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Efficacy and Tolerability of Fluticasone Propionate
/Salmeterol MDI Compared With Concurrent Fluticasone Propionate and Salmeterol MDI in Adult Patients with Persistent Asthma: A Randomized, Double-Blind 12-Week Study
Mahesh PA1, Rebello CJ2*, Purandare SM2, Gogtay JA2 and Bill Brashier2
1Department of Chest Medicine, Allergy, Asthma & Chest Research Centre, India
2Department of Clinical Research, Cipla Ltd, India
Submission: February 21, 2017; Published: September 25, 2017
*Corresponding author: Juliet Rebello, Department of Clinical Research, Cipla Ltd 4th floor, North Block, R&D Centre, Vikhroli (W), Mumbai – 400 083, India, Tel: +912225756430; Email firstname.lastname@example.org
How to cite this article: Mahesh P, Rebello C, Purandare S, Gogtay J, Bill B. Efficacy and Tolerability of Fluticasone Propionate/Salmeterol MDI
Compared With Concurrent Fluticasone Propionate and Salmeterol MDI in Adult Patients with Persistent Asthma: A Randomized, Double-Blind 12-Week
Study. Int J Pul & Res Sci. 2017; 2(2): 555583. DOI:10.19080/IJOPRS.2017.02.555583
Background: The use of a single inhaler to administer a dry powder formulation of fluticasone (FP) and salmeterol (SM) is at least as effective as concurrent administration of the mono-components from individual dry powder inhalers. Whether the same applies to the pressurised metered dose inhaled (pMDI) formulation of these products which, unlike the dry powder formulations are not breath-actuated, has not been established.
Objective: This study assessed the non-inferiority of the combination fluticasone/salmeterol pMDI (Cipla Ltd) versus concurrent administration of fluticasone and salmeterol administered via two separate pMDIs in patients with asthma.
Methods: In this 12-week, randomized, double blind study, patients with mild to moderate persistent asthma were randomized (1:1) to two inhalations twice daily of fluticasone/salmeterol pMDI 125/25mcg [FP/SM 125/25mcg] or concurrent administration of Flixotide Evohaler and Serevent Evohaler [FP 125mcg and SM 25mcg] for 12 weeks. The primary endpoint was the change from baseline in morning peak expiratory flow rate (mPEFR) at week 12. Secondary endpoints included change at 12 weeks from baseline in forced expiratory volume in 1 second (FEV1), asthma symptom scores, and rescue medication use. Tolerability was also assessed.
Results: Three hundred and sixty subjects (mean age of 41.3 years) were randomized to FP/SM 125/25mcg combination (n=183 patients) or concurrent FP 125mcg plus SM 25mcg (n = 177 subjects). Demographic and baseline clinical characteristics including baseline lung function was similar between the 2 groups. The adjusted mean increase at week 12 from baseline (PP population) in mPEFR was 38.7L/min in the FP/SM 125/25mcg group versus 33.4L/min in the concurrent FP 125mcg plus SM 25mcg group. The adjusted mean treatment difference was 5.2L/min and the one sided 97.5% confidence limit for the treatment difference was -3.6 to 14.0L/min. Similar results were observed for the ITT population. At week 12, no significant difference in changes from baseline FEV1, daytime, nighttime asthma symptom scores and rescue medication was observed between the two treatment groups. Overall, adverse events (AEs) and other tolerability measures were comparable between the two groups.
Conclusion: Administration of FP/SM 125/25 HFA pMDI as a combination was at least as effective as concurrent administration of the mono-components in improving overall asthma control in subjects with mild to moderate persistent asthma.
Asthma affects both children and adults. It is currently estimated that as many as 300 million people worldwide of all ages and all ethnic backgrounds suffer from asthma . Inhaled corticosteroids (ICS) are the drugs of choice for the management of subjects with persistent asthma. Studies have demonstrated that the combination of a long acting beta agonist and an inhaled corticosteroid provides better overall asthma control than
doubling the dose of inhaled steroids alone [2,3].
