Patients aged between 18 to 60 years, body mass index between 18.5 to 30 kg/m², and receiving pharmacotherapy for asthma in 6 months preceding screening: either inhaled corticosteroids or inhaled long-acting β₂ agonists, or a combination of both the drugs were qualified for study enrollment. Asthma was defined as per the definition by the Global Initiative for Asthma Workshop Report 2004, as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment⁸.

After a written informed consent, patients were washed out from existing treatments as follows: Oral corticosteroids: month; Parenteral corticosteroids: 1 month; inhaled anticholinergics: 24 hours; inhaled cromolyn or nedocromil sodium: 1 month; oral short-acting β₂ agonist: 12 hours; oral long-acting β₂ agonists: 24 hours; inhaled long-acting β₂ agonists: 24 hours; anti-histamines: 72 hours; and oral and parenteral macrolide antibiotics: 30 days. All patients had a forced expiratory volume in 1 second (FEV₁) between 40% and 80% of predicted normal, and showed bronchodilator reversibility to salbutamol of ≥12% and ≥0.20 L in FEV₁.

This was a 4-week, multicenter (8 centers in India), randomized, open-label, active-controlled study. Eligible patients discontinued use of their current asthma therapy, underwent washout as applicable and entered a 2-week run-in period when they were permitted use of salbutamol through a pressurized metered dose inhaler (2 puffs of 100 mcg per actuation) as rescue medicine for relief of asthma symptoms as needed. Patients recorded their morning and evening peak expiratory flow rates (PEFR), use of rescue medication, and daytime and nighttime asthma symptoms in a daily diary.

Women of child bearing potential had to be practicing an acceptable method of birth control for the duration of the study as judged by the investigator(s), [such as condoms, foams, jellies, diaphragm, intrauterine device (IUD), oral or log acting injected contraceptives] for atleast 2 months prior to study entry, or be postmenopausal for at least 1 year, surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy has been performed on the subject), with a negative urine pregnancy test. Patients with history or presence of: allergy or hypersensitivity or idiosyncratic reactions to fluticasone and salmeterol; severe exacerbation of asthma that required hospitalization in last 2 months; occupational asthma; change of asthma medication in preceding 4 weeks; associated COPD; active respiratory tract infection; alcohol dependence, alcohol abuse or drug abuse or addiction with any recreational drug within past one year; and inability to follow use of DPI correctly were excluded.

After the run-in period, patients who met the following criteria were randomized 1:1 to receive SPARC device S/FP 25/250 mcg or Seretide Accuhaler^® (GSK) S/FP 25/250 mcg: past use of inhaled corticosteroids: no more than 12 puffs per day of salbutamol for more than 3 of last 7 days of 2-week run-in; past use of inhaled long-acting β₂ agonists: no more than 6 puffs per day of salbutamol for more than 3 of last 7 days of 2-week run-in; patients who awakened due to asthma: no more than 3 of last 7 nights during 2-week run-in; and FEV₁ within +15% of the screening value and within 40- 80% of the predicted normal. Twice daily S/FP was administered in morning and evening for 4 weeks. Patients were provided with salbutamol pressurized metered dose inhaler (pMDI) as rescue medication. Other asthma medications were not allowed during the study.

After baseline visit, follow-up clinic visits were scheduled in the morning at weeks 1, 2, 3, and 4 after randomization. Patients experiencing worsening of asthma were withdrawn from the study per following criteria: best pre dose FEV₁ obtained is 20% below the value obtained at baseline pre dose FEV₁; or any of the following occur: there were equal to or more than 2 days in which 12 or more puffs of salbutamol/ day were used, there were equal to or more than 2 nights in which awakenings due to asthma required treatment with salbutamol, there were equal to or more than 3 days when PEFR values fell below baseline i.e. 20% decrease in the mean morning PEFR recorded on the diary cards from the 7 days preceding a clinic visit.

Morning peak expiratory flow (PEF; primary variable) assessed the efficacy of twice-daily dosing with S/FP DPI 25/250 mcg at the end of the 12-hour dosing interval. Evening PEF also was assessed. PEF measurements were to be made ≥6 hours after rescue medication use whenever possible and always before dosing with study medication. Measurements were recorded in a daily diary by the patient using a hand-held peak flow meter (Pulmopeak^®).

