Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Albuterol multidose dry powder inhaler and albuterol hydrofluoroalkane versus placebo in children with persistent asthma Y P Paul Y. Qaqundah, M.D.,1 Herminia Taveras, Ph.D., M.P.H.,2 Harald Iverson, Ph.D.,3 and Paul Shore, M.D., M.S.4 ABSTRACT Background: Many children struggle with albuterol hydrofluoroalkane (HFA) inhalers. Albuterol multidose dry powder inhaler (MDPI) may simplify rescue bronchodilator use in children. Objective: To demonstrate the comparability of albuterol MDPI and albuterol HFA in children with asthma. Methods: This phase II, multicenter, double-blind, double-dummy, single-dose, five-period, crossover study randomized patients (ages 4 –11 years) with persistent asthma and prestudy forced expiratory volume in 1 second (FEV1) of 60 –90% of predicted to 1 of 10 treatment sequences that contained albuterol MDPI (90 and 180 g), albuterol HFA (90 and 180 g), and placebo MDPI and placebo HFA. Efficacy was evaluated by measuring the area under the baseline-adjusted percent-predicted FEV1–time curve over 6 hours (PPFEV1 AUC0 – 6) after dosing. Safety was evaluated by adverse events. Results: The full analysis set included 61 patients. Albuterol MDPI and albuterol HFA significantly improved PPFEV1 AUC0 – 6 versus placebo (p ⱕ 0.0107). Mean improvement (⫾ standard error [SE]) in PPFEV1 AUC0 – 6 versus placebo with albuterol MDPI at 90 and 180 g was similar (21.2 ⫾ 4.87 [95% confidence interval {CI}, 11.60 –30.81], and 22.6 ⫾ 4.87 [95% CI, 13.00 –32.20], %䡠hour, respectively). Mean improvement (⫾ SE) with albuterol HFA 180 g was significantly (p ⫽ 0.0226) greater versus albuterol HFA 90 g (23.7 ⫾ 4.85 [95% CI, 14.13–33.23], and 12.5 ⫾ 4.85 [95% CI, 2.93–22.05], %䡠hour, respectively). All doses of albuterol were well tolerated. Conclusion: Albuterol MDPI 90 and 180 g and albuterol HFA 180 g provided similar and significant FEV1 improvements versus placebo; albuterol HFA 90 g was significant versus placebo but seemed less effective based on absolute improvements in FEV1. ClinicalTrials.gov identifier: NCT01899144 (Allergy Asthma Proc 37:350 –358, 2016; doi: 10.2500/aap.2016.37.3986) T A O N pproximately 6.8 million children in the United States currently have asthma, a chronic respiratory disorder that causes chest tightness, shortness of breath, wheezing, and cough as a result of inflammatory and hyperreactive airway obstruction.1–3 Albuterol, a short-acting 2 adrenergic agonist, has a bron- O D From the 1Department of Pediatrics, Hoag Medical Group, Huntington Beach, California, 2Clinical Research and Development, Teva Pharmaceuticals, Miami, Florida, 3 Statistics Department, Teva Pharmaceuticals, Miami, Florida, and 4Clinical Research and Development, Teva Pharmaceuticals, Frazer, Pennsylvania This study was sponsored by Teva Branded Pharmaceutical Products R&D, Inc. Medical writing assistance was provided by Lisa Feder, Ph.D., Peloton Advantage, and was funded by Teva Branded Pharmaceutical Products R&D, Inc. Teva provided a full review of the article H. Taveras and H. Iverson are employees of Teva Pharmaceuticals, Miami, Florida. P. Shore was an employee of Teva Pharmaceuticals, Frazer, Pennsylvania, at the time of manuscript preparation. P.Y. Qaqundah has no conflicts of interest pertaining to this article Presented in poster format at the American Academy of Allergy, Asthma & Immunology annual scientific meeting, Los Angeles, California, March 4 –7, 2016. A subset of the data was presented in poster format at the American Thoracic Society International Conference, San Francisco, California, May 13–18, 2016 Address correspondence to Paul Y. Qaqundah, M.D., Hoag Medical Group, 19582 Beach Blvd., Suite 350, Huntington Beach, CA 92648 E-mail address: [email protected] Published online August 15, 2016 Copyright © 2016, OceanSide Publications, Inc., U.S.A. 350 O C chodilatory effect that rapidly reverses acute airflow obstruction and alleviates the symptoms of an acute asthma attack.3 The safety and efficacy of long-term inhaled albuterol use is well documented.4 