Efficacy And Safety Evaluation Of A Dry Powder Inhaler Containing Salmeterol Xinafoate 25 Mcg/Fluticasone Propionate 250 Mcg In Subjects With Asthma: A Randomized, Open Label, Comparative, Active Controlled, Parallel Groups, And Multi-Centric Study.
S Bardapurkar ., H Dumra, V Karkhanis, V Chandarana, A Khoja, N Prasad, R Bhagat, A Keni, N Mumbai, S Mumbai
asthma, dry-powder inhaler, efficacy, fev1, fluticasone, pef, pulmonary function, safety, salmeterol, twice-daily dosing
S Bardapurkar ., H Dumra, V Karkhanis, V Chandarana, A Khoja, N Prasad, R Bhagat, A Keni, N Mumbai, S Mumbai. Efficacy And Safety Evaluation Of A Dry Powder Inhaler Containing Salmeterol Xinafoate 25 Mcg/Fluticasone Propionate 250 Mcg In Subjects With Asthma: A Randomized, Open Label, Comparative, Active Controlled, Parallel Groups, And Multi-Centric Study.. The Internet Journal of Asthma, Allergy and Immunology. 2008 Volume 7 Number 2.
Background: Dry powder inhalers have now an established role in inhalation therapy with wide variation in design characteristics impacting their suitability for use in different patient populations. SPARC device structure enables higher amount of the inhaled drug to be delivered to lungs, making possible a reduction in administered dose. Objective: This study was planned to compare efficacy and safety of SPARC device containing Salmeterol 25 mcg/Fluticasone Propionate 250 mcg with Seretide Accuhaler® (GSK) containing Salmeterol 50 mcg/Fluticasone Propionate 500 mcg. Methods: This was a 4-week, randomized, open-label, active-controlled, multicenter study (N= 113) of patients aged 18- 60 years with asthma, reversible bronchial obstruction, and FEV1 40- 80% of the predicted normal. After washout from ongoing asthma treatments, there was a 2-week run-in period when patients were permitted use of rescue medication (Salbutamol metered dose inhaler). Patients who successfully competed the run-in period with FEV1 40- 80% of the predicted normal were randomized 1:1 to SPARC device or Seretide Accuhaler® for a 4-week treatment period. Patients received twice daily inhalation between 8.00 a.m. to 10.00 a.m. and between 8.00 p.m. to 10.00 p.m. with approximately 12 hour interval between the two doses.Results: The improvements in SPARC device group (S/FP 25/250 mcg) were similar to Seretide Accuhaler® group (S/FP 50/500 mcg). The FEV1 increased by 9.73% of predicted normal value in test group and 7.82% in reference group after 4-weeks of treatment. Although the S/FP 25/250 mcg group showed a trend towards more improvement than S/FP 50/500 mcg group in evening peak expiratory flow rate, all differences in subjective and objective outcome measures were not statistically significant. None of the safety measures included in this study showed important clinical differences between treatments. Conclusion: Administered at half the dose of Seretide Accuhaler®, the efficacy of Sun device is not statistically significantly different on efficacy parameters evaluated.
Asthma is one of the world's most prevalent diseases, affecting between 100 million and 150 million people, according to the World Health Organization (WHO). In the UK, 1400 people die on average each year, of which 90% of cases are preventable (based on statistics from Asthma UK). In the US, the American Lung Association claims that the disease affects over 20 million people and results in the death of over 5,000 people every year1. According to the National Family Health Survey-2 (NFHS-2) conducted during the period of 1998-99, the estimated prevalence of Asthma in India was 2468 per 100,000 persons2. The prevalence was higher in rural than in urban areas (2649 vs. 1966).
Dry powder inhalers (DPIs) store the pharmacologically active powder as large aggregates of fine micronized particles. The aggregates are dispensed into an aerosol by airflow through the inhaler. Drug delivery is actuated and driven by the patient's own inspiratory effort. DPIs have been available since 1967 and now have an established role in inhalation therapy. Multi-unit dose DPIs offers good patient convenience, particularly for combination therapies, and also better compliance3. All currently available DPIs are breath-actuated, thus the respirable cloud is produced in response to patient’s effort.