The combination of the long acting beta agonist (LABA),
salmeterol, and the inhaled corticosteroid (ICS), fluticasone
propionate has been shown to be effective and well tolerated in
the treatment of persistent asthma [4,5]. Salmeterol/ fluticasone
improve lung function and controls symptoms and exacerbations
more effectively in subjects with asthma, symptomatic on
regular ICSs [6-11]. These effects are thought to be due to the
complementary mechanisms of action of fluticasone propionate
and salmeterol which interact in a synergistic manner at the
receptor, molecular, and cellular levels . For optimal drug
interaction, both these drugs should reach the same target cell
together in adequate concentrations, which can be achieved by
their co administration .
Previous studies have shown that the use of a single
inhaler to administer a dry powder formulation of fluticasone
(FP) and salmeterol (SM) is at least as effective as concurrent
administration of the mono-components from individual dry
powder inhalers [14,15]. Whether the same applies to the pMDI
formulation of these products which, unlike the dry powder
formulations are not breath-actuated, has not been established.
This study was designed to assess the non-inferiority of
a fluticasone/salmeterol HFA pMDI combination (Cipla Ltd)
versus concurrent administration of fluticasone and salmeterol
administered via two separate inhalers in subjects with asthma.
This 12-week, double blind randomized study was
conducted at 18 study sites [Trial registration number:
CTRI/2010/091/003029]. The study protocol was approved
by the ethics committee at each center and, all subjects gave
written, informed consent prior to enrolment or performance
of any study related procedures. The study was conducted in
conformance with the guidelines for ethical treatment of human
subjects that have their origin in the Declaration of Helsinki and
its amendments and are consistent with the Guideline for Good
Clinical practice [ICH GCP E6] and applicable local regulatory
Male and female subjects eligible for inclusion in the trial
were aged 18 to 65 years with persistent asthma, as defined by
the GINA 2007 guidelines  and using an ICS (≥400μg and
≤800μg of beclomethasone dipropionate (BDP) or equivalent
per day) for at least 4 weeks prior to study entry. Symptomatic
subjects had a pre-bronchodilator forced expiratory volume in
one second (FEV1) of ≥60% and ≤90% of the predicted normal
value and demonstrated a ≥12% and 200 mL improvement
in FEV1 within 15-30 minutes after inhalation of salbutamol
(400μg). All subjects were able to perform the required
pulmonary function tests, and demonstrated correct use of the
Subjects were excluded if they had any of the following:
contraindication to ICS or LABA use; hypersensitivity to the
study medications or any of the excipients; lower respiratory
tract infection in the last 4 weeks prior to screening; chronic
obstructive pulmonary disease or other relevant pulmonary
disease other than asthma; any change in asthma therapy (other
than inhaled short-acting β2- agonists as rescue medication)
or admission to a hospital for the treatment of asthma within
4 weeks; and/or oral or systemic corticosteroid use within 4
weeks before study entry or >4 times during the preceding
12 months. Subjects were also excluded if they had a smoking
history of ≥10 pack years or clinically relevant abnormal
This was a randomized, double-blind, double-dummy, parallel
group 12-week non-inferiority study comparing a combination
pMDI containing hydrofluoroalkane (HFA)-propelled fluticasone
propionate 125 mcg and salmeterol 25 mcg (FP/SM 125/25mcg)
(Cipla Ltd, India) with two single pMDIs taken concurrently:
one containing HFA-propelled fluticasone propionate 125μg
(FP 125mcg) (Flixotide Evohaler TM Allen and Hanburys, UK)
and the other containing chlorofluorocarbon (CFC)-propelled
salmeterol 25μg (SM 25mcg) (Serevent TM Allen and Hanburys,
Eligible subjects were randomized (1:1) by means of a
computer-generated randomization list to receive the fixed dose
combination of FP/SM 125/25mcg or concurrent FP 125mcg
and SM 25mcg. Subjects underwent a 3 to 4-week run-in period
during which they received only short-acting [β2-agonist rescue
medication (salbutamol as needed) and/or their regular ICS at a
Subjects were randomized at the end of the run-in period,
if they fulfilled two of the following criteria as recorded in the
diary card during the last 7 days of the run-in period.
Daytime symptom score (diary data) of ≥1 on any 2
Use of short-acting β2-agonists more than twice daily
on any 2 days.
Night-time symptoms score (diary data) of ≥1 on one
or more occasion.
Additionally, FEV1 at randomization had to be within 15% of
that recorded at the beginning of the 3- week run-in and had to
remain within the range of 60-90% predicted.
