Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a novel, once daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This study aimed to assess the 24-h bronchodilatory effect following 14 days of treatment with inhaled NVA237 in patients with mild, moderate or severe COPD. This was a randomized, double-blind, placebo-controlled, two-period, crossover, multicenter study. A total of 33 patients (≥ 40 years; smoking history of ≥ 10 pack-years) were randomized to receive NVA237 50 μg once daily followed by placebo or placebo followed by NVA237 50 μg for 14 days. Treatment periods were separated by a 7-14 day washout period. The primary variable was the mean forced expiratory volume in 1 s (FEV(1)) derived from the area under the curve (AUC) between 0 and 24 h post-dose on Day 14. The 24-h FEV(1) profiles showed a consistent bronchodilator effect for NVA237 versus placebo on Day 14. Least square (LS) mean difference in FEV(1) AUC(0-24 h) values between NVA237 and placebo was 163 mL (P < 0.001). There were significant increases in mean FEV(1) AUC(0-12 h) (LS mean difference 165 mL, P = 0.001) and FEV(1) AUC(12-24 h) (161 mL, P < 0.001) versus placebo. NVA237 significantly improved peak FEV(1) (by 208 mL, P < 0.001) and trough FEV(1) (by 154 mL, P = 0.003) versus placebo on Day 14. NVA237 was well tolerated; all adverse events were mild or moderate in intensity and not related to study drug. NVA237 50 μg once daily was well tolerated and showed significant and sustained 24-h bronchodilation in patients with COPD.     

NVA237, a long-acting muscarinic antagonist, as an emerging therapy for chronic obstructive pulmonary disease

Bronchodilation with a long-acting muscarinic antagonist (LAMA) or long-acting β(2)-agonist is central to the management of chronic obstructive pulmonary disease (COPD). Tiotropium, the first LAMA available for use in COPD, has been shown to be an effective bronchodilator and is generally safe and well tolerated. However, tiotropium has limitations that include a high incidence of dry mouth, slow onset of action and, in some studies, a part of the patient population did not achieve clinically significant bronchodilation. It also remains unclear whether tiotropium reduces progressive deterioration of lung function in patients with COPD. An ideal LAMA would provide clinically meaningful bronchodilation, deliver symptom relief, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations and reduce mortality risk. A 24-h duration of action, rapid onset of action and a good safety and tolerability profile are also desirable. The once-daily LAMA, NVA237 (glycopyrronium bromide), may meet some of these characteristics. NVA237 has high selectivity for the muscarinic type-3 (M(3)) receptor which might potentially result in a higher therapeutic index than tiotropium, which is less selective for M(3). Phase II studies showed that NVA237 once daily provides clinically significant 24-h bronchodilation with a rapid onset of action and a favourable safety and tolerability profile. Phase III studies are ongoing that will assess the long-term safety and efficacy of NVA237.     

Cardiovascular Safety of QVA149, a Combination of Indacaterol and NVA237, in COPD Patients

ABSTRACT

This study assessed the cardiovascular safety of QVA149, an inhaled, once daily, bronchodilator combination containing two 24-hour bronchodilators, the long-acting β₂-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237). In this randomised, double-blind, placebo-controlled, parallel-group study, 257 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) were randomised to receive QVA149 (indacaterol/NVA237) 600/100 μg, 300/100 μg or 150/100 μg, indacaterol 300 μg or placebo, once daily for 14 days. The primary endpoint was change from baseline in 24-h mean heart rate versus placebo on Day 14. 255 patients were included in the safety analysis (mean age 63.8 years, 76.5% male, post-bronchodilator forced expiratory volume in one second [FEV₁] 53.2% predicted, FEV₁/FVC [forced vital capacity] 50.0%, mean 24-h heart rate 79.6 bpm). There were no clinically significant differences in the 24-h mean heart rate on Day 14 between the three doses of QVA149 and placebo or indacaterol. The confidence intervals of these treatment differences (contrasts) were within the pre-specified equivalence limit (-5 to 5 bpm). No clinically relevant differences in QTc interval (Fridericia's) were observed between groups on Days 1, 7 and 14. Once-daily QVA149 was well tolerated in COPD patients with a cardiovascular safety profile and overall adverse event rates similar to placebo.     