Secondary efficacy variables, determined by spirometry at clinic visits, included morning pre-dose FEV₁. Predose FEV₁ was assessed in all patients at baseline and weeks 1, 2, 3, and 4. FEV₁ reading was to be obtained in triplicate and the highest of three values was recorded. Prior to accepting a FEV₁ reading, a check for reproducibility was performed on a set of three values as follows: the highest forced vital capacity (FVC) of the three values (efforts) obtained is within 0.2 L of next highest FVC; the highest FEV₁ of the three values (efforts) obtained is within 0.2 L of next highest FEV₁. If any of the two above mentioned criteria had not been met, an additional spirogram was obtained. Subjects were to complete a daily diary for 4 weeks, recording in morning and evening, the severity and the frequency of asthma attacks, use of rescue medication, morning and evening PEF, and night time and day time asthma symptom severity scores. A 5- point scale was used to describe any asthma related symptoms such as wheeze, shortness of breath or cough experienced during the day and during night. Daytime symptoms were rated on a 5-point scale as: 0- no symptoms; 1- symptoms for one short period during the day; 2- symptoms for two or more short periods during the day which did not affect normal daily activities; 3- symptoms for most of the day which did not affect normal daily activities; and 4- symptoms for most of the day which did affect normal daily activities. Nighttime symptoms were rated on a 5-point scale as: - no symptoms; 1- symptoms causing awakening once during the night; 2- symptoms causing awakening twice or more; 3- symptoms causing patient to be awake most of the night; 4- symptoms so severe that patient could not sleep. Subject’s global impression of change and investigator rated clinical global impression (CGI) of Change based on symptom relief were assessed relative to baseline at end-of-study. The 7 point scale was as follows: 1- very much improved, 2- much improved, 3- minimally improved, 4- no change, 5- minimally worse, 6- much worse, 7- very much worse.

Safety was evaluated based on adverse events (AEs), routine laboratory evaluations, vital signs, serum cortisol, and physical examinations. Information was derived by questioning subjects in general terms, by subjects’ spontaneous reports, or by observation. Routine laboratory investigations were performed at screening and end of study of study visits; and consisted of hemogram (hemoglobin, total and differential leucocyte counts and platelet count), blood glucose, and serum cortisol AM. Urinalyses was performed only at screening visit. All women subjects had to undergo a urine pregnancy test at screening. Physical examinations were performed at screening, during study visits and at end of study. The following body systems were assessed: ear-nose-throat, eyes, respiratory, cardiovascular, gastrointestinal, hepatic, genitourinary, neurological, hematopoietic-lymphatic, endocrine-metabolic, dermatological and musculoskeletal.

Efficacy analyses included data from all randomized patients who took any study medication and completed any morning evening PEF (primary variable) diary entries after randomization. Two-sided statistical tests were used, with statistical significance defined as p≤0.05. A sample size of 74 patients was estimated to provide 80% power to detect a change of at least 40 L/min from baseline (assuming population SD= 60 L/min) in the morning PEF. Safety analyses included data from all randomized patients who had taken a dose of randomized study medication. Analyses were conducted using the intent-to-treat and per-protocol populations.

Analysis of covariance (ANCOVA) was used to assess treatment by group differences and changes from baseline. The time course of responses to treatment was depicted through graphical displays. All tests are two-tailed and the significance level is ≤0.05.

Of the 137 patients who entered the run-in period, 113 were randomized and 96 completed the study without any major protocol violations (Fig. 2). Demographic and baseline clinical characteristics were similar across treatment groups (Table 1).

Pulmonary Function. Evaluation of pulmonary function variables measured at the end of the 4-week twice-daily dosing by ANCOVA revealed both S/FP doses led to significant (p< 0.0001) improvement over baseline (Table 2). A comparison of S/FP 25/250 mcg group and S/FP 50/500 group showed no statistically significant differences between the two. There was an immediate increase in the morning PEF, evening PEF, and FEV₁ after 1 week of treatment in the S/FP 25/250 mcg and S/FP 50/500 groups (an increase of 30.96 L/min, 37.82 L/min, and 0.26 L, and 23.79 L/min, 26.27 L/min, and 0.17 L/min respectively). Improvement in weeks 2, 3, and 4 continued though it was incrementally less compared with week 1 (Fig. 3A, 3B, 4). Change from baseline in morning PEF, evening PEF, and FEV₁ in the S/FP 25/250 mcg and S/FP 50/500 groups was 47.17 L/min, 50.71 L/min, 0.29 L and 40.94 L/min, 39.86 L/min, 0.25 L respectively at week 2; 60.44 L/min, 64.39 L/min, 0.34 L and 48.23 L/min, 49.36 L/min, 0.22 L respectively at week 3; and 65.98 L/min, 85.97 L/min, 0.33 L, and 56.28 L/min, 57.19 L/min, 0.27 L respectively at week 4. The S/FP 25/250 mcg group showed a trend towards more improvement than S/FP 50/500 mcg group (p=0.0769) in evening PEF (Table 2 and Figure 3A). Similarly, FEV₁ increased by 9.73% of predicted normal value in test group and 7.82% in reference group after 4-weeks of treatment.

Changes from baseline in rescue medication use and symptom-related variables were significantly better in both S/FP groups (p≤ 0.001, Table 3, Fig. 5). Over the 4-week randomized treatment period, the percentage of patients with a symptom-free day was greater in both treatment arms compared with baseline (p≤ 0.001, Table 3).

Nighttime asthma control variables (recorded in morning, approximately 12 hours after evening dose) were similar in both S/FP groups, with significantly improved scores compared to baseline (p≤ 0.001, Table 3). Significant differences from baseline were observed for symptom-free asthma days, asthma control days, and rescue medication-free days (p≤ 0.001, Table 3). Results were not significantly different between the two S/FP treatment groups for these variables.

The percentage of patients with clinically meaningful improvement from baseline was similar (97% to 100%) in both S/FP treatment groups.

Safety

Both treatments were well tolerated. Most AEs were mild (53%) or moderate (47%) in intensity. Overall AEs are presented in Table 4. One AE was considered drug related by the investigator (an episode of diarrhea that lasted 2 days and resolved with treatment). One patient discontinued because of a serious AE: patient randomized to S/FP 50/500 mcg developed cellulitis, however, the event was considered unrelated to drug. Both treatment groups were not associated with any clinical laboratory abnormalities. There was no clinically significant reduction in serum cortisol levels. No oropharyngeal candidiasis was reported. Physical examination and vital signs were within normal limits. There were no treatment emergent clinically significant abnormalities in electrocardiogram.

Figure 1

Figure 1. SPARCDry Powder Inhaler Device

Figure 2

Figure 2. Patient disposition. S = salmeterol xinafoate; FP = fluticasone propionate; DPI = dry powder inhaler; N = number of patients; ITT = intent to treat; PP = per protocol.

Figure 3

Figure 3. (A) evening and (B) morning PEF during the 4-week treatment period. Baseline was defined as the mean value for the last 7 days of the run-in period, excluding the day of randomization value. S = salmeterol xinafoate; FP = fluticasone propionate; DPI = dry powder inhaler; PEF = peak expiratory flow; b.i.d. = twice daily.

Figure 4

Figure 4. FEV during the 4-week treatment period. Baseline was defined as the mean value for the last 7 days of the run-in period, excluding the day of randomization value. S = salmeterol xinafoate; FP = fluticasone propionate; DPI = dry powder inhaler; FEV = forced expiratory volume in one second; b.i.d. = twice daily.

Figure 5

Figure 5. Percentage patients requiring rescue medication during the 4-week treatment period. Baseline was defined as the mean value for the last 7 days of the run-in period, excluding the day of randomization value. S = salmeterol xinafoate; FP = fluticasone propionate; DPI = dry powder inhaler; b.i.d. = twice daily.

Figure 6

Figure 7

Figure 8

Figure 9