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Respiratory Medicine (2015) 109, 170e179
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier .com/locate /rmed
Therapeutic equivalence of budesonide/formoterol delivered via
breath-actuatedinhaler vs pMDI
Kevin R. Murphy a,*, Rajiv Dhand b, Frank Trudo c,Tom Uryniak c,
Ajay Aggarwal c, Göran Eckerwall d
a Allergy, Asthma, and Pulmonary Research, Boys Town National
Research Hospital, Department ofPediatrics, University of Nebraska
Medical Center, Creighton University School of Medicine, Omaha,
NE68132, United Statesb Department of Medicine, University of
Tennessee Graduate School of Medicine, 1924 Alcoa Highway,U114,
Knoxville, TN 37920, United Statesc AstraZeneca LP, 1800 Concord
Pike, Wilmington, DE 19850, United Statesd AstraZeneca,
Pepparedsleden 1, Mölndal, Sweden
Received 18 August 2014; accepted 23 December 2014Available
online 3 January 2015
KEYWORDSBreath-actuated;Asthma;Budesonide;Formoterol;Pressurized
metered-dose;Inhaler
* Corresponding author.E-mail address: Kevin.Murphy@boy
http://dx.doi.org/10.1016/j.rmed.200954-6111/ª 2015 The Authors.
Pubcreativecommons.org/licenses/by-nc-
Summary
Rationale: To assess equivalence of twice daily (bid)
budesonide/formoterol (BUD/FM)160/4.5 mg via breath-actuated
metered-dose inhaler (BAI) versus pressurized metered-doseinhaler
(pMDI).Methods: This 12-week, double-blind, multicenter,
parallel-group study, randomized adoles-cents and adults (aged �12
years) with asthma (and �3 months daily use of inhaled
corticoste-roids) to BUD/FM BAI 2 � 160/4.5 mg bid, BUD/FM pMDI 2 �
160/4.5 mg bid, or BUD pMDI2 � 160 mg bid. Inclusion required
prebronchodilator forced expiratory volume in one second(FEV1) �45
to �85% predicted, and reversibility of �12% in FEV1 (ages 12
to
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Budesonide/formoterol via breath-actuated inhaler 171
Conclusions: BUD/FM 2 � 160/4.5 mg bid BAI is therapeutically
equivalent to BUD/FM conven-tional pMDI. The introduction of BUD/FM
BAI would expand options for delivering
inhaledcorticosteroid/long-acting b2-agonist combination therapy to
patients with moderate-to-severe asthma.
ClinicalTrials.gov NCT01360021.ª 2015 The Authors. Published by
Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Inhaled corticosteroids (ICSs) are recommended as first-line
treatment for patients with persistent asthma, andthe addition of
an inhaled long-acting b2-agonist (LABA)can be considered to
improve lung function and symptomsin patients whose asthma is not
well controlled on ICSalone [1,2]. Combination ICS/LABAs are
available asbreath-actuated dry powder inhalers (DPI) and
manually-actuated pressurized metered-dose inhalers
(pMDIs).However, to date, a breath-actuated option in a pMDIdevice
has not been available for the delivery of a com-bination of
ICS/LABA. For some patients, poor coordina-tion between actuation
and inhalation with use of a pMDIcan lead to dosing errors [3]. A
breath-actuated pMDIinhaler (BAI) could provide an alternative
option for thosepatients unable to overcome poor hand-lung
coordination[4]. This study was designed to compare the
therapeuticefficacy and safety of combined
budesonide/formoteroldelivered by a BAI currently in clinical
development withthose of combined budesonide/formoterol delivered
by apMDI in patients with moderate-to-severe,
symptomaticasthma.
Methods
Patients
Inclusion and exclusion criteria were designed to
selectasthmatic patients aged �12 years who required medium-to
high-dose ICSs and demonstrated reversibility of airflowobstruction
with an inhaled bronchodilator after a run-inperiod. Patients must
have used ICSs daily for �3 monthsbefore study entry and required
consistent use of stabledaily doses of medium- to high-dose ICSs in
the 30 daysbefore study entry. Minimum daily doses permitted
were:beclomethasone dipropionate 504 mg/d (chlorofluorocarbonpMDI)
or 160 mg/d (actuation counter pMDI), budesonide400 mg/d,
flunisolide 1000 mg/d, fluticasone 264 mg/d (chlorofluorocarbon
pMDI) or 300 mg/d (Diskus), triam-cinolone acetonide 800 mg/d,
mometasone 400 mg/d, orciclesonide 160 mg/d.
