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Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6–<12 years)
David S. Pearlman, MD
Correspondence information about the author MD David S. Pearlman
Email the author MD David S. Pearlman
,
Göran Eckerwall, MD, PhD
,
Julie McLaren, MD
,
Rosa Lamarca, PhD
,
Margareta Puu, PhD
,
Ileen Gilbert, MD
,
Carin Jorup, MD
,
Kristina Sandin, DDS
,
Miguel J. Lanz, MD
Open Access
DOI: http://dx.doi.org/10.1016/j.anai.2017.01.020
Article Info
Abstract
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References
Article Outline
Introduction
Methods
Patient Population and Eligibility
Study Design
Concomitant Medications
Efficacy and Safety Evaluations
Statistical Analyses
Results
Patients
Efficacy
Lung function
Symptom-Related Variables and Asthma Exacerbations
Health-Related Quality of Life
Safety and Asthma Worsening
Discussion
eSupplement
Adjunct Medication
Additional Exclusion Criteria
Sensitivity Analysis
References
Abstract
Background
The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old.
Objective
To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma.
Methods
This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting β2-agonist. Children symptomatic during a 7–28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 μg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 μg (160/9 μg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 μg (160/4.5 μg) BID (n = 95), or budesonide pMDI 80 μg (160 μg) BID (n = 92) for 12 weeks.
Results
Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 μg vs budesonide (P≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 μg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments.
Conclusion
Budesonide/formoterol pMDI 160/9 μg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 μg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone.
Trial Registration
ClinicalTrials.gov Identifier: NCT02091986.
Introduction
It is estimated that approximately 3 million (10.6%) children in the United States currently have asthma.1Guidelines from the National Asthma Education and Prevention Program identify the addition of a long-acting β2-agonist (LABA) to a low-dose inhaled corticosteroid (ICS) in a fixed-dose combination as a recommended step 3 treatment option for patients 5 to 11 years old with asthma to manage symptoms not adequately controlled by a low-dose ICS alone.2
Previous studies have provided evidence that budesonide/formoterol pressurized metered-dose inhaler (pMDI) has greater efficacy and a similar safety profile compared with budesonide alone in patients at least 12 years old with asthma[3], [4] and children 6 to younger than 12 years old with symptomatic asthma previously treated with an ICS alone.[5], [6] Morice et al5 reported a statistically significant improvement in morning peak expiratory flow (PEF; primary end point) budesonide/formoterol pMDI 80/4.5 μg × 2 inhalations (160/9 μg) twice daily (BID) versus budesonide pMDI 200 μg BID over 12 weeks, with similar safety profiles reported for the 2 treatments. In a 26-week safety study, Berger et al6 found no differences in the number or severity of adverse events (AEs) or clinically important safety variables (eg, serum glucose and potassium, heart rate, and electrocardiographic measurements) between budesonide/formoterol pMDI 320/9 μg BID versus budesonide 400 μg BID via dry powder inhaler (DPI). Secondary efficacy end points in the study showed greater benefit for pulmonary function and health-related quality-of-life (HRQoL) outcomes with the combination vs budesonide alone.6
The Childhood Asthma Safety and Efficacy (CHASE) program was developed in conjunction with the Food and Drug Administration (FDA). The objective of the program was to study the efficacy and safety of budesonide and formoterol as single agents and in combination in children 6 to younger than 12 years with asthma. A 6-week budesonide dose-confirmatory study (CHASE 1; NCT01136382) demonstrated statistically significant improvements in lung function (ie, morning PEF [primary outcome], forced expiratory volume in 1 second [FEV1], evening PEF, and forced expiratory flow between 25% and 75% of forced vital capacity [FEF25%–75%]) and asthma symptom variables (ie, reliever medication use, nighttime awakenings, and awakenings with reliever use) with budesonide pMDI 160 μg BID vs placebo.7 CHASE 2 (NCT01136655) was a formoterol dose-finding study, which compared the bronchodilatory effect of 3 single doses of formoterol pMDI (2.25, 4.5, and 9 μg), formoterol DPI (12 μg), and placebo in children with asthma.8 All formoterol pMDI doses and the DPI formulation showed significantly higher average 12-hour FEV1 (area under curve) vs placebo (primary outcome); the 2 higher pMDI dosages were statistically superior to the lowest formoterol pMDI dose and not significantly different from the 12-μg DPI dose. In addition, formoterol 4.5 μg and 9 μg, but not 2.25 μg, resulted in significant improvement in FEV1 at 12 hours after dosing vs placebo. The incidence of AEs was low in each formoterol dose group, and no serious AEs were reported.8
Based on the results of the budesonide dose-confirming CHASE 1 trial and the formoterol dose-finding CHASE 2 study and FDA feedback at an end-of-phase 2 meeting, this study, CHASE 3, evaluated the efficacy and safety of 2 fixed-dose combinations of budesonide/formoterol pMDI 160/9 μg or 160/4.5 μg BID compared with budesonide pMDI 160 μg BID alone in children 6 to younger than 12 years with persistent asthma symptoms when on low-dose ICS.
