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The New England Journal of Medicine Dec 1997An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children. The role of long-acting beta2-adrenergic-receptor... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children. The role of long-acting beta2-adrenergic-receptor agonists, such as salmeterol, needs to be defined.
METHODS
We conducted a randomized, double-blind, placebo-controlled, parallel-group, one-year study of 241 children (mean [+/-SD] age, 9.3+/-2.4 years) with clinically stable asthma and less than one month of prior glucocorticoid use. We compared inhaled beclomethasone dipropionate (200 microg twice daily) with salmeterol xinafoate (50 microg twice daily) and placebo (lactose). The primary outcome measure, airway responsiveness (as assessed with a methacholine challenge) was evaluated before treatment; after 3, 6, 9, and 12 months of treatment (12 and 36 hours after study medications had been withheld); and 2 weeks after the end of treatment. Spirometry, symptoms, use of rescue medication (200 microg of albuterol inhaled as needed), and adverse effects were also assessed.
RESULTS
During months 1 through 12 overall, beclomethasone was associated with significantly less airway hyperresponsiveness than salmeterol (P= 0.003) or placebo (P<0.001). This effect was lost two weeks after treatment had been stopped. As compared with placebo, beclomethasone was associated with less variability between morning and evening in the peak expiratory flow (P=0.002), as was salmeterol (P=0.02). Beclomethasone was also associated with a reduced need for albuterol as rescue therapy (P<0.001) and fewer withdrawals because of asthma exacerbations (P=0.03), but salmeterol was not (P=0.09 and 0.55, respectively). During months 1 through 12, linear growth was 3.96 cm in the children receiving beclomethasone, as compared with 5.40 cm in the salmeterol group (P=0.004) and 5.04 cm in the placebo group (P=0.018). Height was not measured after treatment ended.
CONCLUSIONS
Beclomethasone was effective in reducing airway hyperresponsiveness and in controlling symptoms of asthma, but it was associated with decreased linear growth. Salmeterol was not as effective as beclomethasone in reducing airway hyperresponsiveness or in controlling symptoms; however, it was an effective bronchodilator and was not associated with rebound airway hyperresponsiveness, masking of symptoms, or adverse effects.
Topics: Administration, Inhalation; Adolescent; Adrenergic beta-Agonists; Albuterol; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchodilator Agents; Child; Double-Blind Method; Female; Glucocorticoids; Growth; Humans; Male; Placebos; Pulmonary Ventilation; Salmeterol Xinafoate
PubMed: 9385125
DOI: 10.1056/NEJM199712043372304 -
The Cochrane Database of Systematic... Apr 2016This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. The use of topical (intranasal) corticosteroids has been widely advocated for the treatment of chronic rhinosinusitis given the belief that inflammation is a major component of this condition.
OBJECTIVES
To assess the effects of intranasal corticosteroids in people with chronic rhinosinusitis.
SEARCH METHODS
The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 8); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015.
SELECTION CRITERIA
Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing intranasal corticosteroids (e.g. beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide) against placebo or no treatment in patients with chronic rhinosinusitis.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis. Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse events of local irritation or other systemic adverse events. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.
