Incidence Of On-treatment Adverse Events Research Articles

Efficacy and safety of mepolizumab in Korean patients with severe eosinophilic asthma from the DREAM and MENSA studies.

Background/AimsThe efficacy and safety of mepolizumab in patients with severe eosinophilic asthma has been evaluated in a global clinical trial programme. This post hoc analysis assesses the efficacy and safety of mepolizumab in Korean patients.MethodsData from Korean patients in the Phase III, placebo-controlled, randomised DREAM (MEA112997/NCT01000506) and MENSA (MEA115588/NCT01691521) studies were included. Patients ≥ 12 years old with severe eosinophilic asthma received mepolizumab (DREAM: 75, 250 or 750 mg intravenously [IV]; MENSA: 75 mg IV or 100 mg subcutaneously [SC]), or placebo every 4 weeks for 52 weeks (DREAM) or 32 weeks (MENSA). The primary outcome was the rate of clinically significant asthma exacerbations. Secondary outcomes included forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire (ACQ) and St George’s Respiratory Questionnaire (SGRQ) scores (MENSA only). Blood eosinophil counts (BEC) and safety were assessed throughout.ResultsReductions in the rate of clinically significant asthma exacerbations were observed with the approved (100 mg SC) and bioequivalent (75 mg IV) doses of mepolizumab in Korean patients who participated in DREAM and MENSA. In MENSA, trends for improvements from baseline at week 32 in pre-bronchodilator FEV1 (75 mg IV group), ACQ-5 and SGRQ scores (in both treatment groups) were seen versus placebo in Korean patients. Incidence of on-treatment adverse events was similar in Korean patients versus non-Korean patients as were observed reductions from baseline in BEC.ConclusionsMepolizumab treatment provided clinical benefits for Korean patients with severe eosinophilic asthma; the safety profile is consistent with the overall population.

Efficacy and Safety of Once-Daily Inhaled Umeclidinium in Asian Patients with COPD: Results from a Randomized, Placebo-Controlled Study.

PurposePrevious studies demonstrating efficacy and safety of once-daily umeclidinium (UMEC) in patients with chronic obstructive pulmonary disease (COPD) have included few Asian patients. This study evaluated efficacy and safety of UMEC 62.5 mcg versus placebo in Asian patients with COPD.Patients and MethodsA Phase III, randomized, double-blind, parallel-group study. Patients (aged ≥40 years with COPD, pre-, and post-albuterol forced expiratory volume in 1 s [FEV1]/forced vital capacity ratio <0.70 and low risk of exacerbations) were randomized 2:1 to once-daily UMEC 62.5 mcg or placebo via the ELLIPTA inhaler for 24 weeks. Primary endpoint was change from baseline (CFB) in trough FEV1 on Day 169. Secondary endpoints were weighted mean FEV1 over 0–6 hrs post-dose on Day 1 and CFB in Transition Dyspnea Index (TDI) focal score on Day 168.ResultsA total of 306 patients were included in the modified intent-to-treat population (UMEC: 205; placebo: 101). UMEC versus placebo provided a statistically significant improvement in least squares (LS) mean trough FEV1 between baseline and Day 169 (154 mL [95% confidence interval (CI): 113, 194]; p<0.001). A clinically meaningful difference of 125 mL in favor of UMEC (95% CI: 103, 147; p<0.001) was also seen in LS weighted mean FEV1 0–6 hrs post-dose on Day 1. A LS mean treatment difference in TDI focal score of 0.9 units in favor of UMEC was seen on Day 168 (95% CI: 0.3, 1.5; p=0.004). Incidence of on-treatment adverse events (AEs) was lower in the placebo (55%) versus UMEC arm (60%); non-fatal serious AEs, drug-related AEs, and AEs leading to withdrawal were similar with UMEC and placebo.ConclusionOnce-daily UMEC 62.5 mcg resulted in statistically significant and clinically meaningful improvements in lung function and dyspnea, compared with placebo, in Asian patients with COPD, with no new safety concerns observed.

Exploring the Comparative Efficacy and Safety of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol in Moderate Symptomatic COPD: A Randomized Non-Inferiority Crossover Trial

SESSION TITLE: Late-Breaking Abstracts SESSION TYPE: Late-Breaking Abstract Slide PRESENTED ON: Wednesday, November 1, 2017 at 02:45 PM - 04:15 PM PURPOSE: In a prior study of long-acting muscarinic antagonist (LAMA) treatment in patients with stable chronic obstructive pulmonary disease (COPD), a significant increase in change from baseline (CFB) in trough forced expiratory volume in 1 second (FEV1) was observed with umeclidinium (UMEC) vs tiotropium (TIO) (53 mL [95% confidence interval {CI}: 25, 81], p<0.001; Feldman G, Int J COPD 2016;11:719-730). We hypothesized that this efficacy difference would also be shown during once-daily fixed-dose combination treatment with the LAMA/long-acting β2-agonist (LABA) combinations UMEC/vilanterol (UMEC/VI) and TIO/olodaterol (TIO/OLO). METHODS: This randomized, open-label, 2-period, crossover study (204990, NCT02799784) recruited inhaled corticosteroid-free COPD patients with a modified Medical Research Council dyspnea score ≥2, FEV1/forced vital capacity ratio <0.70 and post-albuterol FEV1 50-70% predicted. Patients were randomized to receive UMEC/VI (62.5/25 mcg once daily) via an ELLIPTA inhaler followed by TIO/OLO 5/5 mcg (2 puffs once daily) via a RESPIMAT inhaler (each for 8 weeks with an interim 3-week washout), or vice versa. The primary endpoint was CFB in trough FEV1 at Week 8 with a non-inferiority (NI) margin of -50mL in the per protocol (PP) population. If NI was established, superiority was tested in the intent-to-treat (ITT) population. Rescue medication use and adverse events (AEs) were also assessed. RESULTS: 236 patients (mean age 64.4 years, 60% male) were included in the ITT population (PP population, n=227). The primary endpoint of CFB in trough FEV1 at Week 8 in the PP population confirmed NI of UMEC/VI vs TIO/OLO (175 mL vs 122 mL; least squares [LS] mean difference 53 mL [95% CI: 26, 80]; p<0.001). CFB in trough FEV1 in the ITT population was superior at Week 8 with UMEC/VI (180 mL) vs TIO/OLO (128 mL; LS mean difference 52 mL [95% CI: 28, 77]; p<0.001]). CFB in mean rescue use (puffs/day; Weeks 1-8) favored UMEC/VI over TIO/OLO (-0.94 vs -0.68; p<0.001). The incidence of on-treatment AEs was similar in both groups (UMEC/VI, n=59 [25%]; TIO/OLO, n=71 [31%]). CONCLUSIONS: In this first, direct, once-daily LAMA/LABA comparison, statistically significant and clinically meaningful improvements in lung function were observed in patients receiving UMEC/VI vs TIO/OLO. Both LAMA/LABAs were well tolerated. Funding: GSK (204990 [NCT02799784]) CLINICAL IMPLICATIONS: An efficacy gradient exists in the LAMA/LABA class. DISCLOSURE: Ana Sousa: Employee: GSK, Shareholder: Holds stocks and shares in GSK David Lipson: Employee: GSK, Shareholder: Holds stocks and shares in GSK Lee Tombs: Other: Contingent worker contracted by GSK Chris Compton: Employee: GSK, Shareholder: Holds stocks and shares in GSK Bernardino Alcázar Navarrete: Consultant fee, speaker bureau, advisory committee, etc.: GSK, Novartis AG, Boehringer Ingelheim, Chiesi, Laboratorios Menarini, Gebro, AstraZeneca, Other: Non-financial support from: GSK, Novartis AG, Boehringer Ingelheim, Chiesi, Laboratorios Menarini, Grant monies (from industry related sources): Novartis AG, Laboratorios Menarini, Other: Patent: P201730724 The following authors have nothing to disclose: Gregory Feldman No Product/Research Disclosure Information

A randomised, phase III trial of once-daily fluticasone furoate/vilanterol 100/25 μg versus once-daily vilanterol 25 μg to evaluate the contribution on lung function of fluticasone furoate in the combination in patients with COPD

BackgroundThe contribution of fluticasone furoate (FF) on lung function in the FF/vilanterol (VI) 100/25 μg combination has been demonstrated numerically, but not statistically. MethodsThis multicentre, randomised, double-blind, controlled trial (GlaxoSmithKline study number 200820; clinicaltrials.gov NCT02105974) enrolled ≥40-year-old patients with chronic obstructive pulmonary disease (COPD), a ≥10-pack-year smoking history, a post-bronchodilator forced expiratory volume in 1 s (FEV1) 30–70% of the predicted value, a FEV1/forced vital capacity ratio of ≤0.70, ≥1 COPD exacerbation in the previous 12 months requiring corticosteroids, antibiotics and/or hospitalisation, and current COPD symptoms. Participants received FF/VI 100/25 μg or VI 25 μg once daily. The primary endpoint was the change from baseline in trough FEV1 at day 84. Findings1620 patients were randomised and received at least one dose of FF/VI 100/25 μg (n = 806) or VI 25 μg (n = 814). At day 84, the FF/VI 100/25 μg group showed an adjusted mean treatment difference of 34 mL over VI 25 μg in change from baseline trough FEV1 (95% confidence interval [CI] 14–55; p = 0.001). There was no significant difference between the groups in the percentage of rescue medication-free 24-h periods. The FF/VI 100/25 μg group demonstrated a 42% risk reduction compared with the VI 25 μg group in time to first moderate/severe COPD exacerbation (95% CI 22–57; nominal p < 0.001). The incidence of on-treatment adverse events was similar between the groups. InterpretationThe contribution of FF in the FF/VI 100/25 μg combination on lung function in COPD was statistically significant. FundingGlaxoSmithKline.

Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, ­Double-Blind Studies

Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease (COPD). In two 12-week, double-blind, parallel-group studies, patients with COPD were randomized 1:1:1 to once-daily umeclidinium (UMEC; 62.5 μg and 125 μg) or placebo (PBO), added to twice-daily fluticasone propionate/salmeterol (FP/SAL; 250/50 μg). In both studies, the primary efficacy measure was trough forced expiratory volume in 1 second (FEV1) at Day 85. Secondary endpoints were weighted-mean (WM) FEV1 over 0–6 hours post-dose (Day 84) and rescue albuterol use. Health-related quality of life outcomes (St. George's Respiratory Questionnaire [SGRQ] and COPD assessment test [CAT]) were also examined. Safety was assessed throughout. Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV1 (Day 85: 0.127–0.148 L) versus PBO+FP/SAL. Similarly, both UMEC+FP/SAL doses provided statistically-significant improvements in 0–6 hours post-dose WM FEV1 versus PBO+FP/SAL (Day 84: 0.144–0.165 L). Rescue use over Weeks 1–12 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL (Study 1, 0.3 puffs/day [both doses]; Study 2, 0.5 puffs/day [UMEC 125+FP/SAL]). Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL (except for Day 84 Study 2). In Study 1, no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL; however, in Study 2, statistically significant improvements were observed with UMEC 62.5+FP/SAL (Day 28) and UMEC 125+FP/SAL (Days 28 and 84) versus PBO+FP/SAL. The incidence of on-treatment adverse events across all treatment groups was 37–41% in Study 1 and 36–38% in Study 2. Overall, these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD.

Efficacy and safety of fluticasone furoate/vilanterol (50/25 mcg; 100/25 mcg; 200/25 mcg) in Asian patients with chronic obstructive pulmonary disease: a randomized placebo-controlled trial

Background and objective:Three strengths of fluticasone furoate/vilanterol (FF/VI) were previously evaluated for the treatment of chronic obstructive pulmonary disease (COPD) in a program of global Phase 3 studies that included only a small subgroup of Asian patients. This study further evaluated the efficacy and safety of the same three strengths of FF/VI exclusively in Asian patients.Methods:A randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients with post-bronchodilator FEV1/FVC ≤0.70, FEV1 ≤70% predicted and modified Medical Research Council score ≥2 were randomized (1:1:1:1) to placebo, FF/VI 50/25 mcg, 100/25 mcg or 200/25 mcg once daily via the ELLIPTA dry powder inhaler. The primary efficacy endpoint was change from baseline in trough FEV1 at Week 24.Results:The intent-to-treat population comprised 643 patients. Statistically significant (p < 0.001) improvements in trough FEV1 were observed with all strengths of FF/VI versus placebo at Week 24 (0.14–0.19 L). Reduction of supplemental albuterol use was observed with all strengths of FF/VI versus placebo. The incidence of on-treatment adverse events (AEs) was 48% with FF/VI 200/25 mcg and 37–40% with other treatments. The incidence of on-treatment serious AEs was 4–9% with FF/VI treatments versus 9% with placebo; however, the study only covered a 6 month treatment period and was not powered to assess effects on exacerbations. No clinically significant treatment effects versus placebo were identified for electrocardiogram, vital signs, 24 hour urinary cortisol excretion and pneumonia.Conclusions:All strengths of FF/VI improved lung function with an acceptable safety profile. There is no evidence to suggest that dose adjustment may be required in Asian patients using FF/VI 100/25 mcg for the treatment of COPD.Clinical trial registration:NCT01376245.

One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2–4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis

The novel long-acting β2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2–4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 μg) QD via Respimat®, formoterol 12 μg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 μg, 883 received olodaterol 10 μg, 885 received placebos, and 460 received formoterol 12 μg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 μg (marketed and registered dose) and 10 μg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.

Fluticasone furoate/vilanterol 200/25 mcg in Asian asthma patients: A randomized trial

This study investigated the efficacy and safety of the inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combination fluticasone furoate (FF)/vilanterol (VI) in Asian asthma patients. A 12-week, double-blind, double-dummy, active-comparator, parallel-group, multicenter study. 309 Asian asthma patients (≥12 years, uncontrolled with high-strength ICS or mid-dose ICS/LABA) were randomized (1:1) and included in the intent-to-treat population; 155 received once-daily FF/VI 200/25 mcg and 154 received twice-daily fluticasone propionate (FP) 500 mcg. The primary endpoint was change from baseline in daily evening peak expiratory flow (PEF) averaged over 12 weeks. Secondary endpoints were mean change from baseline in % rescue-free 24-h periods, daily morning PEF, % symptom-free 24-h periods, and overall Asthma Quality of Life Questionnaire score. Safety assessments were performed. For change from baseline in daily evening PEF, the adjusted mean treatment difference for FF/VI versus FP of 28.5 L/min (95% confidence interval [CI]: 20.1, 36.9) was clinically and statistically significant (p < 0.001). For change from baseline in % rescue-free 24-h periods, the adjusted mean treatment difference (1.0%; 95% CI: -7.3, 9.2) was not statistically significant (p = 0.821). Statistical significance could not be inferred for the remaining endpoints due to the statistical hierarchy employed. Incidence of on-treatment adverse events was similar with FF/VI (26%; 3% treatment-related; n = 1 serious) and FP (27%; 3% treatment-related; n = 2 serious); none were fatal. No further safety concerns were identified. FF/VI improved evening PEF over 12 weeks versus FP in Asian patients, with a similar safety profile. The results are generally consistent with a global study comparing the same treatments.

A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma

To our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS). Evaluate the dose-response, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS. In this double-blind, three-period crossover study, 350 subjects were randomized toa sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250mcg oncedaily (OD), UMEC 15.6 or 31.25mcg twice daily (BID), or placebo, administered for 14 days (12-14-day washout). Trough forced expiratory volume in one second (FEV1), 0-24-hweighted mean (WM) FEV1, and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup. Subjects had a mean baseline pre- and post-bronchodilator FEV1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 OD (0.066L; p=0.036) and UMEC 125 OD (0.088L; p=0.005) versusplacebo, but not other OD or BID doses. UMEC increased 0-24-hWM FEV1 versus placebo (0.068-0.121L [p≤0.017] with no clear dose-response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9-21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters. The modest trough FEV1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma. NCT01641692.

The effect of fluticasone furoate/umeclidinium in adult patients with asthma: A randomized, dose-ranging study

We evaluated the dose-response of umeclidinium (UMEC; a long-acting muscarinic antagonist) combined with fluticasone furoate (FF; an inhaled corticosteroid [ICS]) in patients with asthma. In a double-blind, three-period crossover study, 421 subjects (symptomatic on ICS), were randomized to a sequence of three of seven treatments: FF 100mcg alone, FF 100mcg combined with UMEC (15.6, 31.25, 62.5, 125, or 250mcg), or vilanterol 25mcg (a long-acting β-agonist), inhaled once-daily for 14 days (12-14-day washout). Trough forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and safety were assessed. Period baseline was a significant covariate, indicating a potential carryover effect between treatment periods. Across all treatment periods, trough FEV1 improved with FF/UMEC 125 and 250 versus FF (treatment difference 0.055L [both doses]; p=0.018). FF/UMEC increased morning (15.9-22.9L/min) and evening (16.2-28.8L/min) PEF versus FF. As intended assessments were confounded, post hoc Period 1 data analyses were performed, demonstrating significant increases in trough FEV1 with FF/UMEC 31.25, 62.5, and 250 versus FF. Trough FEV1 improvements with FF/UMEC were greater in subjects with fixed (0.095-0.304L) versus non-fixed (-0.084 to 0.041L) obstruction. The incidence of on-treatment adverse events was 13-25% across groups. No treatment-related effects on laboratory parameters were reported. FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS; benefit may be most prominent in those with fixed obstruction. The carryover effect suggests future UMEC studies should use an alternative design. ClinicalTrials.gov: NCT01573624.

Effect of Once-Daily Fluticasone Furoate/Vilanterol on 24-Hour Pulmonary Function in Patients With Chronic Obstructive Pulmonary Disease: A Randomized, Three-Way, Incomplete Block, Crossover Study

BackgroundAvailable inhaled corticosteroid/long-acting β2-agonist combinations for chronic obstructive pulmonary disease (COPD) require twice-daily administration. The combination of fluticasone furoate (FF) and vilanterol (VI) FF/VI is being developed in a novel dry powder inhaler for the treatment of COPD and asthma with the potential for once-daily dosing. Results from Phase II studies have shown clinically and statistically significant improvements over placebo in trough (24-hour postdose) forced expiratory volume in 1 second (FEV1) after once-daily dosing with FF or VI (VI concurrently with an inhaled corticosteroid) in asthma and VI in COPD. ObjectivesThis Phase III, multicenter, randomized, double-blind, placebo-controlled study was designed based on guidance from drug regulators with the goal of evaluating the 24-hour spirometric effect of once-daily FF/VI in patients with COPD. MethodsPatients (aged ≥40 years) who completed a 2-week placebo run-in period were randomized to 1 of 18 three-course sequences of placebo and 2 of 3 dose combinations of FF/VI (50/25 μg, 100/25 μg, and 200/25 μg), dosed once daily in the morning. Each 28-day treatment period was separated by a 2-week, single-blind, placebo washout period. The primary end point was time-adjusted (weighted mean) 0 to 24-hour FEV1 (AUC) at the end of each 28-day treatment period (period days 28–29). Safety profile assessments included incidence of adverse events (AEs) (defined according to the Medical Dictionary for Regulatory Activities), 12-lead ECG outputs, vital signs (pulse rate, diastolic and systolic blood pressure) and clinical laboratory assessments (including fasting serum glucose and potassium) and 24-hour serum cortisol. The pharmacokinetics of FF and VI were assessed at the end of each 28-day treatment period with FF/VI. ResultsEighty-seven patients were screened; 54 completed run-in and were randomized to double-blind treatment. The mean patient age was 57.9 years, and 46% were male. The majority of patients were current smokers (83%) and were receiving short-acting β2-agonists within the 3 months before screening (63%). All 3 strengths of once-daily FF/VI demonstrated significantly higher 0 to 24-hour (period days 28–29) change from period baseline weighted mean FEV1 than placebo: adjusted mean improvements from placebo in FEV1 for FF/VI were 220 to 236 mL (all, P < 0.001). Improvements versus placebo in change from period baseline serial FEV1 measures were observed at each time-point and with each strength of FF/VI over the 0 to 25-hour period (period days 28–29), indicating sustained bronchodilation. The overall incidence of on-treatment AEs was low (10%–12% with FF/VI; 4% with placebo); 2 serious AEs were reported during washout periods (1 AE after FF/VI 50/25 μg and 1 AE after placebo) but neither was considered treatment related. No serious AEs were reported during the treatment periods or during the follow-up period. No clinically or statistically significant differences from placebo were reported for serum glucose or potassium. No significant effects on vital signs, ECG, or 24-hour serial serum cortisol were reported. The extent of systemic exposure to FF and VI at steady state was low for all strengths of FF/VI. ConclusionsFF/VI inhaled once daily in the morning for 28 days produced significant improvements in pulmonary function with a prolonged (>24 hours') duration of action in this population of patients with COPD. The combination was well tolerated. ClinicalTrials.gov identifier: NCT01072149.