Methods
Patient Population and Eligibility
This study included patients 6 to younger than 12 years with a documented clinical diagnosis of asthma as defined by the American Thoracic Society9 for at least 6 months before the run-in visit (visit 2). Patients were required to have used medium-dose ICS or, alternatively, fixed-dose ICS plus LABA for at least 4 weeks before enrollment (visit 1). Patients on fixed-dose ICS plus LABA were switched to a comparable dose of ICS without LABA for at least 48 hours before the run-in visit.
During the run-in visit or before randomization (visit 3), FEV1 reversibility of at least 12% from pre-bronchodilator levels within 15 to 30 minutes after administration of a standard and equivalent dose of 2 to 4 inhalations of albuterol (90 μg per inhalation, labeled to reflect the dose delivered by the actuator mouthpiece; in the United States) or salbutamol (100 μg per inhalation, labeled to reflect the dose delivered from the canister valve; outside the United States) with or without a spacer or either drug given by nebulizer (2.5 mg) was required. At the run-in visit, patients were required to have a morning pre-bronchodilator clinic FEV1 value of 60% to 100% of predicted normal (measured ≥6 hours after the last dose of a short-acting β2-agonist [SABA] and ≥48 hours after the last dose of a LABA). Eligible patients demonstrated the ability to use a DPI for the run-in period and pMDI for the post-randomization period.
Exclusion criteria for the study included hospitalization or emergency treatment for asthma within 6 months before enrollment, treatment, for any reason, with systemic corticosteroids within 6 weeks before enrollment or during the run-in period, or with a β-blocker (including eye drops), or omalizumab, or other monoclonal or polyclonal antibody therapy within 6 months before the run-in visit. The eSupplement (available online) provides additional exclusion criteria and adjunct medication information.
This study was performed in accordance with ethical principles based on the Declaration of Helsinki and its conduct was consistent with International Conference on Harmonization and Good Clinical Practice guidelines and all applicable regulatory requirements. The final study protocol, protocol amendments, and informed consent and assent forms were approved by institutional review boards in each country or region or at each center in accordance with national regulations. After an informed consent and assent process, patients provided written informed consent or assent before enrollment and any study-related activities.
Study Design
This was a phase 3, randomized, double-blinded, parallel-group, multicenter study (registered atwww.clinicaltrials.gov as NCT02091986) performed from April 2014 through April 2016 at 88 sites in the United States, Mexico, Panama, and Slovakia.
The study consisted of an enrollment visit; a run-in visit followed by a single-blinded 7- to 28-day run-in period on low-dose ICS (budesonide DPI 90 μg × 1 inhalation BID [80 μg delivered dose]); and a randomization visit followed by a 12-week, randomized, double-blinded treatment period, including clinic visits at weeks 2, 4, 8, and 12. A follow-up telephone call approximately 2 weeks after the final study visit was conducted to record information about ongoing AEs at the end of study treatment and to document any new AEs and concomitant medications after the end of study treatment.
Patients and parents or guardians were instructed on how to use the DPI (at the run-in visit) and the pMDI (at the randomization visit); inhaler technique was assessed, and further training was given as needed. To be eligible for randomization, patients were required, during the run-in, to have a total combined nighttime and daytime asthma symptom score of at least 1 (0, no symptoms; 1, mild symptoms; 2, moderate symptoms; 3, severe symptoms) or use of rescue medication on at least 4 of 7 consecutive days immediately preceding randomization. Patients also were required to have a predose morning clinic FEV1 of at least 55% (≥6 hours after the last dose of the SABA) at randomization and to not have an absolute increase of at least 5% of the absolute value between the run-in and randomization visits.
Eligible patients were stratified by age group (6–<9 or 9–<12 years) and randomly assigned within their stratum to receive 1 of the following 3 treatments for 12 weeks: budesonide/formoterol pMDI 80/4.5 μg × 2 inhalations (160/9 μg) BID; budesonide/formoterol pMDI 80/2.25 μg × 2 inhalations (160/4.5 μg) BID; or budesonide pMDI, 80 μg × 2 inhalations (160 μg) BID. Randomization was performed using an Interactive Voice Response System/Interactive Web Response System to ensure an even distribution between age groups.