Until recently, the only available inhaler device for delivery of albuterol was the metered-dose inhaler (MDI), which delivers the drug in aerosolized form. Usage errors with MDIs are common, especially in children, because these inhalers require the coordination of actuation with inhalation.5,6 Good inhaler technique is an important aspect of asthma control.7 Proper use of an MDI can be difficult for patients to learn, as demonstrated by two studies, one of which found that ⬎65% of patients failed to use their MDI correctly even after instruction8 and another that found that half of the pediatric patients (55%) enrolled (ages 6 –10 years) used MDIs improperly.9 The inability to coordinate manual actuation with inhalation may compromise drug delivery to the airways, which potentially results in suboptimal efficacy.6 A novel, inhalation-driven, albuterol multidose dry powder inhaler (MDPI) that does not require patient coordination of device actuation with inhalation has been developed with the goal of reducing administra- September–October 2016, Vol. 37, No. 5 Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm tion errors associated with conventional MDIs. An albuterol MDPI (ProAir RespiClick; Teva Pharmaceuticals, Inc., Frazer, PA), approved in March 2015 by the U.S. Food and Drug Administration for adolescent and adult patients with reversible bronchospasm, has been shown to provide efficacy and safety comparable with those of an available albuterol hydrofluoroalkane (HFA) inhaler.10,11 Satisfaction with this device was recently assessed in an open-label study that included patients ⱖ4 years of age with asthma or chronic obstructive pulmonary disease: 83% of the patients reported being somewhat to very satisfied with the MDPI with an integrated dose counter, 92% were satisfied with the ease of holding and handling the inhaler, and 85% were satisfied with the ease of learning to use the inhaler.12 This article reports on a study that was designed to demonstrate the comparability of albuterol MDPI and albuterol HFA in children with persistent asthma. onate per day or equivalent), leukotriene modifiers, or inhaled cromones, or on 2-agonists alone as needed, for a minimum of 4 weeks before the screening visit and with the expectation of maintenance for the duration of the study. Patients were required to have a forced expiratory volume in 1 second (FEV1) value of 60 –90% predicted for age, height, and sex, and to demonstrate at least 15% reversibility of FEV1 within 30 minutes after inhalation of 180 g of albuterol. In addition, patients were required to demonstrate an acceptable inhalation technique with both the MDPI and the HFA, and be able to self-perform spirometry and peak expiratory flow (PEF) measurements. METHODS Y P Study Description This was a phase II, randomized, double-blind, double-dummy, placebo-controlled, single-dose, five-treatment, five-period, ten-sequence, five-way crossover study of pediatric patients at 14 sites across the United States (ClinicalTrials.gov identifier: NCT01899144; study number: ABS-AS-201). The objective of the study was to demonstrate the comparability of albuterol MDPI and albuterol HFA for the treatment of persistent asthma in children ages 4 to 11 years. Ethical Conduct The study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice Consolidation Guideline (E6), and applicable regulations of the U.S. Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314, and European Union Directive 2001/20/EC.13 Before study initiation, the study protocol was submitted to the appropriate independent ethics committee or institutional review board for review and approval. The parents or guardians of all enrolled patients provided written, informed consent before any study-related procedures, and assent from the patients themselves was obtained when applicable. O D T O N Inclusion Criteria Patients who met the following criteria were eligible for inclusion in the study: boys or premenarchal girls between the ages of 4 and 11 years (inclusive) as of the screening visit, in otherwise good