Using tadalafil to relieve shortness of breath in Veterans with COPD and pulmonary hypertension

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

This study is testing if tadalafil can help Veterans with COPD and pulmonary hypertension breathe easier and improve their overall health.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 126 (estimated)
• Ages: 35 Years to 89 Years
• Sex: All
• Sponsor: VA Office of Research and Development (Federal)
• Locations: 5 sites (Aurora, Colorado and 4 other locations)
• Trial ID: NCT05937854 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effectiveness of tadalafil, a phosphodiesterase type-5 inhibitor, in alleviating dyspnea in 126 Veterans suffering from Chronic Obstructive Pulmonary Disease (COPD) and pulmonary hypertension. Participants will be randomly assigned to receive either tadalafil or a placebo, with neither the participants nor the investigators aware of which treatment is being administered. The study will monitor various outcomes, including quality of life, physical activity, exercise endurance, and lung function over a six-month period. The goal is to determine if tadalafil can significantly improve symptoms and overall health in this patient population.

Who should consider this trial

Good fit: Ideal candidates for this study are outpatients with COPD and documented pulmonary hypertension who experience significant shortness of breath.

Not a fit: Patients without COPD or pulmonary hypertension, or those who do not experience dyspnea, may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve the quality of life and reduce symptoms for Veterans suffering from COPD and pulmonary hypertension.

How similar studies have performed: Previous studies on tadalafil for similar conditions have shown mixed results, indicating that this approach may still hold potential for new insights.

Eligibility criteria

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:

   1. Main Pulmonary Artery/Ascending Aorta (PA/A) diameter \> 0.90 on clinically available CT scans within 12 months OR
   2. Main Pulmonary Artery diameter \> 30.8mm on clinically available CT scans within 12 months OR
   3. outpatient echocardiography done within 6 months of enrollment demonstrating PA sys \> 34 mmHg OR
   4. Mean Pulmonary Artery Pressure \> 20 on Right Heart Catheterization done within 6 months of enrollment and when Veteran is clinically stable.
3. Eligible subjects must be dyspneic, as quantitated by a score of at least 20 on the baseline UCSD Shortness of Breath Questionnaire, assessed at the time of the baseline visit.
4. Treatment with at least one long-acting bronchodilator for at least 4 weeks, assessed at the time of the baseline visit by chart review and patient interview.
5. Age 35-89 Years
6. Women of childbearing potential must meet one of the following criteria for the previous three months AND must have a negative pregnancy test on the day of testing. If more than 36 hours since the participant's last pregnancy test, they will be tested again at the study visit.

   1. have been using a contraceptive measure (an intrauterine device (IUD), a contraceptive implant, oral contraceptives, barrier methods, or abstinence)
   2. have a male partner with a vasectomy
   3. have a tubal ligation procedure or a medical diagnosis (such as infertility) or therapies/procedures that precludes pregnancy (such as cancer treatments or endometrial ablation)
   4. are in a same-sex relationship
   5. have a male partner not capable of fathering children because of congenital anomalies, other surgery, or medical treatment
7. Women who are not considered to be of childbearing potential who have been surgically sterilized (for example: removal of ovaries or fallopian tubes, or hysterectomy) or are post-menopausal (no menstrual period for more than 6 months).

Exclusion Criteria:

1. Diagnosis of PH in the following subgroups of the updated WHO Clinical Classification:

   1. Group 1 (Idiopathic, heritable, drug- or toxin-induced, Pulmonary Arterial Hypertension associated with connective tissue disease, congenital heart disease)
   2. Group 2 (left atrial hypertension)
   3. Group 3 PH not attributable to COPD
   4. 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 within 3 months showing greater than moderate aortic stenosis (aortic valve area \<1.0 cm2), greater than moderate 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%. Any aortic or mitral valve replacement.
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 the following retinal disorders: retinitis pigmentosa, 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 listed above. 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: rifampin, systemic anti-fungal azole agents, protease inhibitors, phenobarbital, dilantin.
13. Pregnant, possibly pregnant by report, or if breastfeeding. If found to be pregnant at the study visit, the study visit will not be conducted.
14. Pulmonary veno-occlusive disease
15. Hypoxia (reproducible ambulatory SaO2 \< 90% on supplemental oxygen at rest recorded by a health care provider over 1 week).
16. Diagnosis of Obstructive Sleep Apnea without a prescription for treatment.
17. Newly prescribed (less than 4 weeks duration) bronchodilator or diuretic therapy or new enrollment in pulmonary rehabilitation at the time of Baseline.
18. Students, VA employees, persons with impaired decision making, illiterate and non-English speakers, and terminally ill patients.
19. COPD or CHF exacerbation within the past 4 weeks.
20. On-going therapy with doxazosin.

Women of childbearing potential must have a documented negative pregnancy test and must be using adequate contraception during the study and for 9 months afterward. Monthly pregnancy tests will be done, and compliance with contraception use will be documented at the telephone and clinic visits. Should a female become pregnant at any time during the study, the study medication will be discontinued.

Doxazosin use will be defined as current active prescription and usage of Doxazosin or planned trial (pending prescription) of Doxazosin for treatment of benign prostatic hypertrophy, systemic hypertension, or other indication. A list of alpha-1 antagonists (ex. prazosin, doxazosin, tamulosin, terazosin, etc.) will be included in the patient study medication handout to prompt the patient to avoid any new usage of these drugs during the trial period. On-going therapy with doxazosin is an exclusion criterion due to greater risk of hypotension.

Where this trial is running

Aurora, Colorado and 4 other locations

• Rocky Mountain Regional VA Medical Center, Aurora, CO — Aurora, Colorado, United States (Recruiting)
• Atlanta VA Medical and Rehab Center, Decatur, GA — Decatur, Georgia, United States (Recruiting)
• VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA — Boston, Massachusetts, United States (Recruiting)
• Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE — Omaha, Nebraska, United States (Recruiting)
• Providence VA Medical Center, Providence, RI — Providence, Rhode Island, United States (Recruiting)

Study contacts

• Principal investigator: Sharon I Rounds, MD — Providence VA Medical Center, Providence, RI
• Study coordinator: Sharon I Rounds, MD

Conditions Chronic Obstructive Pulmonary Disease; Pulmonary Hypertension; Dyspnea; COPD; cigarette smoke; lung; echocardiography; chest CT