Reduced Rescue Medication Use Research Articles

Optimal Bronchodilation for COPD Patients: Are All Long-Acting β₂-Agonist/Long-Acting Muscarinic Antagonists the Same?

Bronchodilators provide improvements in lung function and reductions in symptoms and exacerbations, and are the mainstay of pharmacological management of chronic obstructive pulmonary disease (COPD). The Global Initiative for Chronic Obstructive Lung Disease strategy recommends the use of a combination of long-acting β2-agonist/long-acting muscarinic antagonists (LABA/LAMA) as the first-line treatment option in the majority of symptomatic patients with COPD. This review provides an indirect comparison of available LABA/LAMA fixed-dose combinations (FDCs) through discussion of important efficacy and safety data from the key literature, with the objective of providing physicians with a framework for informed decision-making. LABA/LAMA FDCs provided greater benefits compared with placebo and similar or greater benefits compared with tiotropium and salmeterol/fluticasone in improving lung function, dyspnea, health-related quality of life, reducing rescue medication use and preventing exacerbations, although with some variability in efficacy between individual FDCs; further, tolerability profiles were comparable among LABA/LAMA FDCs. However, there is a disparity in the amount of evidence generated for different LABA/LAMA FDCs. Thus, this review shows that all LABA/LAMA FDCs may not be the same and that care should be taken when extrapolating individual treatment outcomes to the entire drug class. It is important that physicians consider the efficacy gradient that exists among LABA/LAMA FDCs, and factors such as inhaler devices and potential biomarkers, when choosing the optimal bronchodilator treatment for long-term management of patients with COPD.

A Network Meta-Analysis of Long-Acting Muscarinic Antagonist (LAMA) and Long-Acting β2-Agonist (LABA) Combinations in COPD.

IntroductionComparative data on the efficacies of long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) combinations for the treatment of moderate-to-very-severe chronic obstructive pulmonary disease (COPD) are limited. The aim of this Bayesian network meta-analysis (NMA) is to assess the relative efficacies of available open combinations (delivered via separate inhalers) and fixed-dose combinations (FDCs, delivered via a single inhaler).MethodsWe conducted a systematic literature review with the aim of identifying randomized controlled trials (RCTs) of ≥8-week duration in adults aged ≥40 years with COPD that compared LAMA + LABA combinations with each other, with tiotropium (TIO), or with placebo. Data on changes from baseline in trough forced expiratory volume in 1 s (FEV1) and on St George’s Respiratory Questionnaire (SGRQ) total score, the Transition Dyspnea Index (TDI) focal score, and rescue medication use at 12 and 24 weeks were extracted from these RCTs and analyzed using a NMA in a Bayesian framework.ResultsData from 44 RCTs were included in the NMA. All FDCs showed improvements relative to placebo in terms of trough FEV1, SGRQ total score, and TDI focal score above clinically relevant thresholds, with the exception of TIO/olodaterol and aclidinium/formoterol, both of which failed to show clinically relevant improvements in SGRQ score at 24 weeks. All FDCs demonstrated reduced rescue medication use versus placebo. Open combinations demonstrated improved efficacy in all outcomes versus placebo, but these improvements did not consistently exceed clinically relevant thresholds for SGRQ and TDI scores. All once-daily FDCs showed improved efficacy versus TIO, but improvements were less consistently observed versus TIO with open dual combinations and combinations containing formoterol or salmeterol administered twice daily. Relative probabilities of improvement between FDCs highlighted potential between-class differences for trough FEV1 but suggested little potential for differences in patient-reported outcomes.ConclusionLAMA + LABA combinations generally showed improved outcomes versus placebo and TIO. FDCs appeared to perform better than open dual combinations. A potential effectiveness gradient was observed between FDCs for objectively assessed functional outcomes, although further prospective trials are required to confirm these findings.FundingGSK.Electronic supplementary materialThe online version of this article (doi:10.1007/s41030-017-0048-0) contains supplementary material, which is available to authorized users.