health, with a documented diagnosis of persistent asthma of at least 6 months’ duration and on stable low-dose inhaled corticosteroid (ⱕ200 g fluticasone propi- O C Exclusion Criteria Patients with a known hypersensitivity to albuterol or any inactive agent in the inhaler formulations, a history of respiratory infection or disorder that was not resolved within 4 weeks before the screening visit, an asthma exacerbation that required oral corticosteroids within 3 months or hospitalization within 6 months of the screening visit, an inability to tolerate or unwillingness to comply with the required washout periods, and/or a history of life-threatening asthma were ineligible for participation in the study. Patients who used prohibited concomitant medications, were treated with systemic corticosteroids within 6 weeks of the screening visit, participated in a previous albuterol MDPI trial at any time, or who received any investigational drug as part of a trial within 30 days of the screening visit were also ineligible. Study participants could not have any nonasthmatic acute or chronic conditions. Randomization Criteria The patients were randomized at the first treatment visit and were permitted to remain in the study if, before dosing at each treatment visit, they continued to be in good health, had not experienced any adverse event (AE) that would prevent further participation, had not used any prohibited concomitant medications, had not used rescue albuterol for at least 6 hours before each treatment visit, and were able to correctly use each inhaler device. Patient’s FEV1 level had to remain within 60 –90% of predicted value and ⫾20% of the study qualifying value measured at the screening visit, and patients could not have experienced an asthma exacerbation or upper respiratory tract infection or received any additional treatment for asthma. Study Design The study design is shown in Fig. 1. Eligible patients were randomized to 1 of 10 treatment sequences based on Latin squares that contained single doses of albuterol MDPI 90 g, albuterol MDPI 180 g, albuterol HFA 90 g, albuterol HFA 180 g, or placebo MDPI Allergy and Asthma Proceedings Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm 351 Figure 1. Study design. FEV1 ⫽ Forced expiratory volume in 1 second; HFA ⫽ hydrofluoroalkane; MDI ⫽ metered-dose inhaler; MDPI ⫽ multidose dry powder inhaler. and placebo HFA (0 g albuterol). The 90 and 180 g doses of albuterol HFA were chosen because they are the approved doses in pediatric patients.14 The 90 and 180 g doses of albuterol MDPI were chosen based on the approved doses of inhaled albuterol HFA in pediatric patients. The intent of the study was to demonstrate the comparability of albuterol MDPI and albuterol HFA inhalers. All the patients received inhalations from two separate MDPIs (active or placebo) and two separate HFAs (active or placebo) to deliver the appropriate doses while maintaining blinding. After the initial screening visit, each patient received one of the five treatments at five treatment visits over the study duration; each treatment visit was separated by a washout period of between 2 and 7 days. At each treatment visit, an initial FEV1 was measured at 30 minutes and again just before dispensation of the study treatment. Additional FEV1 measurements were taken at 5, 15, 30, 45, 60, 120, 180, 240, 300, and 360 minutes after treatment. Blood pressure and pulse rate measurements were recorded within 5 minutes before each FEV1 measurement for up to 4 hours to determine treatment effects. Patients received paper diaries to record morning PEF values between treatment visits, AEs, and the use of rescue medication. Albuterol HFA inhalers (ProAir HFA; Teva Respiratory, LLC, Horsham, PA) were provided as rescue medication. O D T O N Efficacy Spirometry was the primary measurement to evaluate study end points. Each center was provided with a standard spirometer, and site personnel received standardized training. Predicted FEV1 values were computed and adjusted for age, height, and sex for patients ages 4 to 5 years15 and for patients ages 6 to 11 years16 by using the American Thoracic Society/European Thoracic Society criteria applicable to pediatric patients.17 Serial FEV1 measurements (the highest of three acceptable maneuvers) were obtained at 5, 15, 30, 45, 60, 120, 180, 240, 300, and 360 minutes after the completion of study drug administration at each treatment visit. The primary efficacy end point was the baseline-adjusted area under the percentpredicted FEV1-versus-time curve over 6 hours (PPFEV1 AUC0 – 6 [%䡠hour]) after treatment. 352 Y P The baseline-adjusted area under the FEV1-versustime curve over 6 hours (FEV1 AUC0 – 6 [L䡠hour]) after treatment was the secondary efficacy end point. Additional efficacy end points included baseline-adjusted maximum FEV1 and maximum PPFEV1 values within 6 hours after treatment; time, in minutes, to increases of at least 15% and 12% in baseline PPFEV1 in patients within 30 minutes after treatment; duration, in hours, of 15% and 12% responses for those patients who responded within 30 minutes; response rate based on ⱖ15% and ⱖ12% increases in baseline PPFEV1 within 30 minutes after treatment; and time, in minutes, to maximum PPFEV1. O C Safety Safety assessments included tabulation of AEs and serious AEs (SAEs), including severity and relationship to study drug; SAEs were defined as AEs that resulted in death, life-threatening events, events that required or prolonged hospitalization, persistent or significant disability or incapacity, or congenital abnormality or birth defect. Other safety assessments included laboratory evaluations, physical examination findings, and a 12-lead electrocardiogram result. Vital signs were documented, which coincided with FEV1 measurement intervals for up to 4 hours after dosing at each treatment visit. Statistics The intent-to-treat (ITT) population included all randomized patients based on the treatment initially assigned, regardless of the treatment received. All patients in the ITT population who had a baseline assessment at the screening visit and received at least one dose of the study medication with at least one postbaseline assessment were included in the full analysis set, which was the primary analysis set for efficacy parameters. The per-protocol population consisted of all randomized patients who had no major protocol violations determined before unblinding and served as the supportive population. The safety population included all patients in the ITT population who received at least one dose of the study medication. The primary statistical tool was the mixed-effect analysis of variance with fixed effects of sequence, September–October 2016, Vol. 37, No. 5 Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm treatment group, and period; and the random effect for the patient within sequence. An appropriate contrast was derived from this model for the following comparison of interest with respect to the primary efficacy variable, PPFEV1 AUC0 – 6 (%䡠hour): the mean difference between each active group and placebo at each dose level, tested in a sequential manner. The sequential order of comparisons was albuterol MDPI 180 g with placebo, albuterol MDPI 90 g with placebo, albuterol HFA 180 g with placebo, and albuterol HFA 90 g with placebo. Each test was two-sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential manner of performing the tests ensured that the overall alpha level for the entire series was not ⬎0.05. Table 1 Patient demographics and baseline clinical characteristics (ITT population) (N ⴝ 61) RESULTS Sex, no. (%) Boys Girls Age, mean ⫾ SD, y Race, no. (%) White Black Other Height, mean ⫾ SD, cm Weight, mean ⫾ SD, kg BMI, mean ⫾ SD, kg/m2 Duration of asthma, no. (%) 6 mo to ⬍1 y 1 to ⬍5 y 5 to ⬍10 y 10 to ⬍15 y Airway reversibility, mean ⫾ SD, % Baseline PPFEV1, mean ⫾ SD, % Patients Of the 102 patients, ages 4 to 11 years, who were screened for inclusion in the study, 33 did not meet inclusion criteria, 3 were lost to follow-up, 1 withdrew consent, and 4 did not pass the screening for other causes, which resulted in 61 patients