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Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

ABSTRACT: RATIONALE:Targeted lung denervation (TLD) is a novel bronchoscopic treatment for the disruption of parasympathetic innervation of the lungs. OBJECTIVES:To assess safety, feasibility, and dosing of TLD in patients with moderate to severe COPD using a novel device design. METHODS:Thirty patients with COPD (forced expiratory volume in 1 s 30-60%) were 1:1 randomized in a double-blinded fashion to receive TLD with either 29 or 32 W. Primary endpoint was the rate of TLD-associated adverse airway effects that required treatment through 3 months. Assessments of lung function, quality of life, dyspnea, and exercise capacity were performed at baseline and 1-year follow-up. An additional 16 patients were enrolled in an open-label confirmation phase study to confirm safety improvements after procedural enhancements following gastrointestinal adverse events during the randomized part of the trial. RESULTS:Procedural success, defined as device success without an in-hospital serious adverse event, was 96.7% (29/30). The rate of TLD-associated adverse airway effects requiring intervention was 3/15 in the 32 W versus 1/15 in the 29 W group, p = 0.6. Five patients early in the randomized phase experienced serious gastric events. The study was stopped and procedural changes made that reduced both gastrointestinal and airway events in the subsequent phase of the randomized trial and follow-up confirmation study. Improvements in lung function and quality of life were observed compared to baseline values for both doses but were not statistically different. CONCLUSIONS:The results demonstrate acceptable safety and feasibility of TLD in patients with COPD, with improvements in adverse event rates after procedural enhancements.

SUBMITTER: Valipour A

PROVIDER: S-EPMC6878750 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

Valipour Arschang A Shah Pallav L PL Pison Christophe C Ninane Vincent V Janssens Wim W Perez Thierry T Kessler Romain R Deslee Gaetan G Garner Justin J Abele Christine C Hartman Jorine E JE Slebos Dirk-Jan DJ

Respiration; international review of thoracic diseases 20190620 4

<h4>Rationale</h4>Targeted lung denervation (TLD) is a novel bronchoscopic treatment for the disruption of parasympathetic innervation of the lungs.<h4>Objectives</h4>To assess safety, feasibility, and dosing of TLD in patients with moderate to severe COPD using a novel device design.<h4>Methods</h4>Thirty patients with COPD (forced expiratory volume in 1 s 30-60%) were 1:1 randomized in a double-blinded fashion to receive TLD with either 29 or 32 W. Primary endpoint was the rate of TLD-associat ...[more]

PMID: 31220851

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Project description:BackgroundArformoterol tartrate (arformoterol, 15 μg bid) is a nebulized long-acting β2-agonist approved for maintenance treatment of COPD.MethodsThis was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥ 40 years with baseline FEV1 ≤ 65% predicted, FEV1 > 0.50 L, FEV1/FVC ≤ 70%, and ≥ 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization.ResultsAmong 841 patients randomized, 103 had ≥ 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively). Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P = .003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different. Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively). Significant improvements in quality of life (overall St. George's Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo (P < .05).ConclusionsArformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo. Arformoterol was well-tolerated and improved lung function vs placebo.Trial registryClinicalTrials.gov; No.: NCT00909779; URL: www.clinicaltrials.gov.

Project description:Rationale: Targeted lung denervation (TLD) is a bronchoscopic radiofrequency ablation therapy for chronic obstructive pulmonary disease (COPD), which durably disrupts parasympathetic pulmonary nerves to decrease airway resistance and mucus hypersecretion.Objectives: To determine the safety and impact of TLD on respiratory adverse events.Methods: We conducted a multicenter, randomized, sham bronchoscopy-controlled, double-blind trial in patients with symptomatic (modified Medical Research Council dyspnea scale score, ≥2; or COPD Assessment Test score, ≥10) COPD (FEV1, 30-60% predicted). The primary endpoint was the rate of respiratory adverse events between 3 and 6.5 months after randomization (defined as COPD exacerbation, tachypnea, wheezing, worsening bronchitis, worsening dyspnea, influenza, pneumonia, other respiratory infections, respiratory failure, or airway effects requiring therapeutic intervention). Blinding was maintained through 12.5 months.Measurements and Main Results: Eighty-two patients (50% female; mean ± SD: age, 63.7 ± 6.8 yr; FEV1, 41.6 ± 7.3% predicted; modified Medical Research Council dyspnea scale score, 2.2 ± 0.7; COPD Assessment Test score, 18.4 ± 6.1) were randomized 1:1. During the predefined 3- to 6.5-month window, patients in the TLD group experienced significantly fewer respiratory adverse events than those in the sham group (32% vs. 71%, P = 0.008; odds ratio, 0.19; 95% confidence interval, 0.0750-0.4923, P = 0.0006). Between 0 and 12.5 months, these findings were not different (83% vs. 90%; P = 0.52). The risk of COPD exacerbation requiring hospitalization in the 0- to 12.5-month window was significantly lower in the TLD group than in the sham group (hazard ratio, 0.35; 95% confidence interval, 0.13-0.99; P = 0.039). There was no statistical difference in the time to first moderate or severe COPD exacerbation, patient-reported symptoms, or other physiologic measures over the 12.5 months of follow-up.Conclusions: Patients with symptomatic COPD treated with TLD combined with optimal pharmacotherapy had fewer study-defined respiratory adverse events, including hospitalizations for COPD exacerbation.Clinical trial registered with www.clinicaltrials.gov (NCT02058459).

Project description:Background:Formoterol fumarate inhalation solution (FFIS; Perforomist®) is a long-acting ?2-agonist (LABA) marketed in the US as a nebulized COPD maintenance treatment. Because long-term LABA use was associated with a potential increased risk of exacerbation or death in asthma patients, the US Food and Drug Administration (FDA) requested a postmarketing commitment study to evaluate long-term safety in COPD patients. Methods:This was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study. Patients (N=1,071; mean age, 62.6 years; 48.5% male; 89.7% white) with moderate-to-severe COPD on stable COPD therapy received FFIS (20 µg; n=541) or placebo (n=530) twice daily. The primary end point was the combined incidence of respiratory death, first COPD-related ER visit, or first COPD exacerbation-related hospitalization during 1 year post randomization. Noninferiority to placebo was concluded if the two-sided 90% CI of the HR of FFIS to placebo was <1.5. Secondary end points included spirometry. Results:The planned 1-year treatment period was completed by 520 patients; 551 discontinued prematurely (FFIS: 45.7%; placebo: 57.4%). The median treatment duration was approximately 10 and 7 months for FFIS and placebo, respectively. Among 1,071 randomized patients, 121 had ?1 primary event (FFIS: 11.8%; placebo: 10.8%). The estimated HR of a primary event with FFIS vs placebo was 0.965 (90% CI: 0.711, 1.308), demonstrating that FFIS was noninferior to placebo. No respiratory deaths were observed in the FFIS group. Adverse events were similar for FFIS vs placebo (patients with ?1 treatment-emergent adverse events: 374 [69.1%] vs 369 [69.6%], respectively). Compared with placebo, FFIS demonstrated statistically greater improvements from baseline in trough FEV1, FVC, percent predicted FEV1, and patient-reported outcomes (Transition Dyspnea Index). Conclusions:Nebulized FFIS was noninferior to placebo with respect to safety in patients with moderate-to-severe COPD. Additionally, fewer treatment withdrawals and larger lung function improvements were observed with FFIS compared with placebo when added to other maintenance COPD therapies.

Project description:BackgroundNVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD). The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD.MethodsPatients with COPD with a smoking history of ≥ 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 80% and ≥ 30% predicted normal and FEV1/forced vital capacity < 0.70 were enrolled. Patients were randomized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry. The primary outcome measure was trough FEV1 at Week 12.ResultsA total of 822 patients were randomized to NVA237 (n = 552) or placebo (n = 270). Least squares mean (± standard error) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L), versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p < 0.001). Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26. FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints. Transition dyspnoea index focal scores and St. George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p < 0.001) and -2.81 (p = 0.004), respectively. NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31% (p = 0.023) and use of rescue medication by 0.46 puffs per day (p = 0.005), versus placebo. NVA237 was well tolerated and had an acceptable safety profile, with a low frequency of cardiac and typical antimuscarinic adverse effects.ConclusionsOnce-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication.Trial registrationClinicalTrials.gov: NCT01005901.

Project description:PurposeThis study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting β2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD.Materials and methodsIn this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 μg and FF MDI 9.6 μg, and two of either BFF MDI 160/9.6 μg, BFF MDI 80/9.6 μg, or BD MDI 320 μg twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29.ResultsOverall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 μg (least squares mean differences 186-221 mL; all p<0.0001), and BFF MDI 320/9.6 μg demonstrated a significant improvement versus FF MDI 9.6 μg (least squares mean difference 56 mL; p=0.0013). Furthermore, all BFF MDI doses showed significant improvements versus BD MDI 320 μg for all lung function, dyspnea, and rescue medication use secondary efficacy endpoints. All BFF MDI doses were well tolerated, and the safety profile was not substantially different from the monocomponents. There was no evidence of clinically meaningful pharmacokinetic interactions when budesonide and formoterol were formulated together in BFF MDI.ConclusionThe findings presented here confirm that BFF MDI 320/9.6 μg is an appropriate dose to take forward into Phase III studies in patients with COPD.

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Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

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Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

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