24-h bronchodilation and inspiratory capacity improvements with glycopyrrolate/formoterol fumarate via co-suspension delivery technology in COPD

BackgroundSymptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily.MethodsPatients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks’ treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0–24). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity.ResultsGFF MDI treatment significantly increased FEV1AUC0–24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0–12 and 12–24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12–24 compared to 0–12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (−0.84 [p<0.0001] and −1.11 [p=0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (−0.44 [p=0.017] puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings.ConclusionsGFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI.Trial registrationPearl Therapeutics, Inc.; www.clinicaltrials.gov; NCT02347072 and NCT02347085. Registered 21 January 2015.

Baseline Symptom Score Impact on Benefits of Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD

The clinical severity of COPD is currently categorized by symptom burden and exacerbation risk. Previous 24-week phase III trials (NCT01854645 and NCT01854658) that demonstrated better improvement of lung function with glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) (an MDI fixed-dose of GFF 18/9.6 μg) over individual monocomponent MDIs included a cross-section of patients with moderate to very severe airflow limitation and a broad range of COPD symptoms. These post hoc analyses of pooled data investigated whether baseline symptom burden, assessed using the COPD Assessment Test (CAT) score, impacted GFF MDI-associated improvements in lung function, health status, rescue medication use, and exacerbation risk. In 3,699 patients, improvement in FEV1 at week 24 between the GFF MDI and monocomponent MDIs and a placebo MDI was similar in magnitude regardless of baseline CAT score. In contrast, the magnitude of mean difference in the St. George's Respiratory Questionnaire total score for GFF MDI vsmonocomponent MDIs and the placebo MDI increased with increasing baseline CAT scores. Likewise, reduced rescue medication use and lower exacerbation risk were more pronounced in GFF MDI groups with a higher baseline symptom burden. Beneficial effects of GFF MDI on health status, rescue medication use, and exacerbation risk in symptomatic patients with COPD increased as a function of baseline symptom burden, whereas lung function benefits were independent. These data suggest a greater clinical benefit from dual bronchodilators in symptomatic patients than in patients without symptoms. ClinicalTrials.gov; No.: NCT01854645 and NCT01854658; URL: www.clinicaltrials.gov.

LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis.

BackgroundRandomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as β2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD.MethodsThis systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks’ LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.ResultsEighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George’s Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]).ConclusionThe greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use.

Umeclidinium/vilanterol as step-up therapy from tiotropium in patients with moderate COPD: a randomized, parallel-group, 12-week study.

IntroductionPatients with COPD who remain symptomatic on long-acting bronchodilator monotherapy may benefit from step-up therapy to a long-acting bronchodilator combination. This study evaluated the efficacy and safety of umeclidinium (UMEC)/vilanterol (VI) in patients with moderate COPD who remained symptomatic on tiotropium (TIO).MethodsIn this randomized, blinded, double-dummy, parallel-group study (NCT01899742), patients (N=494) who were prescribed TIO for ≥3 months at screening (forced expiratory volume in 1 s [FEV1]: 50%–70% of predicted; modified Medical Research Council [mMRC] score ≥1) and completed a 4-week run-in with TIO were randomized to UMEC/VI 62.5/25 µg or TIO 18 µg for 12 weeks. Efficacy assessments included trough FEV1 at Day 85 (primary end point), 0–3 h serial FEV1, rescue medication use, Transition Dyspnea Index (TDI), St George’s Respiratory Questionnaire (SGRQ), and COPD Assessment Test (CAT). Safety evaluations included adverse events (AEs).ResultsCompared with TIO, UMEC/VI produced greater improvements in trough FEV1 (least squares [LS] mean difference: 88 mL at Day 85 [95% confidence interval {CI}: 45–131]; P<0.001) and FEV1 after 5 min on Day 1 (50 mL [95% CI: 27–72]; P<0.001). Reductions in rescue medication use over 12 weeks were greater with UMEC/VI versus TIO (LS mean change: −0.1 puffs/d [95% CI: −0.2–0.0]; P≤0.05). More patients achieved clinically meaningful improvements in TDI score (≥1 unit) with UMEC/VI (63%) versus TIO (49%; odds ratio at Day 84=1.78 [95% CI: 1.21–2.64]; P≤0.01). Improvements in SGRQ and CAT scores were similar between treatments. The incidence of AEs was similar with UMEC/VI (30%) and TIO (31%).ConclusionUMEC/VI step-up therapy provides clinical benefit over TIO monotherapy in patients with moderate COPD who are symptomatic on TIO alone.

