Gregory Feldman

Efficacy and safety of indacaterol 150 μg once-daily in COPD: a double-blind, randomised, 12-week study

BackgroundIndacaterol is a novel, once-daily (o.d.) inhaled, long-acting β2-agonist in development for chronic obstructive pulmonary disease (COPD). This 12-week, double-blind study compared the efficacy, safety, and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD.MethodsEfficacy variables included 24-h trough FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (primary endpoint) and after Day 1, and the percentage of COPD days with poor control (i.e., worsening symptoms). Safety was assessed by adverse events (AEs), mean serum potassium and blood glucose, QTc (Fridericia), and vital signs.ResultsPatients were randomised (n = 416, mean age 63 years) to receive either indacaterol 150 μg o.d. (n = 211) or placebo (n = 205) via a single-dose dry-powder inhaler; 87.5% completed the study. Trough FEV1 (LSM ± SEM) at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo, a clinically relevant difference of 130 ± 24 mL (p < 0.001). Trough FEV1 after one dose was significantly higher with indacaterol than placebo (p < 0.001). Indacaterol demonstrated significantly higher peak FEV1 than placebo, both on Day 1 and at Week 12, with indacaterol-placebo differences (LSM ± SEM) of 190 ± 28 (p < 0.001) and 160 ± 28 mL (p < 0.001), respectively. Standardised AUC measurements for FEV1 (between 5 min and 4 h, 5 min and 1 h, and 1 and 4 h post-dose) at Week 12 were all significantly greater with indacaterol than placebo (p < 0.001), with LSM (± SEM) differences of 170 ± 24, 180 ± 24, and 170 ± 24 mL, respectively. Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5% (p < 0.001) and was also associated with significantly reduced use of rescue medication (p < 0.001). The overall rates of AEs were comparable between the groups (indacaterol 49.3%, placebo 46.8%), with the most common AEs being COPD worsening (indacaterol 8.5%, placebo 12.2%) and cough (indacaterol 6.2%, placebo 7.3%). One patient died in the placebo group. Serum potassium and blood glucose levels did not differ significantly between the two groups, and no patient had QTc >500 ms.ConclusionsIndacaterol 150 μg o.d. provided clinically significant and sustained bronchodilation, reduced rescue medication use, and had a safety and tolerability profile similar to placebo.Trial registrationNCT00624286

The Efficacy and Safety of the Novel Long-Acting β2 Agonist Vilanterol in Patients With COPD: A Randomized Placebo-Controlled Trial

BACKGROUND Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD. METHODS Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests. RESULTS VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels. CONCLUSIONS VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.

Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial.

BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD. However, the dose of inhaled corticosteroid to use in a once-daily combination is unknown. We compared two strengths of fluticasone furoate (FF) plus vilanterol (VI), the same strengths of the individual components, and placebo. METHODS Multicentre, randomised, 24-week, double-blind, placebo-controlled, parallel-group study in stable, moderate-to-severe COPD subjects (N = 1224). Subjects were randomised to FF/VI (200/25 μg; 100/25 μg), FF (200 μg; 100 μg), VI 25 μg, or placebo, once daily in the morning. Co-primary efficacy endpoints; 0-4 h weighted mean (wm) FEV(1) on day 168, and change from baseline in trough (23-24 h post-dose) FEV(1) on day 169. The primary safety objective was adverse events (AEs). RESULTS There was a statistically significant (p < 0.001) increase in wm FEV(1) (209 ml) and trough FEV(1) (131 ml) for FF/VI 200/25 μg vs. placebo; similar changes were seen for FF/VI 100/25 μg vs. placebo. Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1) (32 ml) was not statistically significant (p = 0.224), the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1) (168 ml) was significantly different (p < 0.001). VI 25 μg significantly improved wm and trough FEV(1) vs. placebo (185 ml and 100 ml, [corrected] respectively). No increase was seen in on-treatment AEs or serious AEs (SAEs), with active therapy vs. placebo. CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1) in subjects with moderate-to-severe COPD, which was not influenced by the dose of FF. These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study. GSK study number: HZC112207. ClinicalTrials.gov: NCT01054885.

Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies

Background Olodaterol is a long-acting β2-agonist with a 24-hour bronchodilator profile. Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving usual-care background therapy. Methods Patients received olodaterol 5 μg or 10 μg or placebo once daily for 48 weeks. Coprimary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0–3) response (change from baseline), and trough FEV1 response at 12 weeks. Secondary end points included additional lung function assessments, use of rescue medications, FEV1 AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks. Results Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively. In both studies, olodaterol 5 μg and 10 μg significantly improved the FEV1 AUC0–3 response (P<0.0001) and trough FEV1 (study 1222.11, P<0.0001; study 1222.12, P<0.05, post hoc) at week 12, with an incidence of adverse events comparable with that of placebo. Secondary end points supported the efficacy of olodaterol. Conclusion These studies demonstrate the long-term efficacy and safety of once-daily olodaterol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy.

Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients

BACKGROUND This study evaluated the dose-response of the new long-acting muscarinic antagonist umeclidinium (GSK573719) in patients with COPD. METHODS This randomized, double-blind, placebo-controlled, parallel-group study evaluated three once-daily doses of umeclidinium (125, 250 and 500 μg) for 28 days in 285 patients with COPD having FEV(1) of 35-70% predicted (mean (SD) age=61.4 (8.41); mean (SD) post-bronchodilator FEV(1)=1.577 (0.450)). The primary endpoint was morning trough FEV(1) at Day 29. Secondary endpoints included 0-6h weighted mean FEV(1) and serial FEV(1) measured over 6h post-dose and at trough. Safety and pharmacokinetics were also assessed. RESULTS All doses of umeclidinium significantly increased trough FEV(1) over placebo from 150 to 168 mL (p<0.001), 0-6h weighted mean FEV(1) from 113 to 211 mL (p<0.001), and serial FEV(1) at each point in time over 24h. Reductions in salbutamol use and improvements in FVC were noted for all doses. Umeclidinium was well tolerated with no apparent treatment-related changes in vital signs. CONCLUSION Once-daily umeclidinium provides clinically significant, sustained improvement in lung function and is well tolerated.

Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/ salmeterol (250/50 mcg) in COPD patients

BACKGROUND Fluticasone furoate/vilanterol (FF/VI) is an inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA), recently approved as once-daily maintenance therapy for COPD. We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol (FP/SAL). METHODS Three 12 week studies comparing FF/VI and FP/SAL were conducted. Patients aged ≥40 years with moderate-to-very severe COPD were randomized to receive double-blind, double-dummy FF/VI 100/25 mcg once-daily, or FP/SAL 250/50 mcg twice-daily for 12 weeks following a 2 week placebo run-in period. The primary endpoint of each study was change from baseline trough in 0-24 h weighted mean FEV(1) (wmFEV(1)) on Day 84. Safety was also assessed. RESULTS In Study 1 (HZC113109) (intent-to-treat n: FF/VI = 260; FP/SAL = 259), the increase from baseline in 0-24 h wmFEV(1) was significantly greater with FF/VI than FP/SAL (Δ80 mL, P < 0.001). In Study 2 (HZC112352) (intent-to-treat n: FF/VI = 259; FP/SAL = 252) and Study 3 (RLV116974) (intent-to-treat n: FF/VI = 412; FP/SAL = 416), the increase from baseline in 0-24 h wmFEV(1) was not significantly greater with FF/VI than FP/SAL (Δ29 mL, P = 0.267; Δ25 mL, P = 0.137). The treatment difference was statistically but not clinically significant in a pooled analysis (Δ41 mL, P < 0.001). Pooled adverse events (FF/VI 27%; FP/SAL 28%) and serious adverse events (FF/VI 2%; FP/SAL 3%) were similar between treatments. CONCLUSIONS Our data suggest that once-daily FF/VI 100/25 mcg provides FEV(1) improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg, although interpretation is limited by differences in individual study outcomes. The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar. CLINICAL TRIAL REGISTRATION clinicaltrials.gov: NCT01323634; NCT01323621; NCT01706328. GlaxoSmithKline study codes: HZC113109; HZC112352; RLV116974.

Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD

Background: Long‐acting muscarinic antagonist (LAMA)/long‐acting &bgr;2‐agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate‐to‐Very Severe COPD (PINNACLE‐1) (NCT01854645) and the Multi‐Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate‐to‐Very Severe COPD (PINNACLE‐2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6‐&mgr;g (GFF) metered dose inhaler (MDI) formulated using the Co‐Suspension Delivery Technology in patients with moderate‐to‐very severe COPD. Methods: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40–80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 &mgr;g, FF MDI 9.6 &mgr;g, or placebo MDI (all twice daily), or tiotropium 18 &mgr;g dry powder inhaler (once daily in PINNACLE‐1 only [open‐label active comparator]). Efficacy and safety were assessed. Results: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE‐1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE‐2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). Conclusions: We conclude that GFF MDI 18/9.6 &mgr;g demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate‐to‐very severe COPD. Trial Registry: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg compared with tiotropium 18 μg in patients with COPD.

Background The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD. This study investigated the efficacy and safety of UMEC versus TIO in COPD. Methods This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study. Patients were randomized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at day 85 (non-inferiority margin −50 mL; per-protocol [PP] population). Other end points included weighted mean FEV1 over 0–24 and 12–24 hours post-dose. Patient-reported outcomes comprised Transition Dyspnea Index score, St George’s Respiratory Questionnaire total score, and COPD Assessment Test score. Adverse events were also assessed. Results In total, 1,017 patients were randomized to treatment. In the PP population, 489 and 487 patients received UMEC and TIO, respectively. In the PP population, change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29–88; P<0.001). Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 (53 mL, 95% CI: 25–81; P<0.001). Improvements in weighted mean FEV1 over 0–24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12–24 hours post-dose (70 mL; P=0.015). Clinically meaningful improvements in Transition Dyspnea Index and St George’s Respiratory Questionnaire were observed with both treatments at all time points. No differences were observed between UMEC and TIO in patient-reported outcomes. Overall incidences of adverse events were similar for UMEC and TIO. Conclusion UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85. Safety profiles were similar for both treatments.

Nebulized formoterol effect on bronchodilation and satisfaction in COPD patients compared to QID ipratropium/albuterol MDI

ABSTRACT Objective: Bronchodilator maintenance treatment improves pulmonary function and health-related quality of life in COPD patients. Pulmonary function and patient preference/satisfaction were compared before and after treatment with a short-acting ipratropium/albuterol combination and long-acting nebulized formoterol. Methods: A randomized, open-label, crossover trial was conducted at 16 centers in the US. COPD subjects (n = 109, 52.8% predicted FEV1) received nebulized formoterol fumarate inhalation solution (Perforomist**, FFIS 20 μg BID) or ipratropium and albuterol combined in a metered-dose inhaler (MDI) (Combivent**, IPR-ALB, QID) for 2 weeks. After a 1-week washout, subjects were crossed over to the other treatment. Efficacy was assessed with 6-h pulmonary function tests and the transition dyspnea index (TDI). Treatment satisfaction and preference were assessed after treatment. Post-hoc subgroup analyses were conducted by age, gender and COPD severity. ** Perforomist is a registered trademark name of Dey LP, Napa, CA, USA † Combivent is a registered trademark of Boehringer Ingelheim, Ridgefield, CT, USA Main outcome measure: Morning pre-dose FEV1 (trough) after 2 weeks of treatment. Results: FFIS significantly increased morning pre-dose FEV1 relative to IPR-ALB (p = 0.0015). FFIS also improved pre-dose FEV1 beyond that of IPR-ALB in subjects who were older (≥65 years), male, and with both moderate and severe/very severe COPD. Post-dose efficacy at 6 h was maintained in the FFIS group compared with IPR-ALB (p ≤ 0.0001). Patient satisfaction and the perception of disease control were significantly greater with FFIS in the older, male, and severe subgroups. Severe subjects preferred FFIS to IPR-ALB. Both FFIS and IPR-ALB treatments resulted in clinically meaningful changes in dyspnea, but no significant differences were observed between treatments. Conclusions: Following a 2-week treatment period, twice-daily nebulized FFIS was significantly more effective in improving lung function than the IPR-ALB combination MDI delivered four times daily. Although the open-label design may limit interpretation of pulmonary function, the crossover design enabled demonstration of greater treatment satisfaction and perception of disease control following nebulized FFIS treatment. Clinical trial registration: Clinicaltrials.gov NCT00462540

Efficacy and safety of twice-daily glycopyrrolate in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation: the GEM1 study

Background The purpose of this study was to confirm the efficacy and safety of twice-daily glycopyrrolate 15.6 µg, a long-acting muscarinic antagonist, in patients with stable, symptomatic, chronic obstructive pulmonary disease (COPD) with moderate-to-severe airflow limitation. Methods The GEM1 study was a 12-week, multicenter, double-blind, parallel-group, placebo-controlled study that randomized patients with stable, symptomatic COPD with moderate-to-severe airflow limitation to twice-daily glycopyrrolate 15.6 µg or placebo (1:1) via the Neohaler® device. The primary objective was to demonstrate superiority of glycopyrrolate versus placebo in terms of forced expiratory volume in 1 second area under the curve between 0 and 12 hours post morning dose at week 12. Other outcomes included additional spirometric end points, transition dyspnea index, St George’s Respiratory Questionnaire, COPD Assessment Test, rescue medication use, and symptoms reported by patients via electronic diary. Safety was also assessed during the study. Results Of the 441 patients randomized (glycopyrrolate, n=222; placebo, n=219), 96% of patients completed the planned treatment phase. Glycopyrrolate demonstrated statistically significant (P<0.001) improvements in lung function versus placebo. Glycopyrrolate showed statistically significant improvement in the transition dyspnea index focal score, St George’s Respiratory Questionnaire total score, COPD Assessment Test score, rescue medication use, and daily total symptom score versus placebo at week 12. Safety was comparable between the treatment groups. Conclusion Significant improvement in lung function, dyspnea, COPD symptoms, health status, and rescue medication use suggests that glycopyrrolate is a safe and effective treatment option as maintenance bronchodilator in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation.