A Sequential Two Phase Multicenter, Randomized Study to Optimize Dose Selection and Evaluate Safety After Treatment with the Holaira* Lung Denervation System in Patients with Moderate to Severe COPD.

1. Diagnosis of COPD with FEV1 30% to 60% and FEV1/FVC <70% (post-bronchodilator);
2. mMRC grade * 2 or CAT score * 10 at the time of enrollment
3 Positive relative change in FEV1 and/or FVC of >12% and >200 mL following administration of ipratropium bromide during reversibility testing (only phase A);
4. Patient *40 and *75 years of age at the time of consent;
5. Women of child bearing potential must have a negative pregnancy test (serum or urine) at screening and agree not to become pregnant for the duration of the study;
6. Smoking history of at least 10 pack years;
7. Non-smoking for a minimum of 2 months prior to consent and agrees to not smoke for the duration of the study;(Negative nicotine test required, unless subject is currently taking smoking cessation medication, patch, gum, etc.)
8. Participated in a pulmonary rehabilitation program and/or confirmed to have been engaged or attempted regular physical activity under professional supervision in the past 12 months and agrees to continue or restart regular physical activity for duration of study;
9. Current influenza vaccination and/or pneumococcus vaccination consistent with local recommendations and/or policy;
10. Patient is a candidate for bronchoscopy in the opinion of the physician or per hospital guidelines;
11.The patient is willing, able and agrees to complete all protocol required baseline and follow up testing assessments including taking and abstaining from certain medications (e.g., tiotropium bromide capsules);
12.Patient has provided written informed consent using a form that has been reviewed and approved by the Ethics Committee (EC).

1. Has been <6 weeks (from start of testing) following the resolution of a COPD exacerbation or active lower respiratory infection (e.g. pneumonia); (NOTE: The start of testing may be delayed in order to accommodate this requirement.)
2. History of recurrent respiratory infections and/or COPD exacerbations (more than 2 hospitalizations within 1 year of enrollment);
3. Prior lung or chest procedure (e.g. lung transplant, LVRS, BLVR, lung implant, metal stent, valves, coils, median sternotomy, bullectomy, segmentectomy or lobectomy, etc);
4. Documented history of asthma diagnosed with onset <30 years of age, cystic fibrosis, tuberculosis, paradoxical vocal cord motion, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis or severe interstitial lung disease or active tuberculosis;
5.Pre-existing diagnosis of pulmonary hypertension, defined as a sustained elevation of the mean pulmonary artery pressure greater than or equal to 25 mm Hg at rest by right heart catheterization; or estimated by echocardiogram to be greater than 40 mm Hg;
6. Pulmonary nodule requiring follow-up or intervention unless proven benign;
7. Inability to perform exercise tolerance testing without physical assistance; (Note: normal walking aids allowed (e.g. cane, walker))
8. Malignancy treated with radiation or chemotherapy within the last 2 years;
9. Failed Cardiac Clearance: defined as myocardial infarction within last 6 months, EKG with evidence of life threatening arrhythmias or acute ischemia, pre-existing documented evidence of an LVEF <45%, stage C or D (ACC/AHA) or Class III or IV (NYHA) congestive heart failure, or any other past or present cardiac findings that make the patient not an acceptable candidate for a bronchoscopic procedure utilizing general anesthesia;
10. Patient has an implantable electronic device;
11. Patient has a PaO2 *7.3 kPa (55 mm Hg) and/or a PaCO2 >8.0 kPa (60 mm Hg) on room air;
12. Uncontrolled diabetes as evidenced by an HbA1C >7%;
13. Known coagulopathy;
14. Known hypersensitivity to anticholinergic drugs or components;
15. Known allergy to medications required for bronchoscopy or general anesthesia (such as lidocaine, atropine, propofol, sevoflurane) that cannot be medically controlled;
16. Based on investigator judgment, the patient is unable to stop taking blood thinning medication (with the exception of aspirin) 7 days before and not re-start until 7 days after the study procedure;
17. Daily use of >10 mg of prednisone or its equivalent at the time of enrollment;
18. Documented history of untreated severe (AHI index >30/hr) obstructive sleep apnea;
19. Body Mass Index <18 or >33 male/34 female
20. The patient has any disease or condition that might interfere with completion of this study (e.g., life expectancy <3 years);
21. Patient is currently enrolled in another clinical trial that has not completed follow-up;
22. Screening Chest CT Scan reveals bronchi anatomy cannot be fully treated with available catheter sizes, presence of severe emphysema (as determined by the CT core lab).
23. In the opinion of the treating investigator, use of the Holaira System is not technically feasible due to patient anatomy or other clinical finding;
24. Previous diagnosis of Alpha 1-antitrypsin deficiency (defined as <0.8 g/l) (Phase A only);
25. Clinically relevant bronchiectasis;
26. Patients who had abdominal surgical procedures on stomach, esophagus or pancreas (e.g. Esophagectomy, Gastrostomy, Gastrectomy, Bariatric surgery, fundoplication, vagotomy);
27. Patients with a GCSI score *>18.0 prior to treatment;
28. Recent (<3 months ago) or narcotic use