Patients had to have asthma symptom scores (nighttimeor daytime)
of >0 on �3 of the last 7 days of the run-inperiod and
prebronchodilator FEV1 �45% and �85% of pre-dicted normal at
baseline. Asthma symptom score isdefined as: 0, no asthma symptoms;
1, you are aware ofyour asthma symptoms but you can easily tolerate
thesymptoms; 2, your asthma is causing you enough discomfort
to cause problems with normal activities (or with sleep); or3,
you are unable to do your normal activities (or to sleep)because of
your asthma.
To ensure reversibility with b2 agonists, patients had tomeet
baseline postbronchodilator criteria (4e6 actuationsof albuterol
pMDI [90 mg/inhalation] or salbutamol pMDI[100 mg/inhalation] or
after inhalation of 2.5 mg nebulizedalbuterol) of a change of �12%
in FEV1 from baseline forpatients aged �12 and
-
Figure 1 Flow chart of study design. BAI, breath-actuated
metered-dose inhaler; bid, twice daily; BUD, budesonide; FM,
for-moterol; pMDI, pressurized metered-dose inhaler; TC, telephone
conversation.
172 K.R. Murphy et al.
The reversibility requirement was designed to ensure pa-tients
are capable of responding to beta agonists andtherefore have a
potential to show a difference in theprimary objective.
Patients were randomized at visit 4 and attended theclinic on 3
further occasions (week 3, 7, and 12), followedby a telephone call
follow-up 2 weeks later. Lung functiontesting, eDiary collection,
and adverse event (AE) checkoccurred at each visit, and device
functionality questioningoccurred at weeks 3, 7, and 12. AEs were
the only datacollected on the telephone call. At visit 4, patients
wererandomized to receive 1 of the 3 following
double-blindtreatments shown in Fig. 1: BUD/FM BAI 160/4.5 mg (Fig.
2),2 inhalations bid plus placebo pMDI, 2 inhalations bid; BUD/FM
pMDI 160/4.5 mg, 2 inhalations bid plus placebo BAI, 2inhalations
bid; or BUD pMDI 160 mg, 2 inhalations bid plusplacebo BAI, 2
inhalations bid. At visit 2 and visit 4, patientswere instructed on
proper inhaler use, and devices wereavailable at each study center
for training purposes and forpatients to practice. Instruction and
practice also occurredprior to dispensing blinded study drug at
visit 4. Confirma-tion of proper device use was accomplished via
patientresponse in their eDiary to device functionality
questions.Additionally, for further confirmation at return visits,
theinvestigator or staff asked the patient if device
instructionswere being followed and provided additional training
ifrequired.
Figure 2 Schematic representation of the breath-actuatedinhaler
device. Trigger flow rate is less than 28 L/min. Dataon file
[9].
Concomitant medications
Patients were allowed the use of a short-acting b2-agonist(SABA)
as rescue medication throughout the study includingenrollment,
run-in, and treatment periods; albuterol pMDI(90
mg/inhalation)/salbutamol pMDI (100 mg/inhalation)were provided by
the study site as rescue medication.Medications not allowed during
the study included paren-teral, oral, or rectal
glucocorticosteroids; leukotriene
antagonists; inhaled disodium cromoglycate; inhalednedocromil
sodium or 5-lipoxygenase inhibitors; methyl-xanthines; inhaled
anticholinergics; any monoclonal orpolyclonal antibody therapy
taken for any reason; orCYP3A4 inhibitors (eg, ketoconazole).
Use of the following medications was allowed during thestudy:
mucolytics and expectorants not containing bron-chodilators;
antihistamines (other than terfenadine, aste-mizole, mizolastine);
allergen-specific immunotherapy ifthe patient had been on a
maintenance regimen for �3months before visit 1 and remained on a
maintenanceregimen during the study; topical, nasal, and/or
ocularformulations of glucocorticosteroids; topical, nasal
and/orocular disodium cromoglycate and/or nedocromil sodium.Other
medication, which was considered necessary for thepatient’s safety
and well-being, could be administered atthe discretion of the
investigator(s).