who met the eligibility criteria and were randomized into the study. All 61 enrolled patients were assessable for efficacy and safety. The per-protocol analysis included 56 patients, and 57 of the 61 enrolled patients completed the study. A total of four patients (7%) withdrew from the study, all for other reasons (erroneously randomized at treatment visit 1; did not meet FEV1 criteria; package insert discretion; did not meet ⬍20% change in FEV1 from qualifying value at screening at treatment visit 2 after 3 attempts). No patients died or discontinued due to AEs. Patient demographics and baseline clinical characteristics are summarized in Table 1. All patients had asthma that was diagnosed at least 6 months before participation in the study, and eight patients had a ⱖ10-year history of asthma. Most of the patients had no previous experience with a dry powder inhaler, and only one patient had no experience with an MDI. O D Efficacy Baseline-adjusted PPFEV1 AUC0 – 6 was significantly greater in all active treatment groups compared with patients who received placebo (p ⱕ 0.0107) (Table 2 and Fig. 2). The patients treated with albuterol MDPI 90 g and 180 g had similar increases in PPFEV1 AUC0 – 6 (Table 2), whereas patients treated with albuterol HFA 180 g had significantly greater PPFEV1 AUC0 – 6 than those treated with albuterol HFA 90 g (p ⫽ 0.0226) (Table 2). Similar patterns were seen in baseline-adjusted FEV1 AUC0 – 6, maximum FEV1 value over 6 hours, and maximum PPFEV1 over 6 hours after treatment (Table 3). The mean and median times to O C Y P 28 (46) 29 (48) 4 (7) 138.7 ⫾ 10.2 38.2 ⫾ 12.8 19.5 ⫾ 4.35 1 (2) 22 (36) 30 (49) 8 (13) 24.1 ⫾ 10.2 72.9 ⫾ 7.2 ITT ⫽ Intent-to-treat; SD ⫽ standard deviation; BMI ⫽ body mass index; PPFEV1 ⫽ percent-predicted forced expiratory volume in 1 second. T O N 38 (62) 23 (38) 9 ⫾ 1.6 12% and 15% response onset among patients who had such responses were comparable between patients treated with albuterol MDPI and those who received albuterol HFA (Table 4). All active treatments resulted in a shorter time to maximum PPFEV1 (⬃45 to 50 minutes) compared with patients who received placebo; no difference was noted between the 90 and 180 g doses for either albuterol MDPI or albuterol HFA (Table 4). Based on a ⱖ15% increase in FEV1 over baseline within 30 minutes after dosing, all active groups had significantly higher response rates than placebo (response rate, 17%; p ⱕ 0.0119), although the response rate with albuterol MDPI (45– 46%) was somewhat greater than the rate for albuterol HFA 90 g (37%) or albuterol HFA 180 g (41%) (Table 4). Using a threshold of ⱖ12% increase in FEV1 value from baseline within 30 minutes of dosing, the response rate was greater than for placebo in all active groups but highest for albuterol MDPI (57–58% for albuterol MDPI; 54% for albuterol HFA 90 g; 47% for albuterol HFA 180 g versus 20% for placebo; p ⱕ 0.0007) (Table 4). Safety There were no deaths or SAEs, and no withdrawals due to AEs. There were two reported AEs after treatment with albuterol MDPI 180 g (otitis media and urticaria), and there were no AEs associated with albuterol MDPI 90 g. Six AEs were reported by five patients after treatment with albuterol HFA 90 g, Allergy and Asthma Proceedings Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm 353 Table 2 Primary efficacy end point, baseline-adjusted PPFEV1 AUC0 – 6 (%䡠hr) (full analysis set) n Mean ⫾ SE 95% CI Active–placebo Mean ⫾ SE 95% CI p Value 90 g–180 g Mean ⫾ SE 95% CI p Value Placebo (N ⴝ 61) Albuterol MDPI 90 g (N ⴝ 61) Albuterol MDPI 180 g (N ⴝ 61) Albuterol HFA 90 g (N ⴝ 61) Albuterol HFA 180 g (N ⴝ 61) 59 25.4 ⫾ 6.25 12.94–37.81 58 46.6 ⫾ 6.27 34.13–59.07 59 48.0 ⫾ 6.24 35.56–60.39 59 37.9 ⫾ 6.25 25.43–50.30 59 49.1 ⫾ 6.26 36.61–61.50 21.2 ⫾ 4.87 11.62–30.81 ⬍0.0001 22.6 ⫾ 4.87 13.00–32.20 ⬍0.0001 12.5 ⫾ 4.85 2.93–22.05 0.0107 ⫺1.4 ⫾ 4.88 ⫺11.00 to 8.23 0.7772 O C Y P 23.7 ⫾ 4.85 14.13–33.23 ⬍0.0001 ⫺11.2 ⫾ 4.87 ⫺20.80 to ⫺1.59 0.0226 PPFEV1 ⫽ Percent-predicted forced expiratory volume in 1 second; AUC0 – 6 ⫽ area under the curve over 6 