Effect of PDE5 Inhibitor on Respiratory Symptoms in COPD Complicated by Pulmonary Hypertension

PULM-002-22F

The investigators will study whether the drug tadalafil improves shortness of breath in 126 Veterans with Chronic Obstructive Pulmonary Disease (COPD) and high blood pressure in the lungs. The investigators will also assess whether tadalafil improves quality of life, home daily physical activity, exercise endurance, the frequency of acute flares of COPD, blood pressure in the lungs, and lung function. Veterans who enroll in the trial will be allocated by chance to either active tadalafil or an inactive identical capsule (placebo). Neither the Veteran nor the investigator will know whether the Veteran is taking tadalafil or placebo. Veterans will be followed closely in clinic or by telephone at 1, 2, 3, 4, 5, and 6 months, with attention to side effects and safety. At 1,3, and 6 months the investigators will repeat the questionnaires and testing of blood pressures in the lung and lung function. The investigators anticipate that the results of this study will determine whether tadalafil improves shortness of breath when added to usual medications for COPD.

2024-04-01

2027-06-01

2027-12-01

Not yet recruiting

Early phase I

126

Inclusion Criteria: 1. Outpatients with COPD, defined as airflow limitation with post-bronchodilator obstruction on baseline visit spirometry, identified by FEV1/FVC \< 70% or \< the lower limit of normal (5th percentile of a normal population based on Global Lung Function Initiative reference equations), OR any emphysema on chest CT noted in a clinical radiology report confirmed by study investigator review. 2. Eligible subjects must have PH documented as follows: -Main Pulmonary Artery/Ascending Aorta (PA/A) diameter \> 1.0 on clinically available CT scans AND transthoracic echocardiography showing normal LVEF with no evidence of moderate-severe aortic stenosis or mitral regurgitation or diastolic dysfunction. Previous CT scan and echocardiogram done within 12 months of enrollment. OR -echocardiography done within 12 months of enrollment demonstrating PA sys \> 40 mmHg AND normal LVEF with no evidence of moderate-severe aortic stenosis or mitral regurgitation or diastolic dysfunction 3. Eligible subjects must be dyspneic, as quantitated by a score of at least 10 on the baseline UCSD Shortness of Breath Questionnaire, assessed at the time of the screening visit. 4. Treatment with at least one long-acting bronchodilator for at least 4 weeks, assessed at the time of the screening visit by chart review and patient interview. 5. AGE 35-89 Years Exclusion Criteria: 1. Diagnosis of PH in the following subgroups of the updated WHO Clinical Classification: Group 1 (Idiopathic, heritable, drug- or toxin-induced, Pulmonary Arterial Hypertension associated with connective tissue disease, congenital heart disease), Group 2 (left atrial hypertension), Group 3 PH not attributable to COPD, Group 4 (chronic thromboembolic PH) or other forms of PH not associated with primary lung disease. 2. Systemic hypotension in the ambulatory setting (at least 3 reproducible measurements of systolic BP \<89 mmHg, recorded by a health care provider over 1 week). 3. Moderate or severe hepatic impairment (Child-Pugh B and C). 4. Severe renal insufficiency (GFR \<30 ml/min/1.73 m2) 5. Echocardiography showing moderate or greater aortic stenosis (aortic valve area \<1.0 cm2), moderate-severe mitral regurgitation, or diastolic dysfunction (Any two of the following: Average E/e' \>14, Septal e' velocity \< 7 or lateral e' velocity \<10, LA volume index \> 34 ml/m2). LVEF \< 50%. 6. Any acute or chronic impairment (other than dyspnea) that limits ability to comply with the study requirements. 7. Current unstable angina, myocardial infarction or stroke within 6 months. 8. Requirement for nitrate therapy for any clinical indication. 9. Active prescription for a PDE-5 inhibitor or other pulmonary vasodilator other than oxygen as a PH treatment. 10. History of non-arteritic anterior ischemic optic neuropathy or crowded optic disc noted on ophthalmology examinations recorded in CPRS. 11. Contraindications: PDE-5i allergy, penile anatomical deformations, sickle cell anemia, multiple myeloma, leukemia, bleeding disorders, active peptic ulcer disease, retinitis pigmentosa or other retinal disorders. In accordance with 38 USC 7332, this information will be kept confidential and will not be disclosed in presentations, publications, or any other dissemination of the study results, or to anyone outside of the IRB-approved study team. 12. Use of any of the following: protease inhibitor, anti-fungal agent, rifampin. 13. Pregnant or breastfeeding women. 14. Pulmonary veno-occlusive disease 16. Hypoxia (reproducible ambulatory SaO2 \< 90% on supplemental oxygen at rest recorded by a health care provider over 1 week). 17. Diagnosis of Obstructive Sleep Apnea without a prescription for treatment. 18. Newly prescribed (less than 4 weeks duration) bronchodilator or diuretic therapy or new enrollment in pulmonary rehabilitation at the time of Screening. 19. Students, VA employees, persons with impaired decision making, illiterate and non-English speakers, and terminally ill patients. 20. Nonadherence to accepted GOLD guidelines for treatment of COPD. 21. COPD or CHF exacerbation within the past 4 weeks. 22. On-going therapy with doxazosin.

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2024-02-13