Cardiovascular safety of QVA149, a combination of Indacaterol and NVA237, in COPD patients

This study assessed the cardiovascular safety of QVA149, an inhaled, once daily, bronchodilator combination containing two 24-hour bronchodilators, the long-acting β(2)-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237). In this randomised, double-blind, placebo-controlled, parallel-group study, 257 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) were randomised to receive QVA149 (indacaterol/NVA237) 600/100 microg, 300/100 microg or 150/100 microg, indacaterol 300 μg or placebo, once daily for 14 days. The primary endpoint was change from baseline in 24-h mean heart rate versus placebo on Day 14. 255 patients were included in the safety analysis (mean age 63.8 years, 76.5% male, post-bronchodilator forced expiratory volume in one second [FEV(1)] 53.2% predicted, FEV(1)/FVC [forced vital capacity] 50.0%, mean 24-h heart rate 79.6 bpm). There were no clinically significant differences in the 24-h mean heart rate on Day 14 between the three doses of QVA149 and placebo or indacaterol. The confidence intervals of these treatment differences (contrasts) were within the pre-specified equivalence limit (-5 to 5 bpm). No clinically relevant differences in QTc interval (Fridericia's) were observed between groups on Days 1, 7 and 14. Once-daily QVA149 was well tolerated in COPD patients with a cardiovascular safety profile and overall adverse event rates similar to placebo.     

Efficacy and safety of the long-acting muscarinic antagonist GSK233705 delivered once daily in patients with COPD

Introduction: GSK233705 is a recently developed inhaled anticholinergic being investigated for the potential treatment of chronic obstructive pulmonary disease (COPD). Objectives: This dose‐ranging, parallel‐group, double‐blind study compared the bronchodilator efficacy, safety and pharmacokinetics of GSK233705 with placebo in patients with moderate‐to‐severe COPD. Methods: Patients were randomised to receive 12.5 µg, 25 µg, 50 µg, 100 µg or 200 µg of GSK233705 or placebo once daily for 28 days. The primary endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV₁) on day 29. Results: The intent‐to‐treat population consisted of 576 patients (mean predicted FEV₁ 51%; mean age 62 years). Treatment with GSK233705 produced statistically significant improvements in pulmonary function compared with placebo. Only the 200 µg dose exceeded the predefined target threshold of 130‐mL difference compared with placebo for the primary endpoint of change from baseline in trough FEV₁ on day 29. No clear pattern of dose response was observed for the other doses. Serial FEV₁ (0–24 h) showed a peak effect around 2 h postdose and tended to decline to clinically insignificant levels compared with placebo at 23 and 24 h. Each dose of GSK233705 was well tolerated. The incidence of adverse events was low and similar across all treatment groups. There were no clinically significant effects on laboratory parameters, vital signs or electrocardiograms. Conclusion: All doses of GSK233705 demonstrated bronchodilatory activity and were well tolerated. Although the onset of bronchodilation was rapid, it was not sustained over 24 h making it unsuitable for once‐daily dosing. Please cite this paper as: Bateman E, Feldman G, Kilbride S, Brooks J, Mehta R, Harris S, Maden C and Crater G. Efficacy and safety of the long‐acting muscarinic antagonist GSK233705 delivered once daily in patients with COPD. Clin Respir J 2012; DOI:10.1111/j.1752‐699X.2011.00278.x.     

Safety, tolerability and efficacy of indacaterol, a novel once-daily beta(2)-agonist, in patients with COPD: a 28-day randomised, placebo controlled clinical trial

In patients with chronic obstructive pulmonary disease (COPD) classified as moderate onwards, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines recommend regular treatment with one or more long-acting bronchodilators, such as beta(2)-agonists or anticholinergics. In contrast to currently available long-acting beta(2)-agonists, which have a duration of action of 12 h, indacaterol has demonstrated effective 24-h bronchodilation on once-daily dosing. A double-blind, randomised, placebo-controlled study was conducted to compare the safety, tolerability and efficacy of indacaterol with that of placebo, over a 28-day period, in patients with moderate COPD (as defined by GOLD 2001 criteria; equivalent to moderate-to-severe COPD in the GOLD 2005 criteria). Patients were randomised 2:2:1 to receive indacaterol 400 microg or 800 microg or placebo once-daily (between 07:00 and 11:00 h) via a single-dose dry-powder inhaler for 28 days. Assessments included monitoring of adverse events (AEs), blood chemistry (including serum potassium and blood glucose), vital signs (blood pressure and heart rate), electrocardiograms and spirometry. One hundred and sixty-three patients were randomised, with 155 (95%) completing the study. There were no statistically significant differences between treatment groups in the overall incidence of AEs, with AEs reported by 35%, 51% and 25% of patients in the indacaterol 400 microg, 800 microg and placebo groups, respectively. The majority of AEs were mild or moderate in severity, and there were no study-drug related serious AEs. There were no statistically significant differences between indacaterol groups and placebo in mean pulse rate and QTc interval, and isolated statistically significant (p<0.05) treatment-placebo differences in mean blood pressure, blood glucose and serum potassium. There was a statistically significant improvement in FEV(1) vs placebo at all post-baseline timepoints for both indacaterol treatment groups; 30 min post-dose, adjusted mean+/-SE FEV(1) indacaterol-placebo differences were: Day 1, 220+/-36 ml and 210+/-36 ml; Day 14, 320+/-50 ml and 270+/-50 ml; Day 28, 260+/-61 ml and 200+/-61 ml for 400 and 800 microg, respectively (all p<0.01 vs placebo). Bronchodilation was still apparent after 24h, with pre-dose (i.e. trough) adjusted mean+/-SE FEV(1) indacaterol-placebo differences of: Day 14, 230+/-44 ml and 210+/-44 ml; Day 28, 220+/-49 ml and 210+/-49 ml for indacaterol 400 and 800 microg, respectively (all p<0.0001 vs placebo). Once-daily indacaterol was well tolerated at doses up to 800 microg with a good overall safety profile. There was no statistical difference at any dose between the safety of indacaterol and placebo. Furthermore, this study supports the previously demonstrated 24-h bronchodilator efficacy of indacaterol.     

Safety of long-acting beta-agonists in stable COPD: a systematic review

BACKGROUND: Some studies have suggested that use of long-acting beta(2)-agonists (LABAs) leads to an increased risk for adverse events in patients with stable COPD. The purpose of this review was to assess the safety, and secondarily the efficacy of LABAs. METHODS: The authors conducted a systematic review with metaanalysis of randomized clinical trials (> or = 1 month in duration) in the published literature that have compared LABAs with placebo or anticholinergics in stable poorly reversible and reversible COPD. RESULTS: MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched to identify 27 studies. LABAs reduced severe exacerbations compared with placebo (relative risk [RR], 0.78; 95% confidence interval [CI], 0.67 to 0.91). There was no significant difference between LABA and placebo groups in terms of respiratory deaths (RR, 1.09; 95% CI, 0.45 to 2.64). Use of LABAs with inhaled corticosteroids reduced the risk of respiratory death compared with LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93). Patients receiving LABAs showed significant benefits in airflow limitation measures, health-related quality of life, and use of rescue medication. Finally, tiotropium decreased the incidence of severe COPD exacerbations compared with LABAs (RR, 0.52; 95% CI, 0.31 to 0.87). CONCLUSION: This review supports the beneficial effects of the use of LABAs in patients with stable moderate-to-severe COPD, and did not confirm previous data about an increased risk for respiratory deaths. Also, our analysis suggests the superiority of tiotropium over LABAs for the treatment of stable COPD patients.     

Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects

Aims: Albiglutide is a glucagon‐like peptide‐1 (GLP‐1) mimetic generated by genetic fusion of a dipeptidyl peptidase‐IV‐resistant GLP‐1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP‐1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non‐diabetic volunteers. Methods: In this single‐blind, randomized, placebo‐controlled trial, 39 subjects (18–60 years, body mass index 19.9–35.0 kg/m²) received placebo (n = 10) or escalating doses of albiglutide (n = 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 + 1 mg; cohort 2: 3 + 6 mg; cohort 3: 16 + 24 mg; cohort 4: 48 + 60 mg; and cohort 5: 80 + 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC_{(0–7 days)})] and maximum plasma drug concentration (C_max) for cohorts 2–5 during week 1. Results: Albiglutide had a terminal elimination half‐life (T_1/2) of 6–8 days and time to maximum observed plasma drug concentration (T_max) of 3–4 days. A greater‐than‐dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose‐dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug‐related AE, followed by constipation, flatulence and nausea. Conclusions: Albiglutide has a half‐life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non‐diabetic subjects.     

稳定期慢性阻塞性肺疾病患者夜间睡眠特点及长效抗胆碱能药物治疗的影响

目的:研究稳定期慢性阻塞性肺疾病(COPD)患者夜间睡眠的特点以及噻托溴铵粉吸入剂治疗对COPD患者肺功能及夜间睡眠的影响。方法:入选2010年9月至2011年8月18例中到重度肺功能受损的COPD患者,基线肺功能检查第1秒用力呼气容积(FEV1)在预计值参考范围的30%~80%,且支气管舒张实验阴性。其中男17例,女1例,年龄54~78(65.7±6.6)岁,平均体质量指数(BMI)为24.1±2.5(19.6~27.3)。入组后予以患者吸入皮质激素(ICS)单药洗脱2周后,予正规的ICS+长效抗胆碱支气管扩张剂(LAMA)治疗3个月。在基线期和3个月后分别进行肺功能及全夜多导睡眠图(PSG)检测。结果:稳定期无需氧疗的中重度肺功能损害COPD患者夜间低氧并不显著[呼吸紊乱指数(RDI)7.1±7.5,最低指脉搏氧饱和度(SpO2)83.9%±8.4%、SpO2低于90%的时间(7.4±12.2)min、平均SpO294.2%±2.4%],且与基础肺功能相关性不大,RDI主要仍与患者BMI相关(r=0.3,P=0.02),但睡眠期存在明显的微觉醒时间(平均微觉醒指数27.1±16.0)。经短期治疗前后肺功能[FEV1、用力肺活量(FVC)、残气量/肺总量比(RV/TLC)]及夜间睡眠低氧状况(夜间睡眠期RDI、最低SpO2、SpO2低于90%的时间、平均SpO2)变化不明显。但其中患者治疗后微觉醒指数明显下降(27.1±16.0比17.1±13.4,P=0.01)。结论:中重度肺功能损害的稳定期COPD患者夜间存在以微觉醒增多为特征的睡眠紊乱,LAMA治疗能提高COPD患者夜间睡眠质量;短期治疗对肺功能影响不大。     

Aclidinium bromide provides long-acting bronchodilation in patients with COPD

Aclidinium bromide is a novel, long-acting, muscarinic antagonist in phase III development for the maintenance treatment of COPD. This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies. A total of 464 patients with moderate to severe stable COPD were randomised to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400 μg), placebo, or open-label tiotropium (18 μg) for 4 weeks. Spirometric measurements were performed at 22–24 h after the first dose and then at weekly intervals, and from 0.5 to 6 h post-dose on day 1 and day 29. Compared with placebo, aclidinium 200 μg and 400 μg significantly increased trough FEV₁ on day 29 versus baseline. During the first 6 h post-dose, the bronchodilatory effect of aclidinium (all doses) on day 1 was comparable to that on day 29. Time to peak FEV₁ was 3 h for aclidinium 100–400 μg. Aclidinium was well tolerated, with no dose-dependent effect on ECG, laboratory parameters, or adverse events. The incidence of AEs was generally comparable to placebo. Aclidinium produced sustained bronchodilation over 24 h and was well tolerated during this short-term study. Based on these data, aclidinium 200 μg was selected as the investigational dose for future clinical trials in COPD.     

Safety,tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of the novel long-acting glucagon analogue HM15136 in overweight and obese patients with co-morbidities

Aim

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of the novel long-acting glucagon analogue HM15136 in overweight/obese patients with co-morbidities, with and without type 2 diabetes (T2D).

Materials and Methods

This was a phase 1, double-blind, randomized, placebo-controlled, two-part trial with a 12-week treatment period of once-weekly subcutaneous HM15136 (0.02/0.04/0.06 mg/kg). Part 1 included patients with dyslipidaemia and/or hypertension and no T2D. Part 2 included patients with dyslipidaemia and/or hypertension plus T2D.

Results

In part 1, 23/27 (85.2%) patients receiving HM15136 and all patients receiving placebo (9/9 [100%]) experienced a treatment-emergent adverse event (TEAE). Five of 27 (18.5%) patients receiving HM15136 developed anti-HM15136 antibodies. Dose-dependent increases in mean HM15136 serum concentration and fasting plasma glucose (FPG) were observed, as were dose-dependent weight reductions of 0.5%/2.3%/2.6% at doses of 0.02/0.04/0.06 mg/kg, respectively. In part 2, 8/12 (66.7%) patients receiving HM15136 and all patients receiving placebo (4/4 [100.0%]) reported a TEAE. Two (16.7%) patients developed anti-HM15136 antibodies. Dose-dependent increases in mean HM15136 serum concentration were observed. FPG of more than 200 mg/dL was reported in 4/9 (44.4%) and 2/3 (66.7%) patients receiving 0.02 and 0.06 mg/kg, respectively. The 0.06 mg/kg dose was not tolerated in part 2 because of hyperglycaemia. Patients receiving 0.02 mg/kg showed a 0.9% weight reduction. No serious TEAEs leading to discontinuation were reported in either study part.

Conclusions

This study of HM15136 provides a preliminary safety and tolerability profile with initial insights into its efficacy profile.     

Efficacy,safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of a new, once-daily extended-release (ER) formulation of tolterodine in treating overactive bladder in older (> or =65) and younger (<65) patients. DESIGN: A 12-week double-blind, placebo-controlled clinical trial. SETTING: An international study conducted at 167 medical centers. PARTICIPANTS: One thousand fifteen patients (43.1% aged > or =65) with urge incontinence and urinary frequency. INTERVENTION: Patients were randomized to treatment with tolterodine ER 4 mg once daily (qd) (n = 507) or placebo (n = 508) for 12 weeks. MEASUREMENTS: Efficacy, measured with micturition charts (incontinence episodes, micturitions, volume voided per micturition) and subjective patient assessments, safety, and tolerability endpoints were evaluated, relative to placebo, according to two age cohorts: younger than 65 and 65 and older. RESULTS: Mean age in the older and younger patient cohorts was 74 (range 65-93) and 51 (range 20-64), respectively. Compared with placebo, significant improvements in micturition chart variables with tolterodine ER showed no age-related differences. Irrespective of age, significantly more tolterodine ER recipients than placebo recipients reported an improvement in urgency symptoms. After 12 weeks of treatment with tolterodine ER, a fivefold increase in the percentage of patients able to finish tasks before voiding in response to urgency was noted in both age groups (<65: from 6.5-32.8%, > or =65: from 5.1-26.2%). Tolterodine ER recipients, irrespective of age, also had significant improvements in their bladder condition than did placebo recipients. Overall, a greater percentage of patients, irrespective of age, perceived any benefit with tolterodine ER than with placebo (P <.001). Dry mouth (of any severity) was the most common adverse event in both the tolterodine ER and placebo treatment arms, irrespective of age (<65: ER 22.7%, placebo 8.1%; > or =65: ER 24.3%, placebo 7.2%). Few patients (<2%) experienced severe dry mouth. No central nervous system, visual, cardiac (per electrocardiogram), or laboratory safety concerns were noted. Withdrawal rates due to adverse events on tolterodine ER 4 mg qd were comparable in the two age cohorts (<65: 5.5%; > or =65: 5.1%; P =.87). CONCLUSIONS: The new, once-daily ER formulation of tolterodine is efficacious, safe, and well tolerated in the treatment of patients with symptoms of overactive bladder, irrespective of age.