hr; MDPI ⫽ multidose dry powder inhaler; HFA ⫽ hydrofluoroalkane; SE ⫽ standard error; CI ⫽ confidence interval. including headache, constipation, diarrhea, and pyrexia. One patient reported upper abdominal pain after treatment with albuterol HFA 180 g, and one case of viral gastritis was reported in a patient who received placebo. There were no clinically significant effects on vital signs or other safety parameter findings. O D T O N DISCUSSION In this phase II, single-dose, five-way crossover study, children with asthma treated with albuterol MDPI and with albuterol HFA, each at dosages of 90 and 180 g, experienced significant improvements in baseline-adjusted PPFEV1 AUC0 – 6 (the primary efficacy end point) compared with the patients who received placebo. The magnitude of effect was similar in patients treated with albuterol MDPI 90 g and 180 g, whereas improvement from baseline was greater in patients treated with albuterol HFA 180 g compared with albuterol HFA 90 g; PPFEV1 AUC0 – 6 in the albuterol HFA 180 g group was similar to that observed in both the albuterol MDPI 90 g and 180 g groups. This pattern was repeated for most of the secondary end points as well. Time to onset and duration of effect, whether measured by ⱖ12% or ⱖ15% response, were similarly greater than placebo with all active treatments. Both albuterol MDPI and albuterol HFA were generally well tolerated, with no SAEs or study withdrawals due to AEs. In a similar randomized, double-blind, placebo-controlled, single-dose, five-way crossover study, 71 adult patients were treated with albuterol MDPI 90 g, albuterol MDPI 180 g, albuterol HFA 90 g, albuterol HFA 180 g, or placebo.11 Although similar to the present study in that patients in all active treatment groups experienced significant (p ⬍ 0.0001) improvements from baseline in PPFEV1 AUC0 – 6, the adult study differed from the pediatric study in that there was no difference between the response of the adult patients treated with albuterol HFA 90 g and albu- Figure 2. Mean percent-predicted FEV1 by treatment and time point (full analysis set). FEV1 ⫽ Forced expiratory volume in 1 second; HFA ⫽ hydrofluoroalkane; MDPI ⫽ multidose dry powder inhaler. 354 September–October 2016, Vol. 37, No. 5 Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 3 Additional efficacy end points (full analysis set) Allergy and Asthma Proceedings Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm 59 0.48 ⫾ 0.14 0.20–0.76 0.40 ⫾ 0.10 0.21–0.59 ⬍0.0001 58 0.88 ⫾ 0.14 0.60–1.16 Albuterol MDPI 90 g (N ⴝ 61) 59 9.83 ⫾ 1.15 7.53–12.12 59 0.19 ⫾ 0.02 0.14–0.24 0.09 ⫾ 0.02 0.05–0.12 ⬍0.0001 58 0.27 ⫾ 0.02 0.23–0.32 ⫺0.01 ⫾ 0.02 ⫺0.04 to 0.02 0.5421 0.10 ⫾ 0.02 0.06–0.13 ⬍0.0001 59 0.28 ⫾ 0.02 0.24–0.33 ⫺0.05 ⫾ 0.10 ⫺0.23 to 0.14 0.6342 4.88 ⫾ 0.85 3.20–6.57 ⬍0.0001 4.38 ⫾ 0.85 2.70–6.06 ⬍0.0001 ⫺0.50 ⫾ 0.86 ⫺2.19 to 1.18 0.5578 59 14.71 ⫾ 1.15 12.42–17.00 58 14.21 ⫾ 1.16 11.91–16.51 3.38 ⫾ 0.85 1.70–5.06 ⬍0.0001 59 13.21 ⫾ 1.15 10.91–15.50 0.07 ⫾ 0.02 0.04–0.10 ⬍0.0001 59 0.26 ⫾ 0.02 0.21–0.31 0.26 ⫾ 0.10 0.08–0.45 0.0062 ⫺1.76 ⫾ 0.85 ⫺3.44 to ⫺0.08 0.0407 5.14 ⫾ 0.85 3.47–6.81 ⬍0.0001 59 14.97 ⫾ 1.15 12.67–17.26 ⫺0.03 ⫾ 0.02 ⫺0.06 to 0.00 0.0688 0.10 ⫾ 0.02 0.07–0.14 ⬍0.0001 59 0.29 ⫾ 0.02 0.24–0.34 ⫺0.19 ⫾ 0.10 ⫺0.38 to 0.00 0.0488 0.45 ⫾ 0.10 0.26–0.64 ⬍0.0001 59 0.93 ⫾ 0.14 0.65–1.21 59 0.74 ⫾ 0.14 0.46–1.02 59 0.93 ⫾ 0.14 0.65–1.20 0.45 ⫾ 0.10 0.26–0.64 ⬍0.0001 Albuterol HFA 180 g (N ⴝ 61) Albuterol HFA 90 g (N ⴝ 61) Albuterol MDPI 180 g (N ⴝ 61) MDPI ⫽ Multidose dry powder inhaler; HFA ⫽ hydrofluoroalkane; FEV1 ⫽ forced expiratory volume in 1 second; AUC0 – 6 ⫽ area under the curve over 6 hours; SE ⫽ standard error; CI ⫽ confidence interval. Baseline-adjusted FEV1 AUC0–6 (L䡠hr): secondary efficacy end point No. patients Mean ⫾ SE 95% CI Active–placebo Mean ⫾ SE 95% CI p Value 90 g–180 g Mean ⫾ SE 95% CI p Value Baseline-adjusted maximum FEV1 over 6 hr, L No. patients Mean ⫾ SE 95% CI Active–placebo Mean ⫾ SE 95% CI p Value 90 g–180 g Mean ⫾ SE 95% CI p Value Baseline-adjusted maximum percent-predicted FEV1 over 6 