To maintain blinding, no member of the study team at the study sites or contract research organizations had access to the randomization scheme during the study except those related to the drug supply chain. The randomization scheme was not disclosed until after the database lock.
Concomitant Medications
During the study, patients could use study-provided albuterol or salbutamol as needed. Prophylactic use of SABA for exercise-induced bronchoconstriction was permitted up to 2 times per week, if part of a regular exercise regimen.
Efficacy and Safety Evaluations
The primary objective was to demonstrate the efficacy of each budesonide/formoterol combination dose compared with budesonide alone in children 6 to younger than 12 years with asthma; the secondary efficacy objective was to compare the efficacy between the 2 doses of budesonide/formoterol. To determine the contribution of formoterol to the budesonide/formoterol combination compared with budesonide alone, the primary efficacy variable was the change from baseline predose clinic FEV1 (value at randomization, week 0) to the 1-hour postdose clinic FEV1 at week 12.
Secondary efficacy variables included other clinic lung function parameters (predose and 15-minute postdose FEV1, predose and 1-hour postdose forced vital capacity [FVC], predose and 1-hour postdose FEF25%–75%, and predose and 1-hour postdose PEF); Pediatric Asthma Quality of Life Questionnaire with Standardized Activities (PAQLQ[S]) scores (23-item patient-reported questionnaire in which each item is measured on a 7-point scale [eg, 1, extremely bothered/all of the time; 7, not bothered/none of the time]; overall score [mean of responses to each question]; and each of 3 domain scores [activity limitations, 5 items; symptoms, 10 items; emotional function, 8 items] are evaluated10); electronic diary (eDiary) variables; time to discontinuation of study drug; and time to occurrence of first protocol-defined asthma exacerbation.
An eDiary was completed by the patient with the help of the parent or guardian each morning and evening to capture morning and evening PEF, FEV1, reliever medication use, asthma symptom scores, and nighttime awakenings from asthma symptoms from the start of the single-blinded run-in period until the patient's last study visit.
Asthma exacerbations were defined as emergency department treatment, inpatient hospitalization, use of systemic steroids, or a change in symptoms requiring an alteration in maintenance asthma therapy.
The safety objective was to compare the safety of the 2 doses of budesonide/formoterol with that of budesonide alone. Safety variables included treatment-emergent AEs, serious AEs, and discontinuations because of AEs. Vital signs were assessed at each visit; physical examination, electrocardiogram, and laboratory analyses (blood) were evaluated at the run-in visit and end-of-study assessment visit or withdrawal from the study.
During the study, eDiary data were monitored for asthma worsening; patients were contacted for clinical evaluation if any of the following predefined criteria for asthma worsening were met on 2 days within any consecutive 7-day period: decrease in morning PEF of at least 15% from baseline (defined as the mean of all values during the 7-day run-in period immediately preceding the randomization visit); or nighttime awakening from asthma requiring reliever medication use; or at least 6 inhalations of albuterol or salbutamol per day for relief of asthma symptoms.
Statistical Analyses
A sample size of 93 patients in each treatment group was estimated to provide 90% power to detect a difference of 0.12 L in 1-hour postdose FEV1 with a common SD of 0.25 L using a 2-sided test at the 5% significance level. The study was not powered to detect a difference between the 2 budesonide/formoterol pMDI doses.
The efficacy analysis set included all randomized patients who received at least 1 dose of study medication and contributed post-baseline data for at least 1 efficacy end point. The safety analysis set included all randomized patients who took at least 1 dose of study medication and for whom data were collected after randomization. Patients who discontinued treatment were encouraged to remain in the study and attend scheduled visits. Primary analysis was based on all available data, regardless of whether patients had discontinued study treatment.
The primary efficacy end point was analyzed by a mixed model for repeated measures. All data collected for patients who remained in the study were included in the model with terms for treatment, age group, visit, and geographic region as factors and baseline FEV1 as a covariate. Treatment-by-visit interaction also was included in the model. Sensitivity analyses were performed on the primary variable to further assess effects of treatment under several scenarios (additional information in the eSupplement).
Secondary outcomes of predose and 1-hour postdose lung function variables evaluating change from baseline to week 12 were analyzed using a mixed model for repeated measures similar to that for the primary efficacy end point. For 15-minute postdose clinic FEV1, the change in FEV1 from predose at baseline to 15 minutes postdose at week 12 was compared between treatment groups using an analysis of cov