Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomized, double-blind, placebo-controlled trial

doi:10.1067/mai.2000.105711

Journal of Allergy and Clinical Immunology

Volume 105, Issue 6, Part 1, June 2000, Pages 1108-1116

Presented in part at the annual meeting of the American Thoracic Society, Chicago, Ill, April 24-29, 1998.

https://doi.org/10.1067/mai.2000.105711 Get rights and content

Abstract

Background: Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control. Objective: Our purpose was to compare the efficacy and safety of salmeterol 50 μg combined with fluticasone 100 μg (in a combination dry powder product) with that of placebo, fluticasone, or salmeterol alone. Methods: A 12-week randomized, double-blind, multicenter study was conducted in 356 patients aged 12 years or older with asthma. After a 14-day screening period, patients were randomized to treatment with salmeterol 50 μg combined with fluticasone 100 μg (combination product), salmeterol 50 μg, fluticasone 100 μg, or placebo administered in the Diskus dry powder inhaler (GlaxoWellcome, UK) twice daily. Results: Mean change in FEV₁ at end point was significantly (P ≤ .003) greater with the combination product (0.51 L) compared with placebo (0.01 L), salmeterol (0.11 L), and flutica-sone (0.28 L). The combination product significantly increased (P ≤ .013) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo, salmeterol, and fluticasone at week 1 and week 12. Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups (P ≤ .020). The combination product significantly increased (P ≤ .012) morning PEF (combination, 52.5 L/min; placebo, –23.7 L/min; salmeterol, –1.7 L/min; fluticasone, 17.3 L/min) and evening PEF at end point compared with the other groups. The combination product significantly (P ≤ .025) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol. All treatments were equally well tolerated. Conclusion: Salmeterol 50 μg and fluticasone 100 μg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses. (J Allergy Clin Immunol 2000;105:1108-16.)

Section snippets

Patients

Male and female patients were eligible for the study if they were at least 12 years old and had a medical history of asthma (as defined by the American Thoracic Society⁶) of at least 6 months’ duration that required pharmacotherapy over the 6 months preceding the study. Patients were required to have an FEV₁ between 40% to 85% of the predicted value based on European Community for Coal and Steel standards for ages 18 years and older (and readjusted for African Americans)7, 8 or Polgar standards

RESULTS

Of 527 patients screened, 356 patients were randomly assigned to treatment. The major reasons for screen failures were lack of reproducible lung function and FEV₁ <40% or >85% predicted. Randomization resulted in comparable treatment groups at baseline with respect to patient demographics and pulmonary lung function (Table I). Mean adherence to treatment ranged from 93% to 100% across treatment groups. No patient was withdrawn from the study because of poor adherence to study medication. The

DISCUSSION

The results of this study demonstrated that the combination product, salmeterol 50 μg/fluticasone propionate 100 μg, offered significant clinical advantages over the administration of salmeterol or fluticasone propionate alone.

Exacerbations of asthma are a major cause of morbidity and mortality and can be classified as mild, moderate, or severe depending on the level of treatment necessary to achieve remission. In the current trial, because patients treated with inhaled corticosteroids at

Acknowledgements

We thank the following investigators for their participation in this study: T. D. Bell, MD, Missoula, Mont; B. L. Charous, MD, Milwaukee, Wis; P. Chervinsky, MD, North Dartmouth, Mass; R. Cohen, MD, Lawrenceville, Ga; J. Condemi, MD, Rochester, NY; G. Davis, MD, Burlington, Vt; D. Elkayam, MD, Bellingham, Wash; S. Galant, MD, Orange, Calif; D. Graft, MD, Minneapolis, Minn; A. Heller, MD, San Jose, Calif; G. Incaudo, MD, Chico, Calif; J. Jeppson, MD, Boise, Idaho; H. Kaiser, MD, Minneapolis,