Prophylactic Ondansetron for the Prevention of Intrathecal Fentanyl- or Sufentanil-Mediated Pruritus: A Meta-Analysis of Randomized Trials.

Pruritus is a common side effect of intrathecal fentanyl or sufentanil that decreases patient satisfaction and may delay hospital discharge. There are conflicting reports about the efficacy of prophylactic ondansetron in reducing the incidence of pruritus. This meta-analysis aimed to assess the effect of prophylactic ondansetron on the incidence of intrathecal fentanyl- or sufentanil-mediated pruritus and the need for rescue treatment. A systematic search on PubMed, Medline, and the Cochrane Central Register of Controlled Trials from January 1, 1994, to January 1, 2014, was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Randomized controlled trials evaluating the efficacy of prophylactic ondansetron on pruritus associated with intrathecal fentanyl or sufentanil were included. The primary outcome was the incidence of pruritus, and the secondary outcome was patients' need for rescue therapy. Sensitivity analyses were conducted to assess the outcomes in obstetric and nonobstetric patients and in patients who received ondansetron before or after intrathecal opioid injection. Analyses used random-effect models. Six randomized controlled trials involving 555 patients were included. In the overall analysis, prophylactic ondansetron did not significantly decrease the incidence of pruritus, but there was a trend toward reduced rescue medication use (risk ratio [RR], 0.57; 95% confidence interval [CI], 0.35-0.91; I = 0%; P = 0.02). Exploratory subgroups, including nonobstetric surgery patients and patients who received ondansetron before spinal opioid administration, also suggest a trend toward less rescue medication use (RR, 0.47; 95% CI, 0.26-0.85; P = 0.01; and RR, 0.62; 95% CI, 0.38-1.00; P = 0.05). IV 8 mg prophylactic ondansetron does not decrease the incidence of fentanyl- or sufentanil-mediated pruritus but may decrease the need for pruritus rescue medication, particularly in specific subgroups. Randomized trials are needed to confirm these results.

Efficacy of Indacaterol/Glycopyrronium in Patients with COPD Who Have Increased Dyspnea with Daily Activities.

Introduction: The Global initiative for chronic Obstructive Lung Disease (GOLD) recommends treating patients with chronic obstructive pulmonary disease (COPD) based on a combined assessment of symptom severity and airflow limitation and/or exacerbation risk. According to GOLD, patients with mild-to-moderate airflow limitation and distressing symptoms such as dyspnea should be treated with a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA). If symptoms persist on monotherapy, GOLD recommends a combination of bronchodilators (LABA/LAMA). Methods: We performed a post-hoc analysis of data from two 26-week, prospective clinical trials to investigate the effect of treating patients with moderate-to-severe dyspnea with the once-daily LABA/LAMA combination indacaterol/glycopyrronium (IND/GLY) 110/50 µg compared with placebo, once-daily tiotropium 18 µg, and twice-daily salmeterol/fluticasone propionate (SFC) 50/500 µg. In this analysis, a Baseline Dyspnea Index (BDI) score ≤7 was used to identify dyspneic patients. Results: In dyspneic patients, IND/GLY significantly improved Transition Dyspnea Index (TDI) total scores compared with tiotropium (0.59 units; p<0.05) and SFC (0.97 units; p<0.05), and significantly increased the likelihood of a patient achieving a 1-unit improvement in TDI compared with tiotropium (odds ratio [OR] 1.87; p<0.05). IND/GLY also significantly improved trough forced expiratory volume in 1 second (FEV1) compared with tiotropium and SFC (p<0.001 and p<0.0001, respectively), and significantly reduced rescue medication use compared with tiotropium (p<0.001). Conclusions: Our analysis indicates that IND/GLY provides additional improvements in dyspnea and lung function compared with tiotropium and SFC in dyspneic patients.

FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator. The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate), a fixed-dose combination of a long-acting β2-agonist (indacaterol) and a long-acting muscarinic antagonist (glycopyrrolate), compared with its monocomponents and placebo in patients with moderate-to-severe COPD. FLIGHT1 and FLIGHT2 were 12-week, identical, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6 μg twice daily), indacaterol (27.5 μg twice daily), glycopyrrolate (15.6 μg twice daily), or placebo, all delivered via the Neohaler device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0-12 hours for FEV1 at Week 12. Secondary objectives included St. George's Respiratory Questionnaire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo. In total, 2,038 patients were included in the pooled analysis. Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0-12 hours compared with its monocomponents (P < 0.001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P < 0.001). The safety profile was comparable across the treatment groups. Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01727141 and NCT 0171251).

Pulmonary Function and Rescue Medication Use in Patients Receiving Omalizumab in Real World Settings: A Systematic Literature Review of Nonrandomized Studies

SESSION TITLE: Allergy and Airway Posters SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: The objective was to provide a summary of the real-world clinical and health economic outcomes associated with omalizumab in the treatment of moderate to severe allergic asthma. METHODS: A systematic literature review was conducted to identify studies of omalizumab in patients ≥12 years with moderate to severe allergic asthma. A search of MEDLINE and EMBASE reference databases was conducted for relevant studies published from 2003 to 2014. Outcomes of interest included rescue medication use and pulmonary function assessments (FEV1, FVC, and PEF). Patient-reported outcomes (PROs) were also reviewed for included studies. Study quality was assessed by 2 reviewers using the Newcastle-Ottawa Quality Assessment Scale of Cohort Studies and the International Society of Pharmacoeconomics and Outcomes Research checklist. RESULTS: A total of 42 studies were included; 20 studies evaluated pulmonary function and 9 evaluated rescue beta-agonist use. Statistically significant improvements in FEV1 were reported in 75% (15/20) of included studies. Improvements in FEV1 ranged from 3.2%-43.6%. Five studies reported changes in FVC or FEV1/FVC. Significant improvements in FVC were observed in 3 studies and in FEV1/FVC in 2 studies. Six studies analyzed PEF with 5 finding significant improvements. Seven studies reported significant reductions in rescue medication use. The percentage of patients with any rescue medication use ranged from 87.0%-97.7% at baseline to 12.5%-49.8% at follow-up. In studies examining change in use from baseline, change at follow-up ranged from 56.1%-78.8%. Among the included studies, 14 utilized patient-reported health-related quality of life (HRQoL) outcomes. The ACT (12 studies) and the AQLQ (4 studies) were the most commonly used surveys to assess asthma control and HRQoL, and improvements were consistently seen after omalizumab was added to therapy. CONCLUSIONS: While patient populations and outcome definitions are heterogeneous, overall, patients with moderate to severe asthma using omalizumab had improvements in FEV1 and PEF and experienced a decrease in the need for rescue beta-agonist medications. Patient-reported asthma control and HRQoL appears to improve among patients utilizing omalizumab in clinical settings. CLINICAL IMPLICATIONS: Asthma patients administered omalizumab during routine clinical use experience significant clinical benefits, including an improvement in pulmonary function and decrease in rescue medication usage. DISCLOSURE: Jonathan Corren: Consultant fee, speaker bureau, advisory committee, etc.: Consultant to Novartis Susan Gabriel: Employee: Novartis Employee Tom Karagiannis: Employee: Novartis employee Kimberly Ruiz: Consultant fee, speaker bureau, advisory committee, etc.: Consultant to Novartis Bethany Sawchyn: Consultant fee, speaker bureau, advisory committee, etc.: Consultant to Novartis Jennifer Colby: Consultant fee, speaker bureau, advisory committee, etc.: Consultant to Novartis Meryl Mendelson: Employee: Novartis employee No Product/Research Disclosure Information

Combined bronchodilators (tiotropium plus olodaterol) for patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), a respiratory disease characterized by a progressive decline in lung function, is considered to be a leading cause of morbidity and mortality. Long-acting inhaled bronchodilators, such as long-acting β2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs), are the cornerstone of maintenance therapy for patients with moderate-to-very-severe COPD. For patients not sufficiently controlled on a single long-acting bronchodilator, a combination of different bronchodilators has shown a significant increase in lung function. Tiotropium, a once-daily dosing LAMA, demonstrated sustained improvements in lung function as well as improved health-related quality of life, reduced exacerbations, and increased survival without altering the rate of decline in the mean forced expiratory volume in 1 second (FEV1) with fairly tolerable side effects. Olodaterol is a once-daily dosing LABA that has proven to be effective in improving lung function, reducing rescue medication use, and improving dyspnea and health-related quality of life, as well as improving exercise endurance with an acceptable safety profile. The combination of olodaterol and tiotropium provided additional improvements in lung function greater than monotherapy with each drug alone. Several well-designed randomized trials confirmed that the synergistic effect of both drugs in combination was able to improve lung function and health-related quality of life without a significant increase in adverse effects. The objective of this paper is to review available evidence on the clinical efficacy and safety of tiotropium, olodaterol, and their combination in patients with COPD.

Glycopyrronium Improved Health Status, Dyspnea, and Reduced Rescue Medication Use in Patients With Moderate-to-Severe COPD: Pooled Analysis From GEM1 and GEM2 Studies

SESSION TITLE: COPD Posters IV SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: Long-acting bronchodilators including muscarinic antagonists are central to the management of symptoms in patients with COPD. Glycopyrronium (GLY) 50 μg q.d. is approved for maintenance bronchodilator treatment in patients with COPD in more than 80 countries including countries within the EU and Japan, Canada, Switzerland and Australia. Here, we present the results of patient reported outcomes from the pooled analysis of GEM1 and GEM2 studies. METHODS: GEM1 and GEM2 were 12-week, multicenter, double-blind, placebo-controlled, replicate studies, designed to assess efficacy and safety of GLY 12.5 μg b.i.d compared with placebo (both delivered via the NeohalerTM device). Change in health status, dyspnea, and rescue medication use were measured by St. George's Respiratory Questionnaire [SGRQ] total score, Transition Dyspnea Index [TDI] focal score, and puffs/day of rescue medication, respectively. RESULTS: Data from 867 patients from the GEM1 and GEM2 studies (GLY, n=437, placebo, n=430) were included in this analysis. Baseline patient demographics were comparable between the two treatment groups. At week 12, compared with placebo, GLY showed a significant reduction in the SGRQ total score [Least Square Mean treatment difference (LSMTD) (95% CI): -4.0 units (-5.6, -2.3), p<0.001] which reached the minimal clinically important difference (MCID) of ≥4 units decrease in SGRQ total score from baseline. GLY also showed a significant improvement in TDI focal score [LSMTD (95% CI): 0.70 units (0.28, 1.12); p=0.001] at week 12 compared with placebo. The proportion of patients achieving the MCID for the SGRQ total score (≥4 units decrease) and TDI focal score (≥1 unit) at week 12 were significantly higher with GLY compared with placebo (SGRQ: GLY, 52%, placebo, 42%, Odds ratio (95%CI) 1.59 (1.19,2.12), p=0.002; TDI: GLY, 54%; placebo, 41%, Odds ratio (95%CI), 1.75 (1.30, 2.36), p<0.001]. The change from baseline in rescue medication use over 12 weeks was significantly lower with GLY compared with placebo [LSMTD (95% CI): -0.66 puffs/day (-0.97, -0.36); p<0.001]. CONCLUSIONS: In COPD patients with moderate-to-severe airflow limitation, treatment with glycopyrronium 12.5 μg b.i.d. improves health status and dyspnea, and reduces rescue medication usage. CLINICAL IMPLICATIONS: Glycopyrronium 12.5 μg twice daily can be an effective treatment option to reduce COPD symptoms and improve quality of life in patients with COPD with moderate-to-severe airflow limitation. DISCLOSURE: Craig Laforce: Consultant fee, speaker bureau, advisory committee, etc.: Consultant to Novartis, Grant monies (from industry related sources): the principal investigator on trials with the following pharmaceutical companies including Novartis Edward Kerwin: Consultant fee, speaker bureau, advisory committee, etc.: Has served on advisory boards, speaker panels, or received travel reimbursement for Novartis Pharmaceuticals, Grant monies (from industry related sources): He has conducted multicenter clinical research trials for approximately forty pharmaceutical companies including Novartis. Selwyn Spangenthal: Consultant fee, speaker bureau, advisory committee, etc.: Has received honoraria from AstraZeneca, Forest, Mylan Labs, and Novartis Peter D'Andrea: Employee: Employee of the study sponsor, Novartis, and no other conflicts Joerg H. Eckert: Employee: Employee of the study sponsor, Novartis, and no other conflicts Michelle Henley: Employee: Employee of the study sponsor, Novartis, and no other conflicts Francesco Patalano: Employee: Employee of the study sponsor, Novartis and no other conflicts No Product/Research Disclosure Information

Indacaterol vs tiotropium in COPD patients classified as GOLD A and B

According to current GOLD strategy, patients with COPD classified as groups A and B may be treated with inhaled bronchodilators, either long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA). However, there is little guidance on which class of agent is preferred and a lack of prospective data to differentiate the two. In this study, we performed post-hoc analyses of pooled data from two prospective, controlled clinical trials comparing the LABA indacaterol and LAMA tiotropium in 1422 patients with moderate airflow limitation and no history of exacerbations in the previous year. This population fits the definitions of GOLD A and B groups and could be further stratified by symptom severity using Baseline Dyspnea Index (i.e. modeling GOLD A or B) and inhaled corticosteroid (ICS) use at baseline. Outcomes measured after 12 weeks of treatment were lung function (forced expiratory volume in 1s; FEV1), health status (St George's Respiratory Questionnaire; SGRQ), symptoms (Transition Dyspnea Index; TDI) and rescue medication use. In 'GOLD A' patients not receiving ICS, differences favored indacaterol versus tiotropium (trough FEV1 0.05L; rescue medication use -0.41 puffs/day; TDI total score 0.94 points; SGRQ total score -3.13 units, all p<0.01). In 'GOLD B, no ICS' patients, compared with tiotropium, indacaterol treatment increased trough FEV1 (0.055L, p<0.05) and permitted a larger reduction in rescue medication use (-0.81 puffs/day, p=0.004). In all patients, and in patients not using ICS, differences favored indacaterol for all variables. Our findings suggest that patients in GOLD groups A and B may experience greater benefits with indacaterol than with tiotropium.

Efficacy and Safety of a Fixed-Dose Combination of Indacaterol and Glycopyrronium for the Treatment of COPD: A Systematic Review

<h3>BACKGROUND</h3> COPD guidelines recommend the combined use of inhaled, long-acting β₂-agonists and long-acting muscarinic antagonists if symptoms are not improved by a single agent. This systematic review assessed the efficacy and safety of the fixed-dose combination of the long-acting β₂-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium (QVA149) compared with its monocomponents (glycopyrronium and indacaterol) and tiotropium for the treatment of moderate to severe COPD. <h3>METHODS</h3> This was a systematic review of randomized, placebo-controlled or crossover trials (3-64 weeks). Primary outcomes were trough FEV₁, severe adverse events, and serious cardiovascular events. <h3>RESULTS</h3> Five trials (4,842 patients) were included. Compared with tiotropium, QVA149 showed a significant increase in trough FEV₁ (70 mL; <i>P</i> < .0001) and a decreased use of rescue medication (−0.63 puffs/d; <i>P</i> < .0001). Patients receiving QVA149 had a 19% greater likelihood of experiencing a minimal clinical important difference (MCID) in the number needed to treat for benefit (NNTB) (NNTB = 11) and a 16% greater likelihood of achieving an MCID in the St. George's Respiratory Questionnaire (SGRQ) (NNTB = 11). Similarly, QVA149 vs glycopyrronium showed a significant increase in trough FEV₁ (70 mL; <i>P</i> < .0001), a significant reduction in rescue medication use (−0.59; <i>P</i> < .0001), and a significant increase in the rate of patients achieving an MCID in the SGRQ (NNTB = 12). QVA149 showed similar levels of safety and tolerability to both comparators. It was not possible to perform a pooled analysis of data comparing QVA149 vs indacaterol. <h3>CONCLUSIONS</h3> Once-daily, inhaled QVA149 showed superior efficacy compared with glycopyrronium and the current standard of care, tiotropium, in patients with moderate to severe COPD.

Assessment of various second-line medications in addition to inhaled corticosteroid in asthma patients: a randomized controlled trial.

Many patients with persistent asthma cannot achieve the treatment goal for asthma with a single controller medication. The aim of the present study was to assess lung function and rescue medication use in asthma patients receiving four different categories of drugs in combination with an inhaled corticosteroid. Patients recruited to the study were randomized into four groups to receive budesonide with either formoterol, doxofylline, montelukast or tiotropium for a period of 3 months. Lung function (i.e. forced expiratory volume in 1 s (FEV1 )) and rescue medication use were determined at baseline and on Day 15, 30, 45, 60 and 90 of treatment. A total of 297 patients completed the study. At baseline, no significant differences (P > 0.05) were observed in any of the outcome measures. Significant within-group improvement in FEV1 was observed in all groups. On Day 90, between-group differences showed that the improvement in FEV1 was significantly (P < 0.05) higher for patients receiving budesonide + formoterol, followed by budesonide + montelukast and budesonide + doxofylline, and least for those receiving budesonide + tiotropium. Similarly, within- and between-group comparisons showed significant (P < 0.05) reductions in rescue medication use in all groups. However, the magnitude of the decrease was greater in the budesonide + formoterol group, followed by the budesonide + montelukast, budesonide + doxofylline and budesonide + tiotropium groups. Based on our findings, among the second-line treatment regimens, budesonide with either montelukast or doxofylline was found to be better than budesonide + tiotropium in patients with mild-to-moderate persistent asthma. Further studies with a longer duration are likely to be useful.

Pulmonary Function Assessment in Mild to Moderate Persistent Asthma Patients Receiving Montelukast, Doxofylline, and Tiotropium With Budesonide: A Randomized Controlled Study

BackgroundThere is no comparative study among asthma patients receiving first-line versus various second-line treatment regimens for mild to moderate persistent asthma. ObjectiveWe assessed the pulmonary function in asthma patients receiving montelukast, doxofylline, and tiotropium with budesonide in a pilot group. MethodsPatients were recruited as per the study criteria and randomly allocated to 4 groups to receive budesonide (400 µg) with formoterol (12 µg), doxofylline (400 mg), montelukast (10 mg), or tiotropium (18 µg) for a period of 3 months. Outcomes included forced expiratory volume in 1 second (FEV1) and rescue medication use. ResultsA total of 167 patients were recruited; among them, 123 patients completed the study. At baseline, no significant difference (P > 0.05) was observed in any of the outcome measures. Significant within-group improvement in FEV1 was observed in all the groups. At day 90, between-group difference revealed that improvement in FEV1 was significantly (P < 0.05) high for budesonide plus formoterol followed by budesonide plus doxofylline, budesonide plus montelukast, and, lastly, budesonide plus tiotropium. Similarly, within-group comparison revealed a significant (P < 0.05) reduction in rescue medication use in all the groups. The intensity in decrease was more in budesonide plus formoterol group followed by budesonide plus doxofylline, budesonide plus montelukast, and budesonide plus tiotropium groups. ConclusionOn the basis of our findings, among the second-line treatment regimens, budesonide plus doxofylline and budesonide plus montelukast was found to be better than budesonide plus tiotropium in patients with mild to moderate persistent asthma. Further studies with a larger sample size are likely to be useful.

Once daily glycopyrronium for the treatment of COPD: pooled analysis of the GLOW1 and GLOW2 studies

Background:Glycopyrronium is a once daily (o.d.) long-acting muscarinic antagonist that is approved for maintenance treatment of COPD. This post-hoc pooled analysis of two phase III studies, GLycopyrronium bromide in COPD airWays 1 and 2 (GLOW1 and GLOW2), evaluated the effects of glycopyrronium compared with placebo and tiotropium over 26–52 weeks in patients with moderate-to-severe COPD.Methods:Patients aged ≥40 years were randomised to 26 weeks’ treatment with glycopyrronium 50 μg o.d. or placebo (GLOW1) or 52 weeks’ treatment with glycopyrronium 50 μg o.d., placebo, or open-label tiotropium 18 μg o.d. (GLOW2). The primary efficacy endpoint in both studies was trough forced expiratory volume in one second (FEV1) at Week 12. Other outcomes included additional spirometry endpoints, moderate or severe exacerbations, dyspnoea, health status, rescue medication use and safety. Serial spirometry over 24 hours was conducted in a subset of patients.Results:Of 1888 subjects randomised, 98.2% were analysed (glycopyrronium 1059, tiotropium 267, placebo 528). Least squares mean (LSM) trough FEV1 was significantly higher with glycopyrronium versus placebo at Week 12 (treatment difference ± standard error [SE]: 103 ± 11.2 mL; p < 0.001), as well as at Day 1 and Weeks 26 and 52. More patients achieved ≥100 mL increase in trough FEV1 from baseline with glycopyrronium versus placebo at all assessments (p < 0.001). Glycopyrronium significantly improved FEV1 immediately after the first dose on Day 1 versus placebo (90 mL at 5 minutes, 144 mL at 15 minutes; both p < 0.001) and versus tiotropium (43 mL at 5 minutes, 65 mL at 15 minutes; both p < 0.001). Glycopyrronium significantly improved other spirometry endpoints and provided clinically meaningful 24 hour bronchodilation versus placebo at most timepoints from Day 1 onwards (p < 0.05). Time to first moderate or severe exacerbation was significantly prolonged with glycopyrronium versus placebo over 26 and 52 weeks (36% and 33%, respectively; both p < 0.001). Glycopyrronium provided significantly greater relief of dyspnoea, improved health status and reduced rescue medication use versus placebo. Glycopyrronium was safe and well tolerated.Conclusions:Glycopyrronium 50 μg o.d. provided early bronchodilation after the first dose that was sustained for 24 hours, and reduced the risk of exacerbations compared with placebo, with efficacy at least equivalent to tiotropium.Trial Registrations:NCT01005901 and NCT00929110.

Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD

Aclidinium is a novel, long-acting muscarinic antagonist indicated for maintenance treatment of COPD. In this 52-week, parallel-group, double-blind study, patients with moderate-to-severe COPD were randomized (1:1) to receive aclidinium twice-daily (BID) 200 μg or 400 μg via a novel, dry powder inhaler (Genuair(®)/Pressair(®)) [Registered trademarks of Almirall, SA, Barcelona, Spain for use within the European Union, Iceland, Norway, and Switzerland as Genuair(®) and within the United States as Pressair(®)]. Safety, the primary objective, was assessed via adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead electrocardiograms. Efficacy was evaluated using spirometry, SGRQ, and rescue medication use. A total of 605 patients were randomized in the study. The percentage of patients reporting any treatment-emergent AE (TEAE) was comparable between groups; most TEAEs were mild or moderate. Anticholinergic TEAEs were reported by low percentages of patients in either treatment group (dry mouth: 200 μg, 1.3%; 400 μg, 2.7%; constipation: 200 μg, 2.9%; 400 μg, 1.7%). Cardiac TEAEs were also reported by a low percentage of patients (<2% for any event in any group) and did not appear to be dose dependent. There were no clinically relevant abnormalities in other safety outcomes. Both aclidinium 200 μg and 400 μg resulted in improvements from baseline to Week 52 in FEV1, with numerically greater increases observed with the higher dose. Clinically important improvements in SGRQ scores and a reduction in rescue medication use were observed throughout the study for both doses. Long-term treatment with aclidinium 200 μg or 400 μg BID was well tolerated, with sustained benefits in lung function and health status in patients with COPD throughout the 1-year study.

Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A meta-analysis–based comparison

Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration. We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen. An indirect meta-analysis-based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed. The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16). Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen.

How Do Children and Their Caregivers Perceive the Benefits of Inhaled Asthma Therapy?

Objective.Although well reported in adults, there is relatively little data on how children with asthma and their parents describe their attitudes to the disease, expectations of therapy, and perception of treatment benefit. We investigated this to determine if they differed from reports by adults with asthma. Methods. We recruited families with an asthmatic child (4–11 years) who had recently been prescribed a change in treatment [starting inhaled corticosteroid monotherapy (ICS) or changing from ICS to inhaled corticosteroid/long-acting β2-agonist combination therapy (ICS/LABA)]. Semi-structured interviews were conducted with the parents and the children if aged 7–11 years. Results. We interviewed 28 parents and 13 children. All children on ICS/LABA had been changed from ICS monotherapy because of poor asthma control. Pediatric asthma had a significant impact on the whole family and both parents and children hoped the new medication would improve symptoms, increase their participation in physical activities, and decrease unscheduled visits to the GP (General Practitioner)/hospital. Positive effects of treatment change were reported by both parents and children, particularly in those changing from ICS to ICS/LABA. The most commonly reported benefits were reduced cough and wheeze, increased participation in sport or play activities, and reduced rescue medication use. These effects resulted in fewer visits to the GP/hospital and better attendance at school. Conclusions. While asthma symptoms prevent adults and children from participating in different types of activities (e.g., school, employment), children and their parents report the same benefits as previously reported in adults with asthma.