AMPLIFY: a randomized, Phase III study evaluating the efficacy and safety of aclidinium/formoterol vs monocomponents and tiotropium in patients with moderate-to-very severe symptomatic COPD.
ABSTRACT: Background:AMPLIFY assessed the efficacy and safety of aclidinium bromide/formoterol fumarate (AB/FF) vs its monocomponents and tiotropium (TIO) in patients with moderate-to-very severe symptomatic COPD (NCT02796677). Methods:In this 24-week, Phase III, double-dummy, active-controlled study, symptomatic patients (COPD Assessment Test score ≥10) were randomized to twice-daily AB/FF 400/12 µg, AB 400 µg, or FF 12 µg, or once-daily TIO 18 µg. Co-primary endpoints were change from baseline at week 24 in 1-hour morning post-dose FEV1 (AB/FF vs AB) and in pre-dose (trough) FEV1 (AB/FF vs FF). Non-inferiority of AB vs TIO in pre-dose FEV1 was also an objective. Normalized area under the curve (AUC)0-3/3 h FEV1 and nighttime and early morning symptoms were also assessed. A subgroup participated in a 24-hour serial spirometry sub-study. Results:A total of 1,594 patients were randomized; 566 entered the sub-study. At week 24, 1-hour post-dose FEV1 significantly improved with AB/FF vs AB, FF, and TIO (84, 84, and 92 mL; all P<0.0001). AB/FF significantly improved trough FEV1 vs FF (55 mL, P<0.001) and AB was non-inferior to TIO. AB/FF significantly improved AUC0-3/3 h FEV1 vs all comparators (P<0.0001) and provided significant improvements in early morning symptoms vs TIO. The 24-hour spirometry demonstrated significantly greater improvements with AB/FF in AUC12-24/12 h vs all comparators, and in AUC0-24/24 h vs FF or TIO at week 24. Conclusion:In patients with moderate-to-very severe symptomatic COPD, twice-daily AB/FF significantly improved lung function vs monocomponents and TIO, and early morning symptom control vs TIO.
Project description:TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10?µg (n=664), BFF MDI 160/10?µg (n=649), FF MDI 10?µg (n=648), BD MDI 320?µg (n=209) or open-label budesonide/formoterol DPI 400/12?µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1?s (FEV1) and FEV1 area under the curve from 0-4?h (AUC0-4). Time to first and rate of moderate/severe exacerbations were assessed.BFF MDI 320/10?µg improved pre-dose trough FEV1versus FF MDI (least squares mean (LSM) 39?mL; p=0.0018), and BFF MDI 320/10?µg and 160/10?µg improved FEV1 AUC0-4versus BD MDI (LSM 173?mL and 157?mL, respectively; both p<0.0001) at week 24. BFF MDI 320/10?µg and 160/10?µg improved time to first and rate of moderate/severe exacerbations versus FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.
Project description:Inhaled corticosteroids are a mainstay of therapy for persistent asthma, but suboptimal adherence with twice-daily use is widespread. Fluticasone furoate (FF) is a new inhaled corticosteroid (ICS) suitable for once-daily dosing in asthma. This study was performed to descriptively assess the efficacy and safety of two doses of FF, with no planned formal statistical hypothesis testing.This was a 24-week double-blind, multicentre, parallel-group study (NCT01431950). Patients aged ? 12 years with moderate-severe persistent asthma and uncontrolled on mid-high dose ICS were stratified by baseline FEV1 and randomised (1:1) to treatment with FF 100 ?g or 200 ?g once daily in the evening. The primary endpoint was change from baseline trough FEV1 after 24 weeks; secondary and other endpoints included peak expiratory flow (PEF) and rescue-free and symptom-free 24-hour periods over Weeks 1-24, and Asthma Control Test™ (ACT) score at Week 24. A pre-specified subgroup analysis of patients by randomisation strata was performed for the primary and selected secondary and other endpoints. Safety assessments included adverse events, laboratory and vital sign measurements, and change from baseline in 24-hour urinary cortisol at Week 24.With FF 100 ?g and 200 ?g, least squares mean trough FEV1 improved from baseline by 208 mL and 284 mL, respectively, at Week 24; treatment difference: 77 mL (95% CI: -39, 192). Similar improvements from baseline in rescue- and symptom-free periods, and morning and evening PEF were observed in both groups. Patients were 42% more likely to be well-controlled (ACT score ? 20) with FF 200 ?g than with FF 100 ?g. Slightly more patients receiving FF 200 ?g vs. FF 100 ?g reported adverse events (63% vs. 59%) and events deemed treatment related (5% vs. <1%). Seven serious adverse events (FF 200 ?g 4; FF 100 ?g 3) were reported, none of which were deemed treatment related. No clinically relevant effects of either dose on 24-hour urinary cortisol were observed.Improvements from baseline in trough FEV1 were observed after 24 weeks of treatment with both doses of FF, with a numerically greater improvement in FEV1 observed in patients receiving FF 200 ?g. Secondary endpoint findings were similar between groups. No safety concerns were identified during the study.
Project description:BACKGROUND:The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ?2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. METHODS:207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25??g via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12??g via metered-dose inhaler plus once-daily tiotropium (TIO) 18??g via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1?s (FEV1) <?50% predicted, or FEV1 <?80% predicted and???2 moderate or 1?severe exacerbations in the prior year. The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0-24-h FEV1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively. RESULTS:The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15?mL [-?13, 43]; Study 207609: 11?mL [-?20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38?mL [10, 66]; Study 207609: 51?mL [21, 82]) and FEV1 at 12 and 24?h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (<?1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies. CONCLUSIONS:FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. TRIAL REGISTRATION:GSK (207608/207609; NCT03478683/NCT03478696).
Project description:Purpose:To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 µg) using innovative co-suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 µg and formoterol fumarate (FF) MDI 9.6 µg, in patients with moderate-to-severe COPD. Methods:In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0-12) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 on Day 7. Safety was assessed. Results:All 185 randomized patients received treatment. All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 µg (all P≤0.0137). For peak change in FEV1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 µg. No significant differences were observed between GFF MDI and FF MDI 9.6 µg for primary and secondary endpoints. The incidence of adverse events was similar between treatments. Conclusion:While all doses of GFF MDI were superior to GP MDI 36 µg for the primary end-point, in this study neither superiority of GFF MDI to FF MDI 9.6 µg nor a clear dose-response was observed. All treatments were well tolerated with no unexpected safety findings.
Project description:Background:Aclidinium/formoterol 400/12 µg is a twice-daily maintenance bronchodilator for COPD. This post hoc study evaluated aclidinium/formoterol vs aclidinium 400 µg, formoterol 12 µg, or placebo in patient subgroups. Patients and methods:Data were pooled from two 24-week Phase III clinical trials (ACLIFORM and AUGMENT). Patients (N=3,394) were analyzed by baseline airflow obstruction severity (moderate/severe), age (<65/?65 years), sex, and exacerbation history (0/?1 exacerbation in the previous 12 months). Changes from baseline vs placebo and mono-therapies were evaluated: morning pre-dose (trough) and morning 1-hour post-dose FEV1, Transition Dyspnea Index (TDI), and moderate/severe exacerbation rates (healthcare resource utilization [HCRU] and EXAcerbations of Chronic pulmonary disease Tool [EXACT] criteria). Results:Aclidinium/formoterol improved the post-dose FEV1 vs placebo and monotherapy in all subgroups (all P<0.01) and trough FEV1 vs placebo (P<0.001) and formoterol (P<0.05) across all subgroups. Improvements in trough FEV1 were observed vs aclidinium in patients with severe airflow obstruction, patients aged <65 years, males, and patients with exacerbation history (P<0.05). Improvements in TDI were observed vs placebo in all subgroups (all P<0.001), monotherapies for patients with moderate (formoterol P<0.05) or severe airflow obstruction (aclidinium P<0.05), patients aged <65 years (aclidinium P<0.01, formoterol P<0.05), males (formoterol P<0.05), and patients with no exacerbation history (formoterol P<0.05). HCRU exacerbation rates were lower for aclidinium/formoterol vs placebo in patients with no exacerbation history (P<0.01). EXACT exacerbation rates were lower for aclidinium/formoterol in patients with moderate airflow obstruction vs placebo and aclidinium, patients aged <65 years vs placebo and ?65 years vs formoterol, males vs placebo, and patients with no exacerbation history vs placebo (all P<0.05). Conclusion:Aclidinium/formoterol significantly improved post-dose FEV1, trough FEV1, and TDI vs placebo across all subgroups and vs monotherapy in many subgroups. These findings further support the benefits of aclidinium/formoterol for all patients with COPD.
Project description:Fluticasone furoate (FF) is a novel, once-daily inhaled corticosteroid (ICS) that has been shown to improve lung function vs. placebo in asthma patients. This study evaluated the efficacy and safety of FF 50 mcg compared with placebo in asthma patients uncontrolled by non-ICS therapy.This 12-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study randomized 248 patients (aged ?12 years) to once-daily FF 50 mcg administered via the ELLIPTA™a dry powder inhaler or placebo. The primary endpoint was change from baseline in pre-dose evening trough forced expiratory volume in one second (FEV1). Secondary endpoints were change from baseline in percentage of rescue-free 24-h periods (powered), evening and morning peak expiratory flow, symptom-free 24-h periods and withdrawals due to lack of efficacy. Other endpoints included Asthma Control Test™, Asthma Quality of Life Questionnaire and ELLIPTA ease of use questions. Safety was assessed throughout the study.There was a significant difference in evening trough FEV1 between FF 50 mcg and placebo (treatment difference: 120 mL; p?=?0.012). There was also a significant difference in rescue-free 24-h periods (11.6%; p?=?0.004) vs. placebo. There were numerically greater improvements with FF vs. placebo for all remaining secondary endpoints. The incidence of adverse events was lower with FF (31%) than with placebo (38%); few were treatment-related (FF 50 mcg: n?=?1, <1%; placebo: n?=?4, 3%).FF 50 mcg once daily significantly improved FEV1 and percentage of rescue-free 24-h periods experienced over 12 weeks vs. placebo, and was well tolerated.www.clinicaltrials.gov, registration number: NCT01436071.
Project description:Inhaled corticosteroid/long-acting ?2-agonist combination therapy is a recommended treatment option for patients with chronic obstructive pulmonary disease (COPD) and increased exacerbation risk, particularly those with elevated blood eosinophil levels. SOPHOS (NCT02727660) evaluated the efficacy and safety of two doses of budesonide/formoterol fumarate dihydrate metered dose inhaler (BFF MDI) versus formoterol fumarate dihydrate (FF) MDI, each delivered using co-suspension delivery technology, in patients with moderate-to-very severe COPD and a history of exacerbations. In this phase 3, randomised, double-blind, parallel-group, 12-52-week, variable length study, patients received twice-daily BFF MDI 320/10?µg or 160/10?µg, or FF MDI 10?µg. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 12. Secondary and other endpoints included assessments of moderate/severe COPD exacerbations and safety. The primary analysis (modified intent-to-treat) population included 1843 patients (BFF MDI 320/10?µg, n=619; BFF MDI 160/10?µg, n=617; and FF MDI, n=607). BFF MDI 320/10?µg and 160/10?µg improved morning pre-dose trough FEV1 at week 12 versus FF MDI (least squares mean differences 34?mL [p=0.0081] and 32?mL [p=0.0134], respectively), increased time to first exacerbation (hazard ratios 0.827 [p=0.0441] and 0.803 [p=0.0198], respectively) and reduced exacerbation rate (rate ratios 0.67 [p=0.0001] and 0.71 [p=0.0010], respectively). Lung function and exacerbation benefits were driven by patients with blood eosinophil counts ?150?cells·mm-3. The incidence of adverse events was similar, and pneumonia rates were low (?2.4%) across treatments. SOPHOS demonstrated the efficacy and tolerability of BFF MDI 320/10?µg and 160/10?µg in patients with moderate-to-very severe COPD at increased risk of exacerbations.
Project description:Morning symptoms associated with COPD have a negative impact on patients' quality of life. Long-acting bronchodilators with rapid onset may relieve patients' symptoms. In the Symptoms and Pulmonary function in the moRnING study, we prospectively compared the rapid onset bronchodilator profile of glycopyrronium (GLY) and tiotropium (TIO) during the first few hours after dosing in patients with moderate-to-severe COPD.Patients were randomized (1:1) to receive either once-daily GLY (50 ?g) or TIO (18 ?g) and corresponding placebos in a cross-over design for 28 days. The primary objective was to demonstrate the superiority of GLY versus TIO in area under the curve from 0 to 4 hours (AUC0-4h) forced expiratory volume in 1 second (FEV1) after the first dose. The secondary objective was to compare GLY versus TIO using the patient reported outcomes Morning COPD Symptoms Questionnaire 3 hours post-inhalation.One-hundred and twenty-six patients were randomized (male 70.2%; mean age 65.7 years) and 108 patients completed the study. On Day 1, GLY resulted in significantly higher FEV1 AUC0-4h after the first dose versus TIO (treatment difference [?], 0.030 L, 95% confidence interval 0.004-0.056, P=0.025). Improvements in morning COPD symptoms from baseline at Days 1 and 28 were similar between GLY and TIO. Post hoc analysis of the FEV1 AUC0-4h by time point on Day 1 showed significant improvements in patients receiving GLY versus TIO at 5 minutes (?=0.029 L, P=0.015), 15 minutes (?=0.033 L, P=0.026), and 1 hour (?=0.044 L, P=0.014). Safety results were comparable between both treatments.The SPRING study demonstrates the superiority of GLY versus TIO in terms of superior bronchodilation in the first 4 hours after administration, thus extending the clinical data that support a faster onset of action of GLY versus TIO.
Project description:BACKGROUND:The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4. METHODS:PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6??g, glycopyrrolate (GP) MDI 18??g, formoterol fumarate (FF) MDI 9.6??g, or placebo MDI, twice-daily for 24?weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1?s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed. RESULTS:The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ?15, and 25.0% had experienced ?1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59?mL [43, 75]), FF MDI (65?mL [48, 81]), and placebo MDI (146?mL [125, 166]); all p?<?0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p?=?0.0168), 15% (p?=?0.0628), and 28% (p?=?0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ?15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p?<?0.0001. All treatments were well tolerated, with no unexpected safety signals. CONCLUSIONS:This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history. TRIAL REGISTRATION:ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).
Project description:BACKGROUND:QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting ?2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD. METHODS:This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ?40?years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1?s (FEV1) ?30% to <80% predicted) to QVA149 110/50?µg o.d. or TIO 18?µg o.d.+ FOR 12?µg twice daily (1:1) for 26?weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety. RESULTS:Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: -0.69 units; 95% CI -2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ?1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68?mL, 95% CI 37?mL to 100?mL; p<0.001) and FVC (+74?mL, 95% CI 24?mL to 125?mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%). CONCLUSIONS:QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD. TRIAL REGISTRATION NUMBER:NCT01120717.