hr, % No. patients Mean ⫾ SE 95% CI Active–placebo Mean ⫾ SE 95% CI p Value 90 g–180 g Mean ⫾ SE 95% CI p Value Placebo (N ⴝ 61) O D O N T O C Y P 355 356 Response rate based on 15% increase in baseline PPFEV1 within 30 min Responders, no. (%) Model estimated rate ⫾ SE 95% CI Difference from placebo ⫾ SE 95% CI p Value Response rate based on 12% increase in baseline PPFEV1 within 30 min Responders, no. (%) Model estimated rate ⫾ SE 95% CI Difference from placebo ⫾ SE 95% CI p Value Time (min) to 15% response among responders within 30 min No. patients Mean ⫾ SD Median Min, max Time (min) to 12% response among responders within 30 min No. patients Mean ⫾ SD Median Min, max Time (min) to maximum PPFEV1 over 6 hr No. patients Mean p Value vs placebo p Value 90 g vs 180 g Duration (hr) of 15% response among responders within 30 min No. patients Mean ⫾ SD 10 (17.0) 0.10 ⫾ 0.04 0.01–0.18 Placebo (N ⴝ 61) 26 (44.8) 0.43 ⫾ 0.09 0.24–0.61 0.33 ⫾ 0.09 0.15–0.51 0.0006 Albuterol MDPI 90 g (N ⴝ 61) 33 (56.9) 0.59 ⫾ 0.09 0.43–0.76 0.45 ⫾ 0.09 0.27–0.64 ⬍0.0001 26 10.7 ⫾ 4.79 8.8 4.8, 18.5 33 11.9 ⫾ 7.20 8.9 3.1, 29.9 58 47.6 0.0130 — 26 2.8 ⫾ 2.37 — — — — — — — — 59 75.9 — — — — 12 (20.3) 0.14 ⫾ 0.05 0.04–0.24 27 10.4 ⫾ 6.96 8.0 4.7, 29.7 27 3.0 ⫾ 2.29 59 45.0 0.0054 0.7667 34 9.9 ⫾ 6.10 8.1 4.7, 29.7 22 2.4 ⫾ 2.21 59 50.1 0.0265 — 32 9.1 ⫾ 5.28 8.1 4.0, 29.4 22 9.4 ⫾ 5.41 8.4 4.0, 26.6 32 (54.2) 0.55 ⫾ 0.09 0.37–0.72 0.41 ⫾ 0.09 0.22–0.59 ⬍0.0001 24 2.8 ⫾ 2.48 59 44.7 0.0048 0.5363 28 9.7 ⫾ 5.70 8.3 4.1, 27.2 24 12.8 ⫾ 7.88 8.4 4.2, 28.7 28 (47.5) 0.47 ⫾ 0.09 0.29–0.64 0.33 ⫾ 0.09 0.14–0.51 0.0007 24 (40.7) 0.37 ⫾ 0.09 0.19–0.54 0.27 ⫾ 0.09 0.10–0.45 0.0027 22 (37.3) 0.30 ⫾ 0.08 0.14–0.47 0.21 ⫾ 0.08 0.05–0.37 0.0119 27 (45.8) 0.43 ⫾ 0.09 0.25–0.62 0.34 ⫾ 0.09 0.15–0.52 0.0005 34 (57.6) 0.60 ⫾ 0.08 0.43–0.77 0.46 ⫾ 0.09 0.28–0.64 ⬍0.0001 Albuterol HFA 180 g (N ⴝ 61) Albuterol HFA 90 g (N ⴝ 61) Albuterol MDPI 180 g (N ⴝ 61) Table 4 Response rates, time to response, and duration of response of albuterol MDPI versus albuterol HFA (full analysis set) O D O N T O C Y P September–October 2016, Vol. 37, No. 5 Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm MDPI ⫽ Multidose dry powder inhaler; HFA ⫽ hydrofluoroalkane; PPFEV1 ⫽ percent-predicted forced expiratory volume in 1 second; SE ⫽ standard error; CI ⫽ confidence interval; SD ⫽ standard deviation; min ⫽ minimum; max ⫽ maximum. 28 3.0 ⫾ 2.49 3.5 0.2, 5.9 32 2.7 ⫾ 2.35 2.3 0.2, 5.9 34 3.3 ⫾ 2.18 3.8 0.1, 5.9 33 3.2 ⫾ 2.24 3.7 0.1, 5.9 — — — — 2.3 0.2, 5.9 1.9 0.2, 5.9 2.9 0.1, 5.9 2.8 0.2, 5.9 — — Albuterol HFA 180 g (N ⴝ 61) Albuterol HFA 90 g (N ⴝ 61) Albuterol MDPI 180 g (N ⴝ 61) Albuterol MDPI 90 g (N ⴝ 61) Placebo (N ⴝ 61) Y P O C CONCLUSION In this study in children ages 4 to 11 years, albuterol MDPI was significantly more effective than placebo across all study end points and had similar safety and efficacy compared with albuterol HFA. Significant improvements in baseline-adjusted PPFEV1 AUC0 – 6 were observed with albuterol MDPI 90 g and 180 g in pediatric patients compared with patients who received placebo. Data from this clinical trial were reviewed by the U.S. Food and Drug Administration in their evaluation and, in April 2016, approval of the expanded indication for treatment of patients 4 years of age and older. T O N Median Min, max Duration (hr) of 12% response among responders within 30 min No. patients Mean ⫾ SD Median Min, max Table 4 Continued O D terol HFA 180 g. In addition, an exploratory analysis indicated that improvements in mean FEV1 AUC0 – 6 in patients treated with albuterol MDPI and albuterol HFA were not significantly different at both the 90and 180-g dosages. Similar to the present study, albuterol dry powder inhalers have been demonstrated to be safe, effective, and easy to use for children with persistent asthma.18 –20 Kemp et al.18 performed dose-ranging and 12-week efficacy and safety studies that compared aerosol and powder albuterol with placebo, and both studies showed similar efficacy and safety profiles between the two formulations. Limitations of this study included the single-dose design, the small patient numbers, and the lack of patient-preference questionnaires to assess inhaler preferences. The strengths of this study included the crossover design, the double-blind, double-dummy dosing, and the high rate of study completion achieved (57 of the 61 enrolled patients completed the study). REFERENCES 1. 