Seretide Accuhaler®, also marketed internationally under the name Advair Diskus™, is a combination of 2 well-accepted drugs (Salmeterol xinafoate and Fluticasone propionate), delivers 11% to 15% of drug to the lung4. It is a multi-unit dose inhaler that houses a coiled strip of 60 double foil-wrapped individual doses.
Sun Pharma Advanced Research Company Limited (SPARC Ltd.) has developed a new dry powder inhaler, ‘SPARC device’ (Fig. 1), whose aim is to help improve the treatment of asthma through greater user appeal and more efficient and consistent drug delivery. The device features include a reliable dose counter, a simple user interface and a discreet and robust, yet modern style expected to deliver the critical benefits required by healthcare professionals and patients. SPARC device is a breath-activated device that holds 60 doses. It is intuitive to use - simply open, inhale and close. SPARC’s device mechanism avoids duplication of doses during its use. Also currently available inhaler devices that are designed to deliver medication directly to the lungs have serious design shortcomings due to which, small fraction of the administered drug reaches the lungs (5-15%5), majority being deposited in the oropharynx.
SPARC device structure enables higher amount of the inhaled drug to be delivered to lungs, making possible a reduction in administered dose.
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.
Study Design and Treatment
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
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
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).
Changes from baseline in rescue medication use and symptom-related variables were significantly better in both S/FP groups (
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 (
Clinical Global Impression
The percentage of patients with clinically meaningful improvement from baseline was similar (97% to 100%) in both S/FP treatment groups.
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.
The range of DPI’s that are currently available falls into three device categories: single-unit dose inhalers in which each dose is loaded into the device before use; multi-dose reservoir inhalers in which a bulk supply of drug is preloaded into the device and multi-unit dose inhalers in which several single doses are individually sealed and discharged each time the device is actuated. As a result of the wide variation in design characteristics of the many DPIs available, their performance characteristics vary considerably and this may impact their suitability for use in different patient populations. The desirable criteria for an ideal device are: portable, robust, intuitive and provides feedback to let the patients understand that the dose has been correctly taken, guaranteeing an accurate and consistent dose delivery. Seretide Accuhaler® is a simple-to-use multi-unit device which created an accepted standard in pulmonary delivery and disease treatment that only a few years ago could not have been anticipated.
The primary goal of this study was to test the clinical efficacy of half the dose administered with SPARC device, S/FP 25/250 mcg, stabilize asthma using a twice-daily dosing regimen and then determine whether asthma control could be maintained clinically. This was compared with Seretide Accuhaler® group (S/FP 50/500 mcg).
The present study showed significantly greater effects on pulmonary function and asthma control with both active treatments compared with baseline. Overall, the efficacy results suggested that despite the inhaled dose being half that of reference, the S/FP doses delivered via the SPARC device were comparable to dose delivered from Seretide Accuhaler® device. The SPARC device group was similar to the Seretide Accuhaler® group in terms of improvements in pulmonary function tests (morning and evening PEFR, FEV1), rescue medication use, nighttime and daytime asthma symptoms, and global impression of change.
The improvement in symptoms of asthma was indicated by clinically and statistically significant improvement in symptom control (nighttime and daytime asthma symptom scores) over the 4-week treatment period (
The present study suggested that there were no safety or tolerability concerns with the SPARC device. The dose of Salmeterol xinafoate 25 mcg and Fluticasone propionate 250 mcg via SPARC device, based on the onset and duration of effect, coupled with tolerability are therefore effective. In conclusion, Salmeterol xinafoate 25 mcg and Fluticasone propionate 250 mcg delivered via SPARC device provide rapid relief with enduring control and convenient bronchodilation for patients with asthma. Further studies to characterize the pharmacodynamic- pharmacokinetic correlation and dose-response at various dose levels, and trials with larger sample sizes are ongoing and planned.