Improvements in Lung Function with Nebulized Revefenacin in the Treatment of Patients with Moderate to Very Severe COPD: Results from Two Replicate Phase III Clinical Trials

Ferguson, Gary T.; Feldman, Gregory; Pudi, Krishna; Barnes, Chris; Moran, Edmund J.; Haumann, Brett; Pendyala, Srikanth; Crater, Glenn

doi:10.15326/jcopdf.6.2.2018.0152

Cited by 26 publications

(57 citation statements)

References 17 publications

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“…However, in patients with comorbid diabetes, it may be more appropriate to limit the use of ICS to the minority of patients with COPD who might benefit. There were no safety issues identified with the use of revefenacin in patients with cardiac risk factors [7,9]. In a preclinical study, revefenacin was shown to be a high-affinity competitive antagonist at human recombinant muscarinic acetylcholine receptors with kinetic functional selectivity for M 3 over M 2 muscarinic acetylcholine receptors [27].…”

Section: Discussionmentioning

confidence: 99%

“…Studies 0126 (NCT02459080) and 0127 (NCT02512510) were replicate, 12-week, randomized, doubleblind, placebo-controlled, multiple-dose, parallel-group, phase 3 trials, and the design and conduct were described previously [7]. The studies were approved conducted according to the principles of the International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline for good clinical practice [14], and the code of ethics of the World Medical Association's Declaration of Helsinki [15]; written informed consent was obtained from all patients.…”

Section: Study Design and Conductmentioning

confidence: 99%

“…The efficacy of revefenacin has been demonstrated in previous randomized, controlled, phase 3 trials in broad populations of patients with moderate to very severe COPD with or without concurrent long-acting ß agonist (LABA). Revefenacin significantly improved lung function (trough forced expiratory volume in 1 second [FEV 1 ] and overall treatment effect FEV 1 ) compared with placebo in two replicate 12-week studies [7]. Revefenacin treatment was shown to improve FEV 1 and respiratory health outcomes in a 52-week study with results similar to tiotropium via HandiHaler ® [8].…”

Section: Introductionmentioning

confidence: 96%

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Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis

Donohue¹,

Kerwin

Barnes

et al. 2020

Preprint

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Background: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 second (FEV1) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD. Methods: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV1, St. George’s Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 μg and placebo: severe and very severe airflow limitation (percent predicted FEV1 30%–<50% and <30%), 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) D, reversibility (≥12% and ≥200 mL increase in FEV1) to short-acting bronchodilators, concurrent use of long-acting β agonists and/or inhaled corticosteroids, older age (>65 and >75 years), and comorbidity risk factors. Results: Revefenacin demonstrated significant improvements in FEV1 versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio >2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio >2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged >75 years.Conclusions: Revefenacin showed significantly greater improvements in FEV1 versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD.Trial registration: Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; 22 May 2015] and 0127 [NCT02512510; 28 July 2015]).

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Section: Discussionmentioning

confidence: 99%

Section: Study Design and Conductmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis

Donohue¹,

Kerwin

Barnes

et al. 2020

Preprint

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“…This is consistent with the safety profile for revefenacin observed in previous studies: administration of once-daily revefenacin 88 and 175 µg through a standard jet nebulizer was well tolerated and produced clinically and statistically significant improvements in trough forced expiratory volume in 1 second relative to placebo at 12 weeks in 2 identical phase 3 trials of patients with moderate to very severe COPD. 21 A potential limitation of this study is that it did not include patients with COPD who have a higher exposure to the metabolite THRX-195518 than healthy subjects. 6,7 Metabolite levels observed in the healthy subjects receiving the 700-µg revefenacin dose in this study were, however, in excess of those reported in patients with COPD at the therapeutic dose (175 µg) and thus represent a higher exposure than anticipated in clinical use.…”