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Budesonide/formoterol via breath-actuated inhaler 173
Study objectives and evaluations
The primary objective of this study was to evaluate ther-apeutic
equivalence of BUD/FM delivered by BAI with BUD/FM delivered by
pMDI. The primary efficacy end points forassessing therapeutic
equivalence were comparison of theeffects of BUD/FM BAI with BUD/FM
pMDI on FEV1 at60 min postdose and FEV1 predose. To ensure that any
po-tential differences in efficacy could be detected, it
wasprespecified that BUD/FM pMDI was superior to BUD pMDI on60-min
postdose FEV1. Subsequent assessment of thera-peutic equivalence
would be established if the 95% confi-dence interval (CI) limits
for the ratio of treatment effectsof BUD/FM delivered by BAI versus
pMDI was containedwithin the equivalence limits of 80e125% [5].
Secondary efficacy end points collected by means of anelectronic
diary (eDiary) included mean change frombaseline for the overall
treatment period for morning andevening peak expiratory flow (PEF),
daytime and nighttimeand total asthma symptom scores,
awakening-free nights(nights without awakening due to asthma
symptoms), day-time and nighttime rescue medication use, and
symptom-free days.
A secondary objective was to assess
patient-reportedfunctionality of the 2 devices. Patients used the
eDiary tocomplete an end-of-study questionnaire through which
thepatient-reported ease of use of each device was evaluated.This
questionnaire contained 2 questions (‘How easy was itto use the
inhaler?’ and ‘How easy is it to determine whenyou will run out of
medicine [from the inhaler]?’). Eachquestion was scored on a
7-point scale, with options rangingfrom ‘Extremely easy’ to
‘Extremely difficult’: (0,extremely easy; 1, very easy; 2, somewhat
easy; 3, neithereasy nor difficult; 4, somewhat difficult; 5, very
difficult; 6,extremely difficult).
Safety evaluations
The safety profile of BUD/FM delivered by pMDI or BAI
wasassessed by comparing the nature, intensity, and severity ofAEs
occurring in each treatment group.
Figure 3 Patient disposition. BAI, breath-actuated
metered-dospMDI, pressurized metered-dose inhaler.
Statistical analyses
To assess the therapeutic equivalence of newly developedBUD/FM
BAI device with the marketed BUD/FM pMDI de-vice, a step-down
procedure was used to address multi-plicity. First, superiority
needed to be demonstrated forBUD/FM pMDI versus BUD pMDI for the
difference in post-dose FEV1 with a statistical significance level
of 5%. If thisrequirement was met, then the 95% CI for the ratio
oftreatment effects was to be used to assess therapeuticequivalence
of BUD/FM pMDI versus BUD/FM BAI. The pri-mary variable for this
comparison was the mean of thepostdose FEV1 measurements obtained
during treatmentperiod (visits 4e7) expressed as ratio of the
predose FEV1 atrandomization (visit 4) to create the
treatment:baselineratio. The logarithm of this value was used for
analysis usingthe analysis of covariance (ANCOVA) model with the
fixedfactors treatment and country, and the logarithm of thepredose
FEV1 at randomization as a covariate.
If the superiority condition was met in comparison to BUDpMDI, a
95% CI for the ratio of treatment effects containedwithin
equivalence limits of 80e125% [5] for FEV160 min postdose and FEV1
predose would establish thera-peutic equivalence of BUD/FM BAI and
BUD/FM pMDI. Themodel used to estimate the ratio of treatment
effects wasthe same for predose FEV1 as for postdose FEV1
describedabove (ie, a multiplicative ANCOVA with the treatment
andcountry as factors and baseline predose FEV1 as a
covariate).
For all variables other than these, pair-wise comparisonswere
made and nominal (unadjusted for multiplicity) pvalues are
reported. All hypothesis testing was conductedusing 2-sided tests.
The p values were rounded to 3 decimalplaces, and all p values
�0.05 after rounding were consid-ered statistically
significant.
Results
Patients
Patient disposition is shown in Fig. 3, and the key
de-mographics of the randomized population are shown in
e inhaler; bid, twice daily; BUD, budesonide; FM,
formoterol;
-
Table 1 Patient demographics and baseline asthma
characteristics.
Characteristic BUD/FM BAI (n Z 71) BUD/FM pMDI (n Z 71) BUD pMDI
(n Z 72)
Sex, n (%)Male 34 (47.9) 24 (33.8) 37 (51.4)Female 37 (52.1) 47
(66.2) 35 (48.6)
Age, y 42.8 (16.2) 42.6 (16.9) 42.7 (14.4)Age group, n (%)12
to
-
Figure 4 Ratio of geometric mean of treatment to baseline:
60-min postdose FEV1 (L) over 12 weeks and treatment average.Ratio
is calculated as geometric mean of treatment average divided by
geometric mean at baseline. Treatment average is definedas the mean
of all available variables after randomization. Baseline for
postdose FEV1 is predose FEV1 at visit 4 (week 0).