MAIN RESULTS
We included 18 RCTs with a total of 2738 participants. Fourteen studies had participants with nasal polyps and four studies had participants without nasal polyps. Only one study was conducted in children. Intranasal corticosteroids versus placebo or no intervention Only one study (20 adult participants without polyps) measured our primary outcome disease-specific HRQL using the Rhinosinusitis Outcome Measures-31 (RSOM-31). They reported no significant difference (numerical data not available) (very low quality evidence).Our second primary outcome, disease severity , was measured using the Chronic Sinusitis Survey in a second study (134 participants without polyps), which found no important difference (mean difference (MD) 2.84, 95% confidence interval (CI) -5.02 to 10.70; scale 0 to 100). Another study (chronic rhinosinusitis with nasal polyps) reported an increased chance of improvement in the intranasal corticosteroids group (RR 2.78, 95% CI 1.76 to 4.40; 109 participants). The quality of the evidence was low.Six studies provided data on at least two of the individual symptoms used in the EPOS 2012 criteria to define chronic rhinosinusitis (nasal blockage, rhinorrhoea, loss of sense of smell and facial pain/pressure). When all four symptoms in the EPOS criteria were available on a scale of 0 to 3 (higher = more severe symptoms), the average MD in change from baseline was -0.26 (95% CI -0.37 to -0.15; 243 participants; two studies; low quality evidence). Although there were more studies and participants when only nasal blockage and rhinorrhoea were considered (MD -0.31, 95% CI -0.38 to -0.24; 1702 participants; six studies), the MD was almost identical to when loss of sense of smell was also considered (1345 participants, four studies; moderate quality evidence).When considering the results for the individual symptoms, benefit was shown in the intranasal corticosteroids group. The effect size was larger for nasal blockage (MD -0.40, 95% CI -0.52 to -0.29; 1702 participants; six studies) than for rhinorrhoea (MD -0.25, 95% CI -0.33 to -0.17; 1702 participants; six studies) or loss of sense of smell (MD -0.19, 95% CI -0.28 to -0.11; 1345 participants; four studies). There was heterogeneity in the analysis for facial pain/pressure (MD -0.27, 95% CI -0.56 to 0.02; 243 participants; two studies). The quality of the evidence was moderate for nasal blockage, rhinorrhoea and loss of sense of smell, but low for facial pain/pressure.There was an increased risk of epistaxis with intranasal corticosteroids (risk ratio (RR) 2.74, 95% CI 1.88 to 4.00; 2508 participants; 13 studies; high quality evidence).Considering our secondary outcome, general HRQL, one study (134 participants without polyps) measured this using the SF-36 and reported a statistically significant benefit only on the general health subscale. The quality of the evidence was very low.It is unclear whether there is a difference in the risk of local irritation (RR 0.94, 95% CI 0.53 to 1.64; 2124 participants; 11 studies) (low quality evidence).None of the studies treated or followed up patients long enough to provide meaningful data on the risk of osteoporosis or stunted growth (children). Other comparisons We identified no other studies that compared intranasal corticosteroids plus co-intervention A versus placebo plus co-intervention A.
AUTHORS' CONCLUSIONS
Most of the evidence available was from studies in patients with chronic rhinosinusitis with nasal polyps. There is little information about quality of life (very low quality evidence). For disease severity, there seems to be improvement for all symptoms (low quality evidence), a moderate-sized benefit for nasal blockage and a small benefit for rhinorrhoea (moderate quality evidence). The risk of epistaxis is increased (high quality evidence), but these data included all levels of severity; small streaks of blood may not be a major concern for patients. It is unclear whether there is a difference in the risk of local irritation (low quality evidence).
Topics: Administration, Intranasal; Adolescent; Adrenal Cortex Hormones; Adult; Beclomethasone; Budesonide; Child; Chronic Disease; Fluticasone; Humans; Mometasone Furoate; Nasal Polyps; Nasal Sprays; Placebos; Quality of Life; Randomized Controlled Trials as Topic; Rhinitis; Severity of Illness Index; Sinusitis; Steroids
PubMed: 27115217
DOI: 10.1002/14651858.CD011996.pub2 -
Respiratory Medicine Jul 1998
Comparative Study Review
Topics: Administration, Inhalation; Administration, Topical; Adolescent; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Body Height; Budesonide; Child; Child, Preschool; Glucocorticoids; Humans; Infant; Randomized Controlled Trials as Topic; Time Factors
PubMed: 10193533
DOI: 10.1016/s0954-6111(98)90438-3 -
The Korean Journal of Internal Medicine Nov 2022We aimed to investigate the oral beclomethasone dipropionate's (BDP) efficacy as an add-on therapy and to clarify the predictive factor for response to oral BDP in...
BACKGROUND/AIMS
We aimed to investigate the oral beclomethasone dipropionate's (BDP) efficacy as an add-on therapy and to clarify the predictive factor for response to oral BDP in Korean ulcerative colitis (UC) patients.
METHODS
Patients with a stable concomitant drug regimen with exposure to oral BDP (5 mg/day) within 30 days before BDP initiation were included. Partial Mayo score (pMS) was used to evaluate response to oral BDP. Clinical remission (CREM) was defined as a post-treatment pMS ≤ 1 point. Clinical response (CRES) was defined as an at least 2-point decrease in post-treatment pMS and an at least 30% decrease from baseline pMS. Patients without CREM or CRES were considered nonresponders (NRs).
RESULTS
Of all, 37 showed CREM, 19 showed CRES, and 44 were NRs. The CREM group included more patients with mild disease activity (75.7% vs. 43.2%, p = 0.011) than NRs. In contrast to NRs, CREM and CRES patients showed significant improvement of post-treatment erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (ESR with p = 0.001, CRP with p = 0.004, respectively). Moreover, the initial rectal bleeding subscore (RBS) was significantly different between CREM and CRES, or NR (both with p < 0.001). In multivariate analyses, initial stool frequency subscore (SFS) of 0 and RBS of 0 were predictive factors for CREM (odds ratio [OR], 15.359; 95% confidence interval [CI], 1.085 to 217.499; p = 0.043 for SFS, and OR, 11.434; 95% CI, 1.682 to 77.710; p = 0.013 for RBS).
CONCLUSION
Oral BDP is an efficacious add-on therapy in Korean UC patients. Patients with initial SFS or RBS of 0 may be particularly good candidates for oral BDP.
Topics: Humans; Beclomethasone; Colitis, Ulcerative; Administration, Oral; Treatment Outcome; Gastrointestinal Hemorrhage; C-Reactive Protein; Republic of Korea
PubMed: 35730132
DOI: 10.3904/kjim.2022.035 -
The New England Journal of Medicine May 2007Treatment guidelines recommend the regular use of inhaled corticosteroids for patients with mild persistent asthma. We investigated whether the symptom-driven use of a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Treatment guidelines recommend the regular use of inhaled corticosteroids for patients with mild persistent asthma. We investigated whether the symptom-driven use of a combination of beclomethasone dipropionate and albuterol (also known as salbutamol) in a single inhaler would be as effective as the regular use of inhaled beclomethasone and superior to the as-needed use of inhaled albuterol.
METHODS
We conducted a 6-month, double-blind, double-dummy, randomized, parallel-group trial. After a 4-week run-in, patients with mild asthma were randomly assigned to receive one of four inhaled treatments: placebo twice daily plus 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler as needed (as-needed combination therapy); placebo twice daily plus 100 microg of albuterol as needed (as-needed albuterol therapy); 250 microg of beclomethasone twice daily and 100 microg of albuterol as needed (regular beclomethasone therapy); or 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler twice daily plus 100 microg of albuterol as needed (regular combination therapy). The primary outcome was the morning peak expiratory flow rate.
RESULTS
In 455 patients with mild asthma who had a forced expiratory volume in 1 second of 2.96 liters (88.36% of the predicted value), the morning peak expiratory flow rate during the last 2 weeks of the 6-month treatment was higher (P=0.04) and the number of exacerbations during the 6-month treatment was lower (P=0.002) in the as-needed combination therapy group than in the as-needed albuterol therapy group, but the values in the as-needed combination therapy group were not significantly different from those in the groups receiving regular beclomethasone therapy or regular combination therapy. The cumulative dose of inhaled beclomethasone was lower in the as-needed combination therapy group than in the groups receiving regular beclomethasone therapy or regular combination therapy (P<0.001 for both comparisons).
CONCLUSIONS
In patients with mild asthma, the symptom-driven use of inhaled beclomethasone (250 microg) and albuterol (100 microg) in a single inhaler is as effective as regular use of inhaled beclomethasone (250 microg twice daily) and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid. (ClinicalTrials.gov number, NCT00382889 [ClinicalTrials.gov].).
Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Albuterol; Anti-Asthmatic Agents; Asthma; Beclomethasone; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Peak Expiratory Flow Rate
PubMed: 17507703
DOI: 10.1056/NEJMoa063861 -
PloS One 2016Ulcerative colitis (UC) is a chronic and remitting inflammatory disease that is characterized by chronic idiopathic inflammation of the colon and bloody diarrhea.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ulcerative colitis (UC) is a chronic and remitting inflammatory disease that is characterized by chronic idiopathic inflammation of the colon and bloody diarrhea. Currently drug treatment is the main intervention for patients with mild to moderate UC. Mesalazine (5-ASA) and beclomethasone dipropionate (BDP) have been widely used for the treatment of UC and have yielded satisfactory results. This study compared the effectiveness of 5-ASA and BDP in the treatment of UC.
METHODS
The PubMed, Medline, SinoMed, Embase, and Cochrane Librinary databases were searched for eligible studies. Data were extracted by two of the coauthors independently and were analyzed using RevMan statistical software, version 5.3. Weighted mean differences (WMDs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Cochrane Collaboration's Risk of Bias Tool was used to assess the risk of bias.
RESULTS
Seven randomized controlled trials that compared BDP with 5-ASA in treating UC were identified as eligible. The methodological quality of the trials ranged from low to moderate. A pooled analysis of effectiveness based on the Disease Activity Index (DAI) or other assessment method after treatment revealed that in the treatment of UC, there are no obvious differences between BDP and 5-ASA in inducing remission and clinical improvement (OR = 0.76, 95% CI = 0.56-1.03, P = 0.08). The total numbers of adverse events associated with BDP and 5-ASA treatments for UC were similar (OR = 1.21, 95% CI = 0.71-2.09, P = 0.48). The safety profiles for these two drugs are good. According to subgroup-analysis, we found no obvious differences of clinical efficacy between BDP and 5-ASA no matter oral or enema administration was used in the treatment of UC. A sensitivity analysis demonstrated the stability of the pooled results.
CONCLUSION
During induction treatment of mild to moderate UC, there is no obvious difference between the two groups with respect to remission and clinical improvement. Given that the upper confidence limit for the OR barely exceeds 1.0 and that the p-value is close to 0.05 for this primary efficacy outcome as well as that the horizontal block lies to the left of the vertical line, it indicates that the clinical efficacy of BDP may be better than 5-ASA. However, taking into account that BDP has the risk of hypothalamic-pituitary-adrenal axis (HPA) suppression, 5-ASA has a potential advantage of safety in the treatment of mild to moderate UC.
Topics: Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Beclomethasone; Colitis, Ulcerative; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Humans; Mesalamine; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27501314
DOI: 10.1371/journal.pone.0160500 -
Journal of Aerosol Medicine and... Aug 2022An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed...
An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation. This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m (Kr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 μg radiolabeled using technetium-99 m [Tc]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; Tc aerosol C/P/Kr gas C/P). All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean ± standard deviation intrapulmonary deposition was 25.50% ± 6.81%, not significantly different to that in healthy volunteers (22.74% ± 9.19%; = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 ± 0.07 and 0.49 ± 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 ± 0.25 and 1.06 ± 0.25, respectively, with sC/P ratios of 1.80 ± 0.40 and 1.94 ± 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated. This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition. Clinical Trial Registration number: NCT03795350.
Topics: Administration, Inhalation; Asthma; Beclomethasone; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Healthy Volunteers; Humans; Lung; Treatment Outcome
PubMed: 35128939
DOI: 10.1089/jamp.2021.0046 -
Respiratory Medicine Dec 2016Since June 2011, the Brazilian health system started providing asthma medications (beclomethasone and salbutamol), totally free of charge to patients with asthma. The... (Observational Study)
Observational Study
BACKGROUND
Since June 2011, the Brazilian health system started providing asthma medications (beclomethasone and salbutamol), totally free of charge to patients with asthma. The aim of this study was to evaluate the impact of the provision of free asthma medications on hospital admissions for asthma in Brazil, using a national hospitalization database (DATASUS), comparing the incidence of hospital admissions before and after the free supply of these drugs.
METHODS
Admissions of patients with 1-49 years of age by the Brazilian public health system with the diagnosis of asthma were compared pre (2008-2010) and post (2012-2014) provision of free medicines (beclomethasone and salbutamol). The number of hospital admissions due to asthma and non-respiratory diseases, as well as the amount spent with asthma hospitalization, were obtained from DATASUS, the Brazilian government open-access public health database system.
RESULTS
Admission rates for asthma significantly decreased from 90.09/100.000 (2008-2010) to 59.85/100.000 (2012-2014), when the period pre and post provision of free medicines were compared [OR 0.67 (CI 0.48-0.92)]. Non-respiratory admission rates remained stable, when both periods were also compared.
CONCLUSION
Asthma hospitalization rates significantly decreased in the three-year period after the provision of free medicines to treat asthma. Our findings suggest that the provision of free medications for asthma may have a particular public health impact by its own in developing countries.
Topics: Adolescent; Adult; Age Distribution; Albuterol; Anti-Asthmatic Agents; Asthma; Beclomethasone; Brazil; Child; Child, Preschool; Databases, Factual; Drug Costs; Female; Glucocorticoids; Health Care Costs; Hospitalization; Humans; Infant; Male; Middle Aged
PubMed: 27888987
DOI: 10.1016/j.rmed.2016.10.008 -
The Cochrane Database of Systematic... 2000Inhaled steroids play a central role in the management of childhood asthma. There is concern about their side effects, especially on growth. However asthma may also... (Review)
Review
BACKGROUND
Inhaled steroids play a central role in the management of childhood asthma. There is concern about their side effects, especially on growth. However asthma may also cause growth retardation. Growth rates are not stable, so randomised controlled parallel group studies are needed to assess the impact of inhaled steroids on growth. This review is confine to one inhaled steroid, beclomethasone, that is known to have significant levels of systemic absorption.
OBJECTIVES
To determine whether inhaled beclomethasone cause significant delay in the linear growth of children with asthma.
SEARCH STRATEGY
The Cochrane Airways Group asthma register was searched. Bibliographies from included studies, and known reviews were searched for additional citations. Personal contact with colleagues and researchers working in the field of asthma were made to identify potentially relevant trials.
SELECTION CRITERIA
Randomized, controlled trials comparing the effects of beclamethasone to non-steroidal medication (placebo or non-steroidal therapy) on the linear growth of children with asthma.
DATA COLLECTION AND ANALYSIS
Data related to the clinical outcome "change in growth" were extracted by two reviewers working independently
MAIN RESULTS
One hundred and fifty-nine citations were identified by the search strategy and bibliography review. Three studies met the inclusion criteria. All used beclomethasone 200 mcg twice daily delivered by dry powder Diskhaler to treat children with mild-moderate asthma. Study duration was 7-12 months. In all three studies, a significant decrease in linear growth occurred in children treated with beclomethasone compared to those receiving placebo or non-steroidal asthma therapy. The average decrease, calculated through meta-analysis, was -1.54 cm per year (95% CI -1.15, -1.94).
REVIEWER'S CONCLUSIONS
In children with mild-moderate asthma, beclomethasone 200 mcg twice daily caused a decrease in linear growth of -1.54 cm per year. These studies lasted a maximum of 54 weeks, so it remains unclear whether the decrease in growth is sustained or whether it reverses with 'catch up' after therapy is discontinued. We are unable to comment on growth effects of other inhaled steroids that have potentially less systemic effects. If inhaled steroids are required to control a child's asthma, we recommend using the minimum dose that effectively controls the child's asthma and closely following growth.
Topics: Age Factors; Anti-Asthmatic Agents; Asthma; Beclomethasone; Child; Child Development; Growth; Humans
PubMed: 10796632
DOI: 10.1002/14651858.CD001282 -
Therapeutic Advances in Respiratory... Oct 2016The high-strength formulation of extrafine beclometasone dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid... (Comparative Study)
Comparative Study Review
The high-strength formulation of extrafine beclometasone dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid treatment, without increasing the dose of the bronchodilator, in patients who are not controlled with previous therapies. Two clinical studies have evaluated efficacy of high-strength BDP/Form as compared with another high-dose fixed combination and BDP monotherapy. Overall, data show that BDP/Form 200/6 μg improves lung function and has beneficial effects on symptoms, use of rescue medication and asthma control, with an acceptable safety profile comparable with that of high-dose fluticasone propionate/salmeterol. Therefore, BDP/Form 200/6 μg could be considered as an effective and safe treatment for patients with asthma who are not adequately controlled with high doses of inhaled corticosteroid monotherapy or medium doses of inhaled corticosteroid/long-acting β2-agonist combinations.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Combinations; Formoterol Fumarate; Humans
PubMed: 27340255
DOI: 10.1177/1753465816654442