medications (eg,
leukotriene modifiers). Adjunct medications were discontinued
before the run-in visit.
Additional Exclusion Criteria
Patients with a significant disease (other than asthma) were
excluded if, in the opinion of the investigator, the condition would
place them at risk during study participation, could affect their
ability to participate in the study, or could influence results from
the study.
Sensitivity Analysis
Sensitivity analyses performed on the primary variable
assessed the effect of treatment in the following scenarios:
(1) including all on-treatment data only; (2) including all data
collected during the study period, except data recorded after
patients were switched to maintenance therapy with another
bronchodilator-containing product (eg, fluticasone/salmeterol);
(3) including all data collected during the study period, except
for spirometry data from patients with predicted normal FEV1 of
at least 150% at any time point other than run-in assessments;
and (4) using a “jump to the reference” analysis (under the
assumption that data are missing not at random), in which, after
early study withdrawal, patients in the budesonide/formoterol
groups would be assigned FEV1 values that are the mean of those
in the budesonide group at each relevant time point, conditional
only on baseline values, and using multiple imputation
techniques.1
eReference
[1] O’Kelly M, Ratitch B. Clinical Trials With Missing Data: A Guide for Practitioners.
West Sussex, UK: John Wiley & Sons; 2014.