2. 3. 4. 5. 6. 7. FastStats—Asthma. Updated: May 14, 2015. Centers for Disease Control and Prevention. Available online at http://www.cdc. gov/nchs/fastats/asthma.htm; accessed August 13, 2015. Albuterol oral inhalation. Updated: September 1, 2010. MedlinePlus. Available online at http://www.nlm.nih.gov/ medlineplus/druginfo/meds/a682145.html; accessed January 29, 2016. Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, U.S. Department of Health and Human Services, 2007. Ramsdell JW, Klinger NM, Ekholm BP, and Colice GL. Safety of long-term treatment with HFA albuterol. Chest 115:945–951, 1999. Burkhart PV, Rayens MK, and Bowman RK. An evaluation of children’s metered-dose inhaler technique for asthma medications. Nurs Clin North Am 40:167–182, 2005. Levy ML, Hardwell A, McKnight E, and Holmes J. Asthma patients’ inability to use a pressurised metered-dose inhaler (pMDI) correctly correlates with poor asthma control as defined by the Global Initiative for Asthma (GINA) strategy: A retrospective analysis. Prim Care Respir J 22:406 – 411, 2013. Baddar S, Jayakrishnan B, and Al-Rawas OA. Asthma control: Importance of compliance and inhaler technique assessments. J Asthma 51:429 – 434, 2014. Allergy and Asthma Proceedings Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm 357 8. 9. 10. 11. 12. 13. 14. Hardwell A, Barber V, Hargadon T, et al. Technique training does not improve the ability of most patients to use pressurised metered-dose inhalers (pMDIs). Prim Care Respir J 20:92–96, 2011. Scarfone RJ, Capraro GA, Zorc JJ, and Zhao H. Demonstrated use of metered-dose inhalers and peak flow meters by children and adolescents with acute asthma exacerbations. Arch Pediatr Adolesc Med 156:378 –383, 2002. ProAir RespiClick [package insert]. Horsham, PA: Teva Respiratory, 2016. Kerwin EM, Taveras H, Iverson H, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of albuterol (salbuterol) multidose dry-powder inhaler and ProAir® hydrofluoroalkane for the treatment of persistent asthma: Results of two randomized double-blind studies. Clin Drug Investig 36:55– 65, 2016. Given J, Taveras H, and Iverson H. Prospective, open-label evaluation of a new albuterol multidose dry powder inhaler with integrated dose counter. Allergy Asthma Proc 37:199 –206, 2016. Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance. Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, 1996. ProAir HFA [package insert]. Horsham, PA: Teva Respiratory, LLC, 2012. 15. 16. 17. 18. 19. 20. Eigen H, Bieler H, Grant D, et al. Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med 163:619 – 623, 2001. Quanjer PH, Borsboom GJ, Brunekreef B, et al. Spirometric reference values for white European children and adolescents: Polgar revisited. Pediatr Pulmonol 19:135–142, 1995. Beydon N, Davis SD, Lombardi E, et al. An official American Thoracic Society/European Respiratory Society statement: Pulmonary function testing in preschool children. Am J Respir Crit Care Med 175:1304 –1345, 2007. Kemp JP, Furukawa CT, Bronsky EA, et al. Albuterol treatment for children with asthma: A comparison of inhaled powder and aerosol. J Allergy Clin Immunol 83:697–702, 1989. Goren A, Noviski N, Avital A, et al. Assessment of the ability of young children to use a powder inhaler device (Turbuhaler). Pediatr Pulmonol 18:77– 80, 1994. Hagmolen of ten Have W, van de Berg NJ, Bindels PJ, et al. Assessment of inhalation technique in children in general practice: Increased risk of incorrect performance with new device. J Asthma 45:67–71, 2008. e T O D 358 Y P O C O N September–October 2016, Vol. 37, No. 5 Delivered by Ingenta to: ? IP: 5.10.31.211 On: Sun, 18 Jun 2017 07:54:11 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm