Maintenance Treatment Of Asthma Research Articles

The Role of Long-Acting Antimuscarinic Agents in the Treatment of Asthma.

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Progress of three kinds of treatment for asthma

Asthma is chronic inflammatory airway disease and may be induced by both genetic factors and epigenetic factors. Asthma has no particularly typical symptoms，and these symptoms include cough, expectoration, suffocation, chest tightness and even breathing difficulties. Drugs for asthma treatment are divided into rescue treatment and maintenance treatment, rescue treatments are for people with mild symptoms of asthma which means the frequency of onset does not exceed two times a week while maintenance treatments with inhalable drugs that deal with inflammation are for all other patients that suffer severely and to increase control. As in recent years, the population with asthma has shown to be increasing worldwide over time, the importance and necessity of understanding the mechanism of asthma and its main treatment methods and principles are also increasing. This article mainly focused on three types of most commonly seen maintenance treatment for asthma, including glucocorticoid, theophylline and leukotriene receptor antagonist.

Efficacy of once-daily, single-inhaler, fixed-dose combination of mometasone/indacaterol/glycopyrronium in patients with asthma with or without persistent airflow limitation: Post hoc analysis from the IRIDIUM study

BackgroundA novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ2-agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL. MethodsPatients with post-bronchodilator FEV1 ≤80% of predicted and FEV1/FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV1, PEF, and FEF25%–75%) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 μg), high-dose MF/IND (320/150 μg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 μg). ResultsOf the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV1, FEF25%–75%, PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively. ConclusionsOnce-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation.

Prevalence and Characteristics of Self-Reported Adult Asthma in Cyprus: A Population-Based Observational Study.

To estimate the prevalence of asthma in adults, by gender and age, in urban and rural areas of Cyprus. This was a population-based, random-digit dialing, telephone nation-wide survey to recruit patients with asthma. Among 8996 random landline-telephone contacted from the five major urban and rural regions of Cyprus, 1914 were finally met the age criterion of ≥18 years old and 572 completed valid screening for prevalence estimation. The participants filled a short screening questionnaire in order for asthma cases to be recognized. Then, asthma cases filled the main ECRHS II questionnaire and were evaluated by a pulmonary physician. All underwent spirometry. Data on demographic characteristics, educational level, profession, smoking status, Body Mass Index (BMI), Total IgE and Eosinophil Cationic Protein levels were measured. The overall prevalence of bronchial asthma in adults in Cyprus was 5.57% (61.1% men and 38.9% women). Among the participants with self-reported bronchial asthma 36.1% were current smokers, while 12.3% were obese (BMI >30). A total value of IgE >115 IU and Eosinophil Cationic Protein (ECP) >20 IU was found in 40% of the participants with established bronchial asthma. Wheezing and chest tightness were the most frequently reported symptoms in asthma patients (36.1% and 34.5%, respectively), while 36.5% experienced at least one exacerbation during the last year. Interestingly, most of the patients were under-treated (14.2% were on maintenance asthma treatment, and 18% used solely reliever medication). This was the first study estimating asthma prevalence in Cyprus. Asthma affects almost 6% of the adult population, with higher prevalence in urban areas and in men compared to women. Interestingly, one-third of the patients were uncontrolled and under-treated. This study revealed that in Cyprus there is space for improvement in the management of asthma.

Nasal TSLP and periostin in infants with severe bronchiolitis and risk of asthma at 4 years of age

