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

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.

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][7][8][9][10][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 [12]. 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 [13].
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. 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 requirements.

Inclusion and exclusion criteria
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 [16] 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 (FEV 1 ) of ≥60% and ≤90% of the predicted normal value and demonstrated a ≥12% and 200 mL improvement in FEV 1 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 pMDI.
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 laboratory parameters.
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 constant dose.
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.

I.
Daytime symptom score (diary data) of ≥1 on any 2 days.
II. Use of short-acting β2-agonists more than twice daily on any 2 days.
III. Night-time symptoms score (diary data) of ≥1 on one or more occasion.
Additionally, FEV 1 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.

Study visits
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 (FEV 1 ) 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).

Efficacy assessments
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 patient.
The secondary efficacy end point was the change in spirometry-derived FEV 1 from baseline to study end or discontinuation (12 weeks or last observation carried forward [LOCF]) For spirometry assessments, 3 technically acceptable FEV 1 measurements were performed according to the American Thoracic Guidelines [16] 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.

Tolerability assessment
Tolerability was assessed using physical examination, vitalsigns measurements; standard laboratory parameters and assessments of AEs.

Study withdrawal
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

Statistical analysis
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.

Study population
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.

Morning peak expiratory flow
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.

Forced expiratory volume in 1 second
As for PEFR, there was a clinically relevant increase from baseline in FEV 1 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, Figure 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.

Rescue medication use
There was a clinically relevant decrease from baseline in rescue medication use (mean number of puffs/day) in both treatment groups (PP population) after 12 weeks of treatment ( Figure 3).

Tolerability
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.

Discussion
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 FEV 1 ), 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 [17]. 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][19][20][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][23][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.

Conclusion
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.