Citations

Abstract Rationale Chronic bronchitis (CB), a common phenotype of chronic obstructive pulmonary disease (COPD), is characterized by pathologic mucus hypersecretion and is associated with substantial morbidity, impaired quality of life, and progressive functional decline, with prior studies demonstrating an average worsening of approximately one point/year on the COPD Assessment Test (CAT). Bronchial rheoplasty (BR) with RheOx® combines mechanical mucous plug disimpaction with pulsed electric field (PEF) energy to ablate and restore the airway mucosa. The RheSolve study was designed to provide evidence of safety and efficacy versus mechanical disimpaction alone. Primary endpoint results have been previously reported; final 2-year outcomes are reported here. Methods RheSolve was a prospective, randomized, double-blind study enrolling 273 patients with COPD and moderate-to-severe CB across 37 centers in the United States and Europe. Participants were randomized 2:1 to BR (n = 185) or a mechanical control procedure (n = 88). Following unblinding at 12 months, 75% of control patients crossed over to BR, precluding valid randomized comparisons beyond that time point; therefore, longer-term outcomes were evaluated using within-patient changes from baseline in the BR cohort. Outcomes included CAT, St George’s Respiratory Questionnaire (SGRQ), Cough and Sputum Assessment Questionnaire (CASA-Q), and pulmonary function tests (PFTs). Results Patients in the BR group represented a moderate to severe COPD CB phenotype at baseline (FEV1 60.9% predicted, emphysema (-950 HU) 11.0%, CAT 27.2 points, SGRQ 64.4) with most patients (93%) receiving a combination of ≥ 2 long-acting medications (LABA, LAMA, inhaled corticosteroids). The BR procedure was well-tolerated with no SAEs related to the device or procedure beyond 12 months. Both groups demonstrated clinically meaningful improvements in CAT, SGRQ, and CASA-Q at 12 months (P < 0.001), which were sustained in the BR group through 24 months. Follow-up was limited to 1 year in the mechanical control group, with outcomes demonstrating a modest regression towards baseline at 12 months (Figure). PFTs were also stable to improved in the BR group (changes from baseline to 24 months: FEV1 % Predicted 0.9 (±10.8) P = 0.319, FVC % Predicted 2.8% (±14.0) P = 0.02, FEV1/FVC -0.5% (±7.2) P = 0.449). Conclusions BR with RheOx® (e.g.,mechanical mucous plug disimpaction and PEF delivery) demonstrated clinically meaningful symptom improvement that was sustained through 24 months supporting BR as a therapeutic option for patients with persistent symptoms despite appropriate medical therapy. This abstract is funded by: Galvanize Therapeutics

Abstract Rationale: The D'Nerva Targeted Lung Denervation (TLD) System uses radiofrequency energy delivered bronchoscopically to the main bronchi to disrupt parasympathetic nerve innervation to the lung. AIRFLOW-3 clinical trial was a randomized, double blind, sham controlled study to determine the impact of TLD on COPD exacerbations. Methods: AIRFLOW-3 patients had symptomatic COPD (CAT ≥10) with moderate to very severe airflow obstruction (GOLD stage II-IV: 25% ≤ FEV1 ≤ 80% predicted, FEV1/FVC<0.70) and GOLD E status (≥2 moderate or ≥1 severe exacerbation in the prior 12 months) despite optimal medical therapy. The primary endpoint was a time-to-first event comparison of the probability of subjects having a moderate or severe exacerbation, between the Treatment arm (TLD + optimal medical therapy) and the Sham Control arm (optimal medical therapy). Results: 388 patients were randomized 1:1 at 32 clinical sites across the US, EU, and UK. Patients were 67.8 (SD 7.1) years of age, ex-smokers with a 46.7 (22.0) pack-year smoking history, and 41.0 (11.8) post bronchodilator FEV1% pred. SGRQ-C and CAT scores were 62.5 (17.0) and 23.6 (6.3), respectively. Over 90% of patients were on triple therapy (LAMA+LABA+ICS) at baseline and through 1 year of follow up. 42% of patients had prior-year COPD hospitalization(s). There was no difference between groups in the analysis of the primary endpoint. At 1 year, the sham arm exhibited a statistical decline in lung function (decrease in FEV1 and FVC) and worsening of gas trapping (increase in RV). Lung function and gas trapping were stable in the treatment arm. The treatment arm exhibited a statistically significant improvement in dyspnea at one year compared to sham (mMRC, and TDI). These observations led to the identification of a subgroup of TLD treatment responders corresponding to an airway predominant phenotype (lung hyperinflation in the absence of significant emphysema) that demonstrated clinically and statistically significant improvements in lung function and exacerbation frequency and severity (Table). Conclusions: The AIRFLOW-3 clinical trial failed to meet its prespecified primary endpoint. Post-hoc analysis of this robust dataset led to the identification of a responder profile that achieved significant and sustained improvements in lung function, and exacerbation reduction. A future clinical study is being designed to confirm these findings.

Abstract Rationale Chronic bronchitis (CB) is characterized by productive cough with excessive mucus production, resulting in quality-of-life impairment and increased exacerbation risk. Bronchial rheoplasty uses an endobronchial catheter to apply nonthermal pulsed electrical fields to the airways. Preclinical studies have demonstrated epithelial ablation followed by regeneration of normalized epithelium. Objectives To evaluate the feasibility, safety, and initial outcomes of bronchial rheoplasty in patients with CB. Methods Pooled analysis of two separate studies enrolling 30 patients undergoing bilateral bronchial rheoplasty was conducted. Follow-up through 6 months (primary outcome) and 12 months included assessment of adverse events, airway histology, and changes in symptoms using the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test and St. George’s Respiratory Questionnaire (SGRQ). Measurements and Main Results: Bronchial rheoplasty was performed in all 30 patients (63% male; mean [SD] age, 67 [7.4]; mean [SD] postbronchodilator FEV1, 65% [21%]; mean [SD] COPD Assessment Test score 25.6 [7.1]; mean [SD] SGRQ score, 59.6 [15.3]). There were no device-related and four procedure-related serious adverse events through 6 months, and there were none thereafter through 12 months. The most frequent nonserious, device- and/or procedure-related event through 6 months was mild hemoptysis in 47% (14 of 30) patients. Histologically, the mean goblet cell hyperplasia score was reduced by a statistically significant amount (P < 0.001). Significant changes from baseline to 6 months in COPD Assessment Test (mean, −7.9; median, −8.0; P = 0.0002) and SGRQ (mean, −14.6; median, −7.2; P = 0.0002) scores were observed, with similar observations through 12 months. Conclusions This study provides the first clinical evidence of the feasibility, safety, and initial outcomes of bronchial rheoplasty in symptomatic patients with CB. Clinical trial registered with www.anzctr.org.au (ACTRN 12617000330347) and clinicaltrials.gov (NCT 03107494).

Abstract For over 150 years, bronchoscopy, especially flexible bronchoscopy, has been a mainstay for airway inspection, the diagnosis of airway lesions, therapeutic aspiration of airway secretions, and transbronchial biopsy to diagnose parenchymal lung disorders. Its utility for the diagnosis of peripheral pulmonary nodules and therapeutic treatments besides aspiration of airway secretions, however, has been limited. Challenges to the wider use of flexible bronchoscopy have included difficulty in navigating to the lung periphery, the avoidance of vasculature structures when performing diagnostic biopsies, and the ability to biopsy a lesion under direct visualization. The last 10–15 years have seen major advances in thoracic imaging, navigational platforms to direct the bronchoscopist to lung lesions, and the ability to visualize lesions during biopsy. Moreover, multiple new techniques have either become recently available or are currently being investigated to treat a broad range of airway and lung parenchymal diseases, such as asthma, emphysema, and chronic bronchitis, or to alleviate recurrent exacerbations. New bronchoscopic therapies are also being investigated to not only diagnose, but possibly treat, malignant peripheral lung nodules. As a result, flexible bronchoscopy is now able to provide a new and expanding armamentarium of diagnostic and therapeutic tools to treat patients with a variety of lung diseases. This State-of-the-Art review succinctly reviews these techniques and provides clinicians an organized approach to their role in the diagnosis and treatment of a range of lung diseases.