BackgroundSevere bronchiolitis is often associated with subsequent respiratory morbidity, mainly recurrent wheezing and asthma. However, the underlying immune mechanisms remain unclear. The main goal of this study was to investigate the association of nasal detection of periostin and thymic stromal lymphopoietin (TSLP) during severe bronchiolitis with the development of asthma at 4 years of age.MethodsObservational, longitudinal, post-bronchiolitis, hospital-based, follow-up study. Children hospitalized for bronchiolitis between October/2013 and July/2017, currently aged 4 years, included in a previous study to investigate the nasal airway secretion of TSLP and periostin during bronchiolitis, were included. Parents were contacted by telephone, and were invited to a clinical interview based on a structured questionnaire to obtain information on the respiratory evolution. The ISAAC questionnaire for asthma symptoms for 6–7-year-old children, was also employed.ResultsA total of 248 children were included (median age 4.4 years). The mean age at admission for bronchiolitis was 3.1 (IQR: 1.5–6.5) months. Overall, 21% had ever been diagnosed with asthma and 37% had wheezed in the last 12 months. Measurable nasal TSLP was detected at admission in 27(11%) cases and periostin in 157(63%). The detection of nasal TSLP was associated with the subsequent prescription of maintenance asthma treatment (p = 0.04), montelukast (p = 0.01), and the combination montelukast/inhaled glucocorticosteroids (p = 0.03). Admissions for asthma tended to be more frequent in children with TSLP detection (p = 0.07). In the multivariate analysis, adjusting for potential confounders, the detection of TSLP remained independently associated with chronic asthma treatment prescription (aOR:2.724; CI 1.051–7.063, p:0.04) and with current asthma (aOR:3.41; CI 1.20–9.66, p:0.02).Nasal detection of periostin was associated with lower frequency of ever use of short-acting beta2-agonists (SABA) (p = 0.04), lower prevalence of current asthma (p = 0.02), less prescription of maintenance asthma treatment in the past 12 months (p = 0.02, respectively). In the multivariate analysis, periostin was associated with lower risk of asthma at 4 years, independently of the atopic status (aOR:0.511 CI 95% 0.284–0.918, p:0.025).ConclusionsOur results show a positive correlation between nasal TSLP detection in severe bronchiolitis and the presence of current asthma, prescription of asthma maintenance treatment and respiratory admissions up to the age of 4 years. By contrast, we found a protective association between nasal periostin detection and current asthma at 4 years, ever diagnosis of asthma, maintenance asthma treatment prescription, and respiratory admissions.

Involvement of esterases in the pulmonary metabolism of beclomethasone dipropionate and the potential influence of cannabis use

Beclomethasone dipropionate (BDP) is an inhaled glucocorticoid used for maintenance treatment of asthma in adults and children. BDP is a prodrug activated in lung when hydrolyzed to its major active metabolite beclomethasone-17-monopropionate (17-BMP), which can be further deactivated to beclomethasone (BOH). The specific hydrolases contributing to these processes have not been identified which warrants an investigation to enable a better assessment of the drug-drug interaction (DDI) liability and a better management of drug efficacy and systemic toxicity. In the present study, the pulmonary metabolism of BDP was investigated using both human lung S9 (HLuS9) and recombinant carboxylesterase 1 (CES1) S9. By employing the relative activity approach, we tested the hypothesis of CES1 being the major enzyme involved. Assessment of other hydrolases were conducted in an assay with selective esterase inhibitors. In addition, the DDI potentials between BDP and Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) were evaluated due to the increasing use of inhaled cannabis both recreationally and medically. The mechanism of DDI was conducted in an in vitro time-dependent inhibition assay, and further interpreted utilizing a proposed model. In HLuS9, BDP was efficiently metabolized almost completely to 17-BMP, which was then converted to BOH at a much lower rate. CES1 was found as a minor contributor accounting for only 1.4% of BDP metabolism in HLuS9, while arylacetamide deacetylase might be the main enzyme involved. Both THC and CBD inhibited the HLuS9 mediated BDP hydrolysis in a reversible manner, with reported IC50 values estimated as 8.98 and 36.8 μM, respectively. Our proposed model suggested a moderately decreased 17-BMP exposure in lung by concomitant THC from a cannabis cigarette, while the effects from orally administered CBD was expected to be of no clinical relevance.

Adherence and Persistence to Single-Inhaler Versus Multiple-Inhaler Triple Therapy for Asthma Management

Treatment guidelines recommend triple therapy for patients with asthma who remain uncontrolled on inhaled corticosteroid/long-acting β2-agonist therapy. Previously, triple therapy was only available via multiple inhalers. Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) is approved as maintenance treatment for asthma; however, real-world information on adherence and persistence is limited. To compare adherence and persistence among adult patients with asthma receiving single-inhaler FF/UMEC/VI versus multiple-inhaler triple therapy (MITT) in the United States. This retrospective cohort study used IQVIA PharMetrics Plus data to evaluate patients with asthma who initiated once-daily FF/UMEC/VI 100/62.5/25 mcg or MITT between September 18, 2017, and September 30, 2019. Inverse probability weighting and multivariable regression adjusted for differences in characteristics between the FF/UMEC/VI and MITT cohorts. Adherence was assessed using proportion of days covered (PDC) and proportion of patients achieving PDC ≥0.8 and PDC ≥0.5. Non-persistence was identified as a >45-day gap between fills. The study included 1396 FF/UMEC/VI and 5115 MITT initiators. Three months after initiation, FF/UMEC/VI users had significantly higher mean PDC versus MITT users (0.68 vs 0.59; P < .001) and 31% more likely to be adherent (PDC ≥0.8; 40.6% vs 31.3%; adjusted risk ratio [95%confidence interval (CI)]: 1.31 [1.13-1.54]; P < .001). Similar patterns were observed at 6 and 12 months post initiation. In addition, FF/UMEC/VI users were 49% more likely to persist at 12 months than MITT users (25.9% vs 15.1%, adjusted hazard ratio [95% CI]: 1.49 [1.39-1.60]; P < .001). Patients with asthma initiating triple therapy with FF/UMEC/VI had significantly better adherence and persistence compared with MITT initiators.

Asthma management with combination of fluticasone and formoterol: the Indian perspectiverspective

Asthma is a major health problem globally that affects people across all the age groups. The prevalence of asthma is increasing worldwide, especially in the low- and middle-income countries. Asthma is controlled with inhaled corticosteroid (ICS) with as-needed or daily low-dose therapy. A step-up therapy to daily combination treatment with low- or medium-dose ICS/long-acting β-agonist (LABA) may be required for those with persistent symptoms. Asthma control levels are low despite the availability of many therapies. The efficacy of inhaled asthma therapy is dependent on the efficiency and reliability with which the drug is delivered to the lungs. Combination of an ICS and a LABA in a single inhaler is a safe, effective, and convenient treatment option for asthma management. Fluticasone and formoterol in combination ensure high potency action against anti-inflammation and rapid bronchodilation, and is a well-established ICS-LABA dual therapy. Rapid bronchodilator action of formoterol and fluticasone’s long-term action against inflammation are vital clinical attributes for optimal asthma maintenance treatment. Fluticasone/formoterol combination therapy is an efficacious and safe alternative treatment option for patients with moderate to severe asthma. The combination of the two in a single inhaler is beneficial with regards to ease of administration and patient compliance.

Lung Deposition of Inhaled Extrafine Beclomethasone Dipropionate/Formoterol Fumarate/Glycopyrronium Bromide in Healthy Volunteers and Asthma: The STORM Study.

Background: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 in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation.Methods:This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m (81mKr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 μg radiolabeled using technetium-99 m [99mTc]) 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; 99mTc aerosol C/P/81mKr gas C/P).Results: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%; p = 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.Conclusions: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.

A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first “digital companion” that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the “outstanding contributions to public health” (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study—IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb)Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-02025-w.

Review of efficacy of ciclesonide for the treatment of asthma in children.