BAI,breath-actuated metered-dose inhaler; BUD, budesonide; FEV1,
forced expiratory volume in 1 s; FM, formoterol; pMDI,
pressurizedmetered-dose inhaler; Trt. Avg., treatment average.
Budesonide/formoterol via breath-actuated inhaler 175
pMDI was estimated to be 1.03, with a CI of 0.99e1.08,confirming
therapeutic equivalence.
Secondary outcomes
The mean change from baseline over time in morning andevening
PEF for the 3 treatment groups is shown in Fig. 6.
Table 2 Treatment group comparisons for postdose andpredose FEV1
(L).
Treatment Ratio of treatment to baseline
LS mean(CV%)a
95% CI p Value
Postdose FEV1BUD/FM BAI vs BUD pMDI 1.11 (1.99) 1.07e1.16
-
Figure 5 Ratio of geometric mean of treatment to baseline:
predose FEV1 (L) over 12 weeks and treatment average. The ratio
iscalculated as geometric mean of treatment average divided by
geometric mean at baseline. Treatment average is defined as themean
of all available variables after randomization. Baseline is defined
as the last predose value before first dose of randomizedtherapy at
visit 4 (week 0). BAI, breath-actuated metered-dose inhaler; BUD,
budesonide; FEV1, forced expiratory volume in 1 s;FM, formoterol;
pMDI, pressurized metered-dose inhaler; Trt. Avg., treatment
average.
176 K.R. Murphy et al.
The most frequently reported AEs were viral upper res-piratory
tract infections, asthma, bronchitis, bacterialupper respiratory
tract infection, nasopharyngitis, oralcandidiasis, and enteritis.
Viral upper respiratory tract in-fections occurred in 2 (2.8%), 5
(7.0%), and 3 (4.2%) of pa-tients in the BUD/FM BAI, BUD/FM pMDI,
and BUD pMDIgroups, respectively. Asthma was listed as an AE in 1
(1.4%),2 (2.8%), and 3 (4.2%) of the patients in the BUD/FM
BAI,BUD/FM pMDI, and BUD pMDI groups, respectively.
Thecorresponding rates for bronchitis were 1 (1.4%), 3 (4.2%),and 0
(0.0%). Other AEs occurred in �2 patients inany group.
Eight patients discontinued treatment because of AEs, ofwhom 5
discontinued because of asthma exacerbations (1,1, and 3 patients
in the BUD/FM BAI, BUD/FM pMDI, and BUD
Figure 6 Self-reported morning (A) and evening (B) PEF.
Baselimetered-dose inhaler; BUD, budesonide; FEV1, forced
expiratorypMDI, pressurized metered-dose inhaler.
pMDI groups, respectively). Other causes of discontinuationwere
gout (BUD/FM BAI), eczema and gingival pain (BUD/FMpMDI), and
bacterial upper respiratory tract infection(BUD pMDI).
Discussion
The aim of this study was to evaluate the therapeuticequivalence
of a BAI and conventional pMDI devicedelivering the BUD/FM
combination. For both postdoseand predose FEV1, the CIs for the
ratio of the treatmenteffects for BUD/FM BAI and pMDI were within
the 95% CIequivalence limits of 80e125%, demonstrating therapeu-tic
equivalence. All secondary end points provide
ne is the mean of run-in period values. BAI,
breath-actuatedvolume in 1 s; FM, formoterol; PEF, peak expiratory
flow;
-
Table 3 Treatment group differences for secondary end
points.
Treatment ANCOVA summary treatment comparisons
LS mean (SE) 95% CI p Valuea
Morning PEF (L/min)
BUD/FM BAI minus BUD pMDI 35.01 (6.72) 21.77 to 48.26
-
178 K.R. Murphy et al.
The BAI device is similar to the pMDI device in manyways
including identical drug formulations, canister, valvetype, and
stem orifice, as well as very similar mouth-pieces. The basic mode
of operation is also the same be-tween the pMDI and BAI devices: a
force is applied to thecanister base, which depresses the metering
valve andreleases a dose. For a pMDI inhaler, the force is
createdwhen the patient presses down on the top of the inhalerwhile
inhaling. For the BAI device, a patient’s inhalationtriggers a
spring, which applies the force for release of themedication
(therefore eliminating the need to coordinateinhalation with manual
actuation). The trigger inspiratoryflow rate is less than 28 L/min
[9] which almost all pa-tients can achieve [10]. The BAI was a new
device to allpatients in the study, and results from the patient
func-tionality study indicated that the ease of use was similarto
the pMDI device.
Patients in both the pMDI and BAI groups reported thattheir
device delivered a dose on greater than 99% of oc-casions. However,
there were differences in the ease ofidentifying when medication
was running out. More pa-tients using the BAI device (55%) than the
pMDI device (41%)found it ‘extremely easy,’ which may be because of
thedifferent dose counters used on each device. The pMDIdevice has
a fuel-gauge-style dose counter, with an arrowpointing to a
circular gauge ranging from 120 to 0, withdemarcations every 5
actuations and numerals every 10actuations. The BAI device has a
mechanical digital counterthat displays the exact number of
actuations remaining,starting at 120 and counting down in
increments of 1 aftereach actuation.
The safety profile of both devices was consistent withthat of
previously published results [6,7]. Noonan et al. [6]compared
BUD/FM pMDI with BUD pMDI, FM DPI, BUD plusFM in separate inhalers
(BUD pMDI þ FM DPI), and placeboin moderate to severe asthma
patients. As with the pre-sent study, all treatments were well
tolerated, and mostAEs were mild to moderate [6]. In the Noonan
study, theincidence of oral candidiasis in the BUD/FM pMDI groupwas
higher than that in other groups [6]. However, in thepresent study,
oral candidiasis was experienced by only 1patient in each patient
group.
Corren et al. [7] also reported safety results from a 12-week
trial of BUD/FM pMDI versus BUD pMDI and FM DPI inpatients with
mild to moderate asthma. As with the presentstudy, the treatments
were well tolerated, and most AEswere of mild or moderate intensity
[7]. In the Corren study[7], the most common AE possibly related to
BUD/FM pMDItreatment was cough (2 patients; 1.6%), with single
(0.8%)additional cases of headache, pharyngolaryngeal pain,tremor,
and jitteriness. In the present study, headacheoccurred in just 1
patient (1.4%) in the BUD/FM BAI groupand in none of the patients
receiving BUD/FM pMDI. Theonly case of cough was reported in the
BUD/FM BAI group,and 1 patient in each of the BUD/FM groups
experiencedtremor.
Conclusion
BUD/FM 160/4.5 mg � 2 inhalations bid administered by aBAI
device is therapeutically equivalent to BUD/FM 160/
4.5 mg � 2 inhalations bid delivered by a conventionalpMDI based
on both predose and postdose FEV1.Furthermore, no difference in
safety profiles was identi-fied. The introduction of BUD/FM BAI
would represent anexpansion of options to help tailor effective
ICS/LABAcombination therapy for patients with moderate-to-severe
asthma.
Funding
This study was supported by AstraZeneca LP. F.T., A.A., andG.E.
are employees of AstraZeneca LP. T.U. is a formeremployee of
AstraZeneca LP.
Author declaration of financial interest
Kevin R. Murphy: Consultancy/Advisory board:
Aerocrine,AstraZeneca LP, Genentech, Greer, Novartis, Meda,
Merck,Mylan, and Teva. Speaker: Aerocrine, AstraZeneca
LP,Genentech, Novartis, Meda, Merck, Mylan, and Teva. Hon-oraria:
Aerocrine, AstraZeneca LP, Genentech, Greer,Novartis, Meda, Merck,
Mylan, and Teva. Research grant:Teva.
Rajiv Dhand: Speaker’s honorarium: Glaxo Smith-Kline.Consultant:
Bayer. Clinical trials: Mylan, Bayer, CardeasPharma.
Frank Trudo: Full-time employee of and shareholder inAstraZeneca
LP.
Tom Uryniak: Former employee of and shareholder inAstraZeneca
LP.
Ajay Aggarwal: Full-time employee of and shareholderin
AstraZeneca LP.
Göran Eckerwall: Full-time employee of and share-holder in
AstraZeneca LP.
Acknowledgments
The authors acknowledge Scientific Connexions (Lyndhurst,NJ,
USA) for medical writing assistance funded by Astra-Zeneca LP
(Wilmington, DE, USA).
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Therapeutic equivalence of budesonide/formoterol delivered via
breath-actuated inhaler vs pMDIIntroductionMethodsPatientsStudy
design and treatmentConcomitant medicationsStudy objectives and
evaluationsSafety evaluationsStatistical analyses
ResultsPatientsEfficacySecondary outcomesSafety
DiscussionConclusionFundingAuthor declaration of financial
interestAcknowledgmentsReferences