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Articles published between 2001 and 2021, reporting change from baseline (CFB) in Asthma Quality of Life Questionnaire (AQLQ) in patients with moderate-to-severe asthma, were identified by a systematic review. Random effects Bayesian NMAs derived estimates of the mean difference in CFB in AQLQ vs. other interventions connected to the network (included 15 studies). Sensitivity analyses explored the impacts of differences in follow-up duration, baseline asthma control, the inclusion of observational studies, adjusting for baseline FEV₁, and low-medium ICS dose arms only. Linear regression analysis compared CFBs in AQLQ and Asthma Control Questionnaire (ACQ) score.
Mean CFB in AQLQ with FP/Sal vs. comparators demonstrated expected ranked effects: mean difference 0.65 [95% credible interval: 0.54, 0.78] versus placebo, 0.58 [ 0.33, 0.84] versus LABA, 0.21 [ 0.13, 0.31] versus ICS alone, 0.06 [−0.04, 0.19] versus other ICS/LABA, and 0.00 [−0.13, 0.14] versus ICS/formoterol MART. Sensitivity analyses largely showed consistent results. Improvements in AQLQ and ACQ were strongly correlated (R = 0.94).
This NMA demonstrates that HRQoL is responsive to treatment, is strongly related to asthma control and that it can be well-managed in patients with moderate-to-severe asthma using regular treatment with inhaled FP/Sal.
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A systematic search was made of PubMed, Embase, Web of Science, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of asthma with ICS, compared with non-ICS treatment (placebo or other active drugs), were reviewed.
Eighty-six RCTs (enrolling 51,538 participants) met the inclusion criteria. Oral or oropharyngeal candidiasis (RR 2.58, 95% CI 2.00 to 3.33), and dysphonia/hoarseness (RR 1.56, 95% CI 1.31 to 1.85) were less frequent in the control group. There was no statistically significant difference in the risk of upper respiratory tract infection, lower respiratory tract infection, influenza, decline in bone mineral density, and fractures between the two groups.
In addition to the mild local adverse events, the long-term use of ICS was safe in patients with asthma.
Global Initiative for Asthma 2016–derived asthma control with fluticasone propionate and salmeterol: A Gaining Optimal Asthma Control (GOAL) study reanalysis
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In 2004, the landmark Gaining Optimal Asthma Control (GOAL) study demonstrated that most patients can achieve asthma control through sustained treatment and that adding a long-acting β₂-adrenoreceptor agonist to an inhaled corticosteroid (ICS) is more effective than ICS alone in this regard. Definitions of asthma control have since evolved, and the consequent implications for the GOAL study findings are unclear.
To evaluate the efficacy of fluticasone propionate and salmeterol and fluticasone propionate alone in achieving and maintaining asthma control, as derived from the Global Initiative for Asthma (GINA) 2016 report.
In total, 3416 patients were stratified by prior medication (ICS-naive [stratum 1], low-dose ICS [stratum 2], or medium-dose ICS [stratum 3]) and randomized to receive fluticasone propionate and salmeterol or fluticasone propionate. The primary end point was the proportion of patients achieving well-controlled or partly controlled asthma; secondary end points included the proportion of patients achieving well-controlled asthma. Control was evaluated during the last 4 weeks of each dose titration.
In all strata, more patients achieved well-controlled or partly controlled asthma with fluticasone propionate and salmeterol vs fluticasone propionate alone (stratum 1: 91% vs 85%; P = .003; stratum 2: 86% vs 82%; P = .07; and stratum 3: 76% vs 66%; P < .001), as well as patients with well-controlled asthma (stratum 1: 64% vs 56%; P = .005; stratum 2: 59% vs 41%; P < .001; and stratum 3: 40% vs 22%; P < .001).
A markedly higher proportion of patients with uncontrolled asthma in each stratum achieved control according to GINA 2016 criteria compared with the original study criteria. The proportion of patients achieving control remained greater with fluticasone propionate and salmeterol than with fluticasone propionate alone.
Formoterol synergy with des-ciclesonide inhibits IL-4 expression in IgE/antigen-induced mast cells byinhibitingJNKactivation
2015, European Journal of Pharmacology
Inhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists (LABA) is the most important treatment for allergic asthma, although the mechanism still remains unclear. However, mast cells play a central role in the pathogenesis of asthma. In this study, we explored the sole or synergetic effects of des-ciclesonide (ICS) and formoterol (LABA) on the cytokines IL-4 and IL-13 and on histamine release from mast cells (RBL-2H3 cells). We found that des-ciclesonide (0.1, 1 and 10 nM) and formoterol (0.1, 1 and 10 μM) alone attenuated DNP–BSA-induced IL-4 and IL-13 production, respectively, in a concentration-dependent manner in DNP-IgE-sensitized mast cells. Des-ciclesonide (0.2 nM) and formoterol (1 μM) alone also reduced histamine production. However, the combination of des-ciclesonide (0.2 nM) and formoterol (1 μM) had a synergistic inhibition effect on IL-4 mRNA expression and protein production but not IL-13 and histamine release. The JNK inhibitor SP600125 (10 μM) inhibited antigen-induced mRNA expression and protein production of IL-4. Des-ciclesonide and formoterol alone inhibited the activation of JNK in a concentration-dependent manner, and the combination of des-ciclesonide (0.2 nM) and formoterol (1 μM) exhibited greater inhibition effect compared with des-ciclesonide (0.2 nM) or formoterol (1 μM) alone. Taken together, these synergistic effects on mast cells might provide the rationale for the development of the most recent ICS/LABA combination approved for asthma therapy.

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^☆: Supported by a grant from GlaxoWellcome Inc, Research Triangle Park, NC.

^☆☆: Reprint requests: Mani Kavuru, MD, Cleveland Clinic Foundation, 9500 Euclid Ave, Desk A90, Cleveland, OH 44195.

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Original articles: Asthma, rhinitis, other respiratory diseasesSalmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomized, double-blind, placebo-controlled trial☆,☆☆

Abstract

Section snippets

Patients

RESULTS

DISCUSSION

Acknowledgements

Lancet

Ann Allergy Asthma Immunol

Respir Med

Respir Med

Ann Allergy Clin Immunol

Clin Ther

Respir Med

Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids

Am J Respir Crit Care Med

Effect of inhaled formoterol and budesonide on exacerbations of asthma

N Engl J Med

Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma

Am J Respir Crit Care Med

Report of the working party of the European community for coal and steel: standardization of lung function tests

Clin Respir Physiol

Reference values for lung function tests

Respir Care

Pulmonary function testing in children: techniques and standards

Original articles: Asthma, rhinitis, other respiratory diseases
Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomized, double-blind, placebo-controlled trial☆,☆☆