Background: Ciclesonide (CIC) is an inhaled corticosteroid (ICS) approved for the maintenance treatment of asthma in patients ages ≥ 12 years. The prodrug aspect of CIC is associated with a safety profile that may make it ideal for children. Objective: The objective was to summarize efficacy results from the eight phase III, randomized, double-blind, controlled trials in children with asthma conducted during CIC clinical development. Methods: Four trials compared CIC 40, 80, or 160 µg/day with placebo. Two trials compared CIC 160 µg/day with fluticasone propionate 200 µg/day, one trial compared CIC 80 or 160 µg/day with fluticasone 200 µg/day, and one trial compared CIC 160 µg/day with budesonide 400 µg/day. Results: The primary end point was met by at least two CIC doses versus placebo in the trials in which the primary end point was the change from baseline in lung function outcome (forced expiratory volume in 1 second [FEV1] % predicted or morning peak expiratory flow [PEF]). A trial that compared CIC with placebo did not meet the primary end point of superiority in time-to-first severe wheeze exacerbation or lack of improvement. The primary end point of noninferiority to the active control (fluticasone or budesonide) in the change from baseline in a lung function outcome (FEV1, morning PEF, evening PEF) was met with the CIC 160-µg dose in all active control trials. CIC generally demonstrated statistically significant improvements in forced expiratory flow at 25%-75% of forced vital capacity, asthma symptoms, rescue medication use, and asthma control when compared with placebo and noninferiority for these outcomes compared with fluticasone or budesonide. Conclusion: In children with asthma, once-daily CIC significantly improved large and small airway function, asthma symptoms, and asthma control, and reduced rescue medication use compared with placebo. CIC was comparable with other ICS used to treat asthma in children, which demonstrated its worth for the pediatric population.

An Indian Perspective on the Use of Fluticasone/Formoterol in Asthma and Chronic Obstructive Pulmonary Disease Patients

Despite rapidly evolving health-care systems, India continues to have a high disease burden for asthma and chronic obstructive pulmonary disease (COPD). The Asia-Pacific Asthma Insights and Management survey clearly revealed that asthma management remains very poor with worst clinical outcomes in India. Potent inhaled corticosteroids (ICS) and quick onset of long-acting beta2-agonist (LABA) are considered to be optimal dual therapy for management of asthma and COPD. Fluticasone's long-term action against inflammation and formoterol's rapid long-term bronchodilator action are vital clinical attributes for optimal asthma maintenance treatment. In an 8- and 12-week trial, dual therapy of fluticasone and formoterol (FF) reported lung function improvements and better control of asthma than its monotherapy. A large clinical study revealed mild adverse events of dual FF than other dual ICS-LABA combinations. Recent pooled analysis of asthma showed that fluticasone shares a lower risk of pneumonia in asthma. Dual ICS-LABA therapies are preferred in COPD individuals with history of exacerbations. Numerous clinical studies showed significant efficacy, dose adjustments/switching, and safety outcomes with dual FF therapy in asthma and COPD. Dual FF inhaler therapy ensures highly potent anti-inflammatory activity and sustained bronchodilation, thus making this a preferred combination in terms of efficacy, safety, and patient adherence in asthma and COPD. This present review focuses on the combination therapy of formoterol and fluticasone for managing asthma and COPD.

Indacaterol/Glycopyrronium/Mometasone: A Review in Asthma

Indacaterol/glycopyrronium/mometasone (Enerzair® Breezhaler®) is a fixed-dose combination of the long-acting β2 agonist (LABA) indacaterol, the long-acting muscarinic antagonist (LAMA) glycopyrronium and the inhaled corticosteroid (ICS) mometasone furoate (hereafter referred to as mometasone) delivered via a capsule-based dry-powder inhaler. It is approved in the EU for use as maintenance treatment in adult patients with inadequately controlled asthma who had experienced one or more exacerbations in the previous year. The approval also includes an optional digital companion (sensor and app) that provides data on the patient's use of the inhaler. In the 52-week IRIDIUM trial in patients with inadequately controlled asthma, indacaterol/glycopyrronium/mometasone improved lung function to a greater extent than LABA/ICS combinations (i.e. indacaterol/mometasone and fluticasone propionate/salmeterol), but superiority in Asthma Control Questionnaire 7 score was not shown. In the 24-week ARGON trial, indacaterol/glycopyrronium/mometasone via a single inhaler was non-inferior to fluticasone propionate/salmeterol + tiotropium via two inhalers with regard to Asthma Quality of Life Questionnaire score. Indacaterol/glycopyrronium/mometasone was generally well tolerated, and the most common adverse events were respiratory in nature. In conclusion, combination therapy with indacaterol/glycopyrronium/mometasone represents a valuable option for the maintenance treatment of asthma, with the convenience of once-daily administration via a single inhaler.