Clinic visits occurred in the morning at enrollment, after the
run-in period (baseline; week 0) and after 3, 6, 9 and 12weeks
of treatment. Procedures at each visit included spirometry
(FEV1) which was performed at the same time of the day (08:00
to 11:00), diary card assessment and vital-signs measurement.Safety measures included adverse events (assessed throughout
the study), vital signs and clinical laboratory parameters
(haematology, clinical chemistry and urinalysis; (assessed at
enrolment and at the end of the study).
The primary efficacy endpoint was the change in mean
morning peak expiratory flow (PEF) from baseline (mean of
the last 14 days of the run-in period) at week 12. Using a mini-
Wright PEF meter (Clement Clarke International, Ltd., Harlow,
United Kingdom), subjects recorded PEF twice daily (in the
morning and in the evening at fixed times 12 hours apart). At
each time point, 3 readings were obtained with the patient in
a standing position. All 3 values were entered into the diary by
The secondary efficacy end point was the change in
spirometry-derived FEV1 from baseline to study end or
discontinuation (12 weeks or last observation carried forward
[LOCF]) For spirometry assessments, 3 technically acceptable
FEV1 measurements were performed according to the American
Thoracic Guidelines  using a calibrated spirometer. All values
had to be within 200mL of each other. If the difference was larger,
measurements were repeated (up to 8 measurements), and
the largest value was reported. Asthma scores were recorded
on a 4-point scale, as follows: daytime: 0 = unrestricted usual
daily activities, no symptoms to 3 = symptoms severe; not able
to perform usual daily activities; nighttime: 0 = no symptoms,
slept through the night to 3 = awake most of the night because
of asthma. Diaries were collected at each study visit and were
checked by the investigators at each institution to ensure
completeness of entries.
Subjects were withdrawn from the study if they had an
asthma exacerbation requiring treatment with oral or systemic
corticosteroids, or used an asthma medication other than their
trial medications and rescue salbutamol
This study was designed to assess the non-inferiority of
FP/ SM 125/25mcg and concurrent FP 125mcg plus SM 25mcg.
The primary population for assessing non-inferiority was the
per-protocol population (PP). Analyses on the intent to treat
population (ITT) were also conducted as a supporting analysis.
An analysis of covariance with factors for treatment, baseline,
gender and age was used to assess non-inferiority. The test for
non-inferiority was 1-sided, at a 0.025 level of significance. Noninferiority
of FP/SM 125/25mcg versus concurrent FP 125mcg
plus SM 25mcg was claimed if the lower limit of the 97.5% CI for the difference between the treatments exceeded the noninferiority
margin of 20 L/min for mPEFR. In accordance, a
sample size of 132 subjects per treatment group was determined
to yield at least 90% power to show non-inferiority between
treatments assuming a common SD of 50L/min and using a
0.025 one-sided significance level.
Differences in the use of rescue medication and in asthma
symptom scores (daytime, and nighttime) were analyzed using
Cochran-Mantel-Haenszel test adjusted for centre effect.
Among the 460 subjects screened for the study, 360
(ITT population) subjects (151 men, 209 women; mean age,
41.3years) were randomized, of which 183 subjects were
randomized to the combination FP/SM 125/25mcg and 177
subjects to concurrent FP 125mcg plus SM 25mcg, 177 subjects)
(Figure 1). The treatment groups were similar with regard to
demographics and baseline clinical characteristics (Table 1).
Overall, 9 (2.5%) subjects were smokers or ex-smokers and
208 (57.7%) subjects were receiving treatment with an ICS at
the time of enrolment. In total, 20 subjects did not complete the
study. The most common reasons for not completing the study
were protocol violations and withdrawal of consent (Figure 1).
There were more subjects who did not complete the study in the
concurrent FP 125mcg plus SM 25mcg group than in the FP/
SM 125/25mcg group. All results reported below are for the PP
population. Results for the ITT population were similar to those
of the PP population for all endpoints.
The two treatment groups were similar with regard to
treatment compliance, with at least 96% of subjects in the FP/
SM 125/25 group and at least 94% of subjects in the FP 125 plus
SM 25 group showing treatment compliance.
At 12 weeks, the adjusted mean increase in the PP
population from baseline in morning PEF was 38.7 L/min in the
FP/SM 125/25mcg combination group versus 33.4L/min in the
concurrent FP 125mcg plus SM 25mcg group. The adjusted mean
treatment difference was 5.2 L/min and the one sided 97.5%
confidence limit for the treatment difference was -3.6 to14.0L/
min indicating that the combination treatment was non-inferior
to the concurrent therapy Table 2 & Table 3.
As for PEFR, there was a clinically relevant increase from
baseline in FEV1 in both the treatment groups after 12 weeks of
treatment. The adjusted treatment difference was -0.007L, with
a one sided 97.5% confidence limit of -0.061 to 0.047L Table 2,
Clinically relevant improvement from baseline was also
observed for median daytime and nighttime asthma symptom
scores after 12 weeks of treatment in both groups. Overall, the
percentages of subjects without any daytime asthma symptoms
(score, 0) increased from 0.6% to 61% in the FP/SM 125/25mcg
combination group and from 2.1% to 63.6% in the concurrent
FP 125mcg plus SM 25mcg group. Similar improvements were
observed for nighttime symptoms in both groups (Figure 3).
There were no differences between groups in the magnitude of
improvement in either daytime or nighttime symptoms.
The incidence of adverse events during the 12-week
treatment period was similar for the two treatment groups, with
97 (53%) subjects in the FP/SM 125/25 group and 83 (47%)
subjects in the FP 125 + SM 25 group reporting any adverse
event. Cough was the most common AE in both groups (n=27
(15%) with the combination treatment and n= 26 (15%) with
the concurrent treatment). There were 28 subjects (15%) and 21
subjects (12%) who reported headache and 20 subjects (11%)
and 21 subjects (12%) reported pyrexia in the combination and
concurrent treatments, respectively.
There was one serious adverse event (acute exacerbation
of asthma) occurring in the FP 125/ SM 25mcg combination
group leading to withdrawal from the study. This serious
adverse event was not related to the study medication, was of
moderate severity, and resolved by the end of the study. There
was one subject in each treatment group (including the subject
who experienced a serious adverse event) who dropped out of
the study due to adverse events. Most of the AEs were of mild
to moderate intensity and both treatments were generally well
tolerated. No clinically significant changes from baseline were
found in vital-sign measurements or laboratory tests in either
group throughout the study.
This study demonstrates that FP/SM 125/25mcg HFA pMDI
is at least as effective as concurrent administration of the monocomponents
from separate inhalers in improving pulmonary
function ( morning PEF and FEV1), asthma symptom scores, and
rescue medication use in subjects with persistent asthma. The
improvement in symptom-related endpoints was consistent
with the improvement observed with lung function parameters.
The results of this study are consistent with those reported
previously for the FP/SM combination product administered
via a dry powder inhaler. In these studies, the improvement in
adjusted mean morning PEFR over weeks 1-12 ranged from 35
L/min to 43 L/min in the combination therapy [14,15]. However,
unlike the prior studies, the current study was conducted with
a MDI rather than a breath-actuated dry-powder inhaler. This
is important since it has been widely established that critical
errors are common with MDI use, even with training, which can
lead to worsening of asthma control . The fact that subjects
in both groups had comparable improvements in all measures of
overall asthma control indicates that subjects received adequate
amounts of drug from the MDI devices used in the study.
Poor adherence with inhaled corticosteroid (ICS) therapy
in asthma is a major factor contributing to poor disease control
and is associated with an increased risk of morbidity and
mortality [1,2] Combination metered dose inhalers that include
both ICS and a LABA can potentially improve adherence and
long term compliance to asthma medications [18-21]. First, the
addition of a bronchodilator means the patient may obtain a
symptomatic benefit and therefore take the medication that also
delivers ICS more regularly. Second, it simplifies the medication
regimen (compared with an ICS and LABA taken separately), an
approach that has the potential to improve adherence [4,5]. In
addition, there are safety concerns regarding the use of LABAs
without concomitant ICS therapy in asthma [22-24] and the
use of a combination inhaler ensures that subjects will not take
LABAs as monotherapy. Finally, in addition to the comparable
improvements in efficacy for the two treatments, the overall AE
profiles were also comparable.
The results of this study indicate that in subjects with mild
to moderate persistent asthma. administration of FP/SM 125/25
HFA pMDI as a combination product was at least as effective
as concurrent administration of the mono-components in
improving overall asthma control as assessed by lung function,
asthma symptoms and rescue medication use.