Section: Discussionmentioning

confidence: 99%

Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

Borin

Barnes

Darpö³

et al. 2019

Clinical Pharm in Drug Dev

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Revefenacin is a novel once-daily, lung-selective, long-acting muscarinic antagonist developed as a nebulized inhalation solution for the maintenance treatment of chronic obstructive pulmonary disease. In a randomized, 4-way crossover study, healthy subjects received a single inhaled dose of revefenacin 175 µg (therapeutic dose), revefenacin 700 µg (supratherapeutic dose), and placebo via standard jet nebulizer, and a single oral dose of moxifloxacin 400 mg (open-label) in separate treatment periods. Electrocardiograms were recorded, and pharmacokinetic samples were collected serially after dosing. The primary end point was the placebo-corrected change from baseline QT interval corrected for heart rate using Fridericia's formula, analyzed at each postdose time. Concentration-QTc modeling was also performed. Following administration of revefenacin 175 and 700 µg, placebo-corrected change from baseline QTcF ( QTcF) values were close to 0 at all times, with the largest mean QTcF of 1.0 millisecond (95% confidence interval [CI], −1.2 to 3.1 milliseconds) 8 hours postdose and 1.0 millisecond (95%CI, −1.1 to 3.1 milliseconds) 1 hour postdose after inhalation of revefenacin 175 and 700 µg, respectively. Revefenacin did not have a clinically meaningful effect on heart rate (within ±5 beats per minute of placebo), or PR and QRS intervals (within ±3 and ±1 milliseconds of placebo, respectively). Using concentration-QTc modeling, an effect of revefenacin > 10 milliseconds can be excluded within the observed plasma concentration range of up to 3 ng/mL. Both doses of revefenacin were well tolerated. These results demonstrate that revefenacin does not prolong the QT interval. x

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“…Inclusion and exclusion criteria for the three studies have been described previously. 11,12 For the 12-and 52-week studies, we enrolled patients aged at least 40 years with moderate to very severe COPD, a smoking history of at least 10 packyears, a postipratropium FEV 1 /forced vital capacity ratio <0.7, and a postipratropium FEV 1 <80% of predicted normal and >700 ml at screening. Patients with a substantially increased risk for cardiovascular events, such as myocardial infarction within the past 6 months, unstable or In the 12-week studies, up to 40% of patients were permitted concomitant use of LABA (LABA cap, controlled through stratification during randomization) with or without ICS.…”

Section: Patients and Treatmentsmentioning

confidence: 99%

Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials

Sethi

Donohue

Ferguson³

et al. 2020

Ther Adv Respir Dis

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Background: Combinations of a long-acting muscarinic receptor antagonist (LAMA), long-acting β-agonist (LABA), and inhaled corticosteroid (ICS) are used for patients with persistent chronic obstructive pulmonary disease (COPD) exacerbations on bronchodilator monotherapy. In this prespecified subgroup analysis, we assessed the efficacy and safety of the LAMA revefenacin in patients with COPD taking concomitant LABA, including ICS/LABA (LABA subgroup). Methods: Efficacy data were obtained from two 12-week, replicate, placebo-controlled trials and safety data were pooled from the 12-week and a 52-week tiotropium-controlled trial. Patients received revefenacin 175 µg or placebo in the 12-week or tiotropium 18 µg in the 52-week studies. The efficacy endpoint was least squares (LS) mean change from baseline in trough forced expiratory volume in 1 second (FEV 1 ). Clinical health outcomes were assessed using the St. George's Respiratory Questionnaire (SGRQ). Results: Revefenacin produced similar improvements from baseline in trough FEV 1 in the non-LABA and LABA subgroups [placebo-adjusted LS mean change (95% confidence interval) in day 85 trough FEV 1 , 150.9 (110.3−191.6) ml and 139.2 (82.9−195.5) ml; p < 0.0001 versus placebo]. Similar improvements were observed in SGRQ scores in the non-LABA and LABA subgroups [−3.3 (−5.4 to −1.2) and −3.4 (−6.3 to −0.6)]. Improvements in lung function and health outcomes were observed regardless of airflow obstruction severity. Revefenacin was well tolerated with more adverse events reported in the LABA than the non-LABA subgroup. Conclusions: Once daily revefenacin for nebulization can be an effective and well-tolerated treatment for patients who require concomitant use of LABA with or without ICS. ClinicalTrials.gov identifiers: NCT02512510, NCT02459080, NCT02518139The reviews of this paper are available via the supplemental material section.

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Improvements in Lung Function with Nebulized Revefenacin in the Treatment of Patients with Moderate to Very Severe COPD: Results from Two Replicate Phase III Clinical Trials

Abstract: For personal use only. Permission required for all other uses.

Cited by 26 publications

References 17 publications

Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis

Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis

Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials

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