Corresponding doses of mometasone furoate (MF) in once-daily inhaled fixed-dose combination (FDC) of indacaterol/mometasone furoate (IND/MF) and indacaterol/glycopyrronium/mometasone furoate (IND/GLY/MF): results from randomized clinical studies

IND/GLY/MF and IND/MF are both once-daily (o.d.) FDCs, recently approved for maintenance treatment of asthma. They have been developed with different MF doses with the goal to tailor therapy to a patient’s needs.

Pharmacokinetics Of Indacaterol/Mometasone Furoate In Healthy Chinese Volunteers: Results From A Randomized, Open-label, Parallel-group Study

Once-daily indacaterol/mometasone furoate (IND/MF) is an inhaled long-acting β2-agonist/inhaled corticosteroid (LABA/ICS), recently approved for maintenance treatment of asthma. Pharmacokinetics of IND and MF after once-daily oral inhalation of IND/MF low- (150/80 μg), medium- (150/160 μg) and high-dose (150/320 μg) for 14 days were assessed in healthy Chinese volunteers.

Pharmacokinetics Of Indacaterol/Glycopyrronium/Mometasone Furoate In Healthy Chinese Volunteers: Results From A Randomized, Open-Label, Parallel-Group Study

Once-daily indacaterol/glycopyrronium/mometasone furoate (IND/GLY/MF) is the first inhaled long-acting muscarinic antagonist/long-acting β2-agonist/inhaled corticosteroid (LABA/LAMA/ICS) approved for maintenance treatment of asthma. The steady-state pharmacokinetics (PK) of IND, GLY and MF were characterized in healthy Chinese volunteers following multiple once-daily oral inhalations of IND/GLY/MF medium-dose (150/50/80 μg) or high-dose (150/50/160 μg). In this randomized, open-label, parallel-group, Phase I study, 24 healthy volunteers aged 18–45 years were randomized 1:1 to receive either IND/GLY/MF medium-dose or high-dose via Breezhaler®, once-daily for 14 days. The pharmacokinetic parameters of IND, GLY and MF were calculated by non-compartmental analysis. Of 22 volunteers who completed the study, PK analysis included 20 volunteers (11 in medium-dose group and 9 in high-dose group) and 2 were excluded due to protocol deviations. At steady state (Day 14), median Tmax was 0.25 h for IND, 0.08 h for GLY and 0.5 h for MF. Cmax and AUC0–24h of IND (mean Cmax: 449 and 395 pg/mL; mean AUC0–24h: 2340 and 2250 h*pg/mL, for medium-dose and high-dose respectively) and GLY (mean Cmax: 354 and 368 pg/mL; mean AUC0–24h: 723 and 713 h*pg/mL, for medium- and high-dose respectively) were similar between medium- and high-dose groups. Cmax (140 and 240 pg/mL) and AUC0–24h (885 and 1890 h*pg/mL) of MF were approximately 2-fold in high-dose versus medium-dose group. IND, GLY and MF were rapidly absorbed after administration. The exposure of IND and GLY were comparable between the IND/GLY/MF medium-dose and high-dose groups and that of MF increased with increasing dose of MF.

PRS29 Cost-Utility Analysis of Fixed Dose Combination (FDC) of Indacaterol Acetate (IND) and Mometasone Furoate (MF) As a Maintenance Treatment of Asthma in Patients not Adequately Controlled with Inhaled Corticosteroids and Inhaled Short Acting beta2-Agonists

To evaluate the cost-utility of IND/MF FDC low-high dose relative to low–high dose of MF or salmeterol/fluticasone (SF) in not adequately controlled asthma patients 12 years or older, from the Italian National Health Service (NHS) perspective. A two-state and four-week cycle Markov model was used to estimate lifetime clinical outcomes and costs. Patients entered the model in stable disease and could experience a non-fatal exacerbation event. The exacerbation rate is dependent upon the therapy a patient is receiving, as per the IND/MF clinical trials. The impact of each type of exacerbation is accounted by applying a utility decrement, obtained from literature, and a treatment cost. Utility values were obtained from the EQ-5D questionnaires in the IND/MF clinical trials. Lifetime costs considered in the analysis were drugs and exacerbation management. Probabilistic sensitivity analyses were carried out, with the aim of evaluating impact of uncertainty around model assumptions. IND/MF-low dose is associated with higher quality of life (+0.533 QALY) than MF-low dose, with an incremental cost of €1,900.09. The incremental cost-utility ratio (ICUR) results of €3,565 per QALY. IND/MF-medium dose is associated with higher quality of life (+0.609 QALY) than MF-medium dose, with an incremental cost of €436.57. ICUR results of €717 per QALY. IND/MF-high dose is associated with higher quality of life (+0.350 QALY) than MF-high dose, with an incremental cost of -€1,297.80, which is a dominant treatment strategy. IND/MF-high dose is associated with higher quality of life (+0.102 QALY) than SF, with an incremental cost of -€1,719.01, which is also dominant. At a threshold of €5,000 per QALY, IND/MF has nearly 100% of probability of being cost-effective compared to all 3 doses of MF. The results indicate that IND/MF is cost-effective among the considered comparisons in a representative cohort of asthma patients 12 years or older in Italy.

PRS39 Fixed Dose Combination (FDC) of Indacaterol Acetate (IND) and Mometasone Furoate (MF) As a Maintenance Treatment of Asthma in Patients not Adequately Controlled with Inhaled Corticosteroids and Inhaled Short Acting beta2-Agonists: A Budget Impact Analisys in Italy

PRS39 Fixed Dose Combination (FDC) of Indacaterol Acetate (IND) and Mometasone Furoate (MF) As a Maintenance Treatment of Asthma in Patients not Adequately Controlled with Inhaled Corticosteroids and Inhaled Short Acting beta2-Agonists: A Budget Impact Analisys in Italy

P450 CLINICAL MEASURES OF ASTHMA CONTROL FROM THE MOMETASONE FUROATE/FORMOTEROL SPIRO TRIAL

Asthma maintenance treatment aims to preserve asthma control in order to reduce the risk of asthma exacerbation. The combination between an inhaled corticosteroid and a fast-acting bronchodilator, systemic corticosteroids (SCS) bursts and other add-on asthma medications are prescribed for asthma worsening to mitigate serious outcomes.1 Primary findings from a 26-week double-blind, randomized-controlled trial in patients ≥12 years of age with persistent asthma comparing mometasone furoate/formoterol (MF/F) to MF did not demonstrate a significant difference in asthma-related hospitalizations, intubations and deaths, but did show a significant reduction in asthma exacerbation.2 The present analysis of additional prespecified endpoints further characterizes MF/F effects on clinical measures of asthma control.

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate following once-daily inhalation as a combination in healthy subjects

Indacaterol (IND), is co-formulated with glycopyrronium (GLY), and mometasone furoate (MF) as a once-daily (o.d.) inhaled fixed-dose combination (IND/GLY/MF) delivered via the Breezhaler® device for maintenance treatment of asthma. We evaluated the steady state plasma pharmacokinetics (PK) of IND, GLY and MF following inhalation of IND/GLY/MF or as monotherapies.This was a randomized, open-label, four-way crossover study. Subjects received IND/GLY/MF 150/50/160 μg (high-dose), IND 150 μg, GLY 50 μg or MF 190 μg (in vitro fine particle mass comparable to 160 μg MF in IND/GLY/MF) via the Breezhaler® device, o.d. for 14 days in each period, with a washout of at least 7 days. PK was characterized on Day 14, up to 24 h post-dose.In total, 36 healthy subjects were randomized. For IND, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.922 (0.878, 0.969) and 1.02 (0.967, 1.08), respectively for the IND/GLY/MF versus IND monotherapy comparison. For GLY, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.986 (0.944, 1.03) and 1.21 (1.09, 1.34), respectively for the IND/GLY/MF versus GLY comparison. For MF, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 1.16 (1.09, 1.24) and 1.17 (1.09, 1.25), respectively for IND/GLY/MF versus MF comparison. Similar systemic exposure was noted for IND/GLY/MF versus monotherapy for all three mono-components, indicating a lack of PK interaction. Multiple inhaled doses of IND, GLY and MF were safe and well tolerated, when administered alone or in combination.There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF.