Targeted Lung Denervation for Moderate to Severe COPD
This first-in-human clinical trial evaluated the novel TLD therapy, designed to ablate the parasympathetic pulmonary nerves surrounding the main bronchi, thereby decreasing bronchomotor tone in patients with COPD. As a feasibility evaluation, this study included a drug 'wash-out' period to establish baseline values in order to understand the effect of this new therapy alone. This study demonstrated TLD to be feasible, safe and well tolerated. The primary endpoint was met in 95% of patients, and technical feasibility was 93%. A tendency toward improvements in lung function, exercise capacity, and HRQL were observed in the 20 W cohort with statistical significance achieved for FVC at 90 days (p=0.016) and 270 days (p=0.036); cycle endurance at 180 days (p=0.03) and SGRQ at 90 days (p=0.042), 180 days (p=0.019), 270 days (p=0.008) and 1 year (p=0.011). These improvements tended to be larger than those seen in the 15 W cohort with statistically significant difference in SGRQ at 1 year (p=0.044). Additionally, early data suggest an additive effect when TLD is combined with inhaled anticholinergic drugs.
Three procedural adjustments were made during the study in response to asymptomatic airway wall effects observed in three of 12 patients in the 20 W group. These effects were postulated to be attributable to a combination of energy delivery to the thin, thermally sensitive tissue of the main carina, imperfect balloon contact that limited surface cooling and, potentially, the higher energy level. Subsequent computer modelling and bench testing confirmed heat accumulation in the thin tissue of the carina, and post hoc analysis of procedural imaging indicated the balloon was not able to accommodate itself to sharply tapering or sudden geometric changes of the airway. As a result, the procedure was modified to more distal electrode placement away from the main carina, more detailed visual assessment of balloon contact before activation, and decrease in overall power to 15 W to further reduce the potential for undesired airway wall effects.
In this study, the 12 patients treated with 20 W tended to have greater changes from baseline in spirometry, exercise capacity and HRQL, when compared with the 10 patients treated with 15 W. The added effect in the 20 W group might be attributable to more effective denervation due to a deeper tissue effect at higher energy. On the other hand, the 20 W group patients were slightly more reversible to ipratropium at baseline, which theoretically, might mean that these patients are more sensitive to TLD therapy. However, we found no difference between the two groups in tiotropium through FEV1 levels. Apart from the airway effects observed, safety profiles for the two energy levels were similar. This might imply that future catheter designs that better accommodate human airway irregularities will ensure better surface cooling and, thus, allow higher energy levels to be used.
In this paper, we introduced TLD, a novel bronchoscopic treatment concept for symptomatic patients suffering from COPD. Based on the concept of ablating parasympathetic pulmonary nerves, TLD was shown to be feasible, safe and well tolerated. TLD has the potential to overcome many of the limitations of inhaled drugs for the treatment of COPD. First, TLD may eliminate inhaler compliance issues for the 63% of new tiotropium users who discontinue treatment after 1 year. Second, TLD would not be subject to the peak and trough variations seen with drugs. Third, TLD may eliminate variable regional drug delivery and deposition in patients with obstructive lung disease by ablating the nerves that travel throughout the bronchial tree independent of regional airflow obstruction. Fourth, by interfering with parasympathetic nerve-derived acetylcholine by two different mechanisms, the combination of TLD +inhaled anticholinergic drugs, as suggested in figure 7, may have a synergistic effect that results in a reduction in airway obstruction and mucus production, as well as inhibition of local airway inflammation induced by non-neural muscarinic action. Further investigation and progressive product development of this novel therapy is warranted, with focus on further refining energy delivery to ablate the nerves and optimise patient selection.
Discussion
This first-in-human clinical trial evaluated the novel TLD therapy, designed to ablate the parasympathetic pulmonary nerves surrounding the main bronchi, thereby decreasing bronchomotor tone in patients with COPD. As a feasibility evaluation, this study included a drug 'wash-out' period to establish baseline values in order to understand the effect of this new therapy alone. This study demonstrated TLD to be feasible, safe and well tolerated. The primary endpoint was met in 95% of patients, and technical feasibility was 93%. A tendency toward improvements in lung function, exercise capacity, and HRQL were observed in the 20 W cohort with statistical significance achieved for FVC at 90 days (p=0.016) and 270 days (p=0.036); cycle endurance at 180 days (p=0.03) and SGRQ at 90 days (p=0.042), 180 days (p=0.019), 270 days (p=0.008) and 1 year (p=0.011). These improvements tended to be larger than those seen in the 15 W cohort with statistically significant difference in SGRQ at 1 year (p=0.044). Additionally, early data suggest an additive effect when TLD is combined with inhaled anticholinergic drugs.
Three procedural adjustments were made during the study in response to asymptomatic airway wall effects observed in three of 12 patients in the 20 W group. These effects were postulated to be attributable to a combination of energy delivery to the thin, thermally sensitive tissue of the main carina, imperfect balloon contact that limited surface cooling and, potentially, the higher energy level. Subsequent computer modelling and bench testing confirmed heat accumulation in the thin tissue of the carina, and post hoc analysis of procedural imaging indicated the balloon was not able to accommodate itself to sharply tapering or sudden geometric changes of the airway. As a result, the procedure was modified to more distal electrode placement away from the main carina, more detailed visual assessment of balloon contact before activation, and decrease in overall power to 15 W to further reduce the potential for undesired airway wall effects.
In this study, the 12 patients treated with 20 W tended to have greater changes from baseline in spirometry, exercise capacity and HRQL, when compared with the 10 patients treated with 15 W. The added effect in the 20 W group might be attributable to more effective denervation due to a deeper tissue effect at higher energy. On the other hand, the 20 W group patients were slightly more reversible to ipratropium at baseline, which theoretically, might mean that these patients are more sensitive to TLD therapy. However, we found no difference between the two groups in tiotropium through FEV1 levels. Apart from the airway effects observed, safety profiles for the two energy levels were similar. This might imply that future catheter designs that better accommodate human airway irregularities will ensure better surface cooling and, thus, allow higher energy levels to be used.
In this paper, we introduced TLD, a novel bronchoscopic treatment concept for symptomatic patients suffering from COPD. Based on the concept of ablating parasympathetic pulmonary nerves, TLD was shown to be feasible, safe and well tolerated. TLD has the potential to overcome many of the limitations of inhaled drugs for the treatment of COPD. First, TLD may eliminate inhaler compliance issues for the 63% of new tiotropium users who discontinue treatment after 1 year. Second, TLD would not be subject to the peak and trough variations seen with drugs. Third, TLD may eliminate variable regional drug delivery and deposition in patients with obstructive lung disease by ablating the nerves that travel throughout the bronchial tree independent of regional airflow obstruction. Fourth, by interfering with parasympathetic nerve-derived acetylcholine by two different mechanisms, the combination of TLD +inhaled anticholinergic drugs, as suggested in figure 7, may have a synergistic effect that results in a reduction in airway obstruction and mucus production, as well as inhibition of local airway inflammation induced by non-neural muscarinic action. Further investigation and progressive product development of this novel therapy is warranted, with focus on further refining energy delivery to ablate the nerves and optimise patient selection.
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