Breathe Easier With Tadalafil Therapy for Dyspnea in COPD-PH (BETTER COPD-PH)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Obstructive Pulmonary Disease; Pulmonary Hypertension; Dyspnea
• Intervention / Treatment: Drug: Placebo; Drug: Tadalafil

Detailed Description

Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the US and is common among Veterans. Dyspnea, a debilitating symptom of COPD, dramatically worsens health related quality of life, is associated with a reduction in daily physical activity and greater health care utilization and is more closely associated with survival than severity of airflow limitation. Thus, it is important to have effective treatments that reduce dyspnea for Veterans with COPD. Pulmonary hypertension (PH) is a common complication of COPD that is associated with severe dyspnea, more frequent acute exacerbations of COPD, and increased mortality. There are multiple causes of PH associated with COPD (COPD-PH), including decreased bioavailable levels of the vasodilator nitric oxide (NO). Phosphodiesterase type-5 inhibitor (PDE-5i) therapy restores NO signaling and improves cardiopulmonary hemodynamics and dyspnea among patients with Pulmonary Arterial Hypertension. However, studies of PDE-5i medications in COPD-PH have shown conflicting results due to differing doses or durations of therapy and differing definitions of PH. In a prior study (ClinicalTrials.gov.identifier: NCT01862536), the investigators investigated the effects of up to 12 months of oral PDE-5i therapy with tadalafil on 6 minute walk distance (6MWD), a measure of exercise capacity in Veterans with COPD-PH, in a multi-center randomized placebo-controlled trial funded by the Department of Veterans Affairs. While tadalafil did not change 6MWD at 6 and 12 months (the primary outcome), the treatment group experienced changes in important secondary outcomes, with clinically meaningful improvement in patient-reported dyspnea and COPD-related health related quality of life after 6 months of therapy. Additionally, over 6 months, dyspnea worsened in the placebo group, and patients receiving PDE-5i therapy suffered fewer exacerbations. A limitation of this study was its small sample size. Given the importance of mitigating dyspnea among patients with COPD, the investigators will assess the effect of maximally tolerated therapy with tadalafil specifically on dyspnea powered as a primary outcome. In 126 participants with COPD-PH (63 treatment and 63 placebo) receiving usual clinical care for COPD, the investigators propose to evaluate effects of tadalafil on dyspnea among patients with COPD-PH in a prospective, double-blind, placebo-controlled clinical trial.

Aim 1: As primary outcome, the investigators will determine whether 6 months of daily oral tadalafil is more effective than placebo in reducing severity of patient-reported dyspnea, assessed by the University of California-San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), in Veterans with COPD-PH. The investigators hypothesize that patients receiving tadalafil will report less dyspnea than those receiving placebo.

Aim 2: As a secondary outcome, the investigators will determine the effectiveness of tadalafil therapy on physical activity, assessed by objective daily step count, and functional capacity, assessed by 6MWD. The investigators hypothesize that patients on tadalafil therapy will have improved physical activity and functional capacity.

Aim 3: As a secondary outcome, the investigators will also assess the effects of tadalafil therapy on time to clinically important deterioration, a validated composite outcome defined as increase > 4U in the total health-related quality of life (St. George's Respiratory Questionnaire, SGRQ), decreased FEV1 of > 100ml, or moderate-severe acute exacerbations of COPD. The investigators hypothesize that Veterans with COPD-PH receiving tadalafil will be less likely to have clinically important deterioration.

Aim 4: In exploratory analyses, the investigators will assess whether changes in noninvasive measures of PH (CT scan, cardiac echo) are associated with changes in dyspnea. The investigators hypothesize that patients receiving tadalafil will have decreased PA/A ratio on CT scan, and decreased ePASP on echocardiography.

This study may provide evidence for a new therapy for dyspnea in COPD complicated by PH.

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sharon I Rounds, MD; Phone Number: (401) 273-7100; Email: sharon.rounds@va.gov
• Study Contact Backup: Name: Ronald H Goldstein, MD; Phone Number: (857) 203-6578; Email: Ronald.Goldstein@va.gov

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Rocky Mountain Regional VA Medical Center, Aurora, CO
      • Contact: Edward Dempsey, MD; Phone Number: 303-399-8020; Email: edward.dempsey@va.gov
      • Contact: Matthew Griffith, MD; Phone Number: 3033998020; Email: matthew.griffith@va.gov
  • Georgia
    • Decatur, Georgia, United States, 30033-4004
      • Atlanta VA Medical and Rehab Center, Decatur, GA
      • Contact: Cherry Wongtrakool, MD; Phone Number: 404-321-6111; Email: Cherry.wongtrakool@va.gov
      • Contact: Mohleen Kang, MD; Phone Number: 4043216111; Email: Mohleen.kang@va.gov
  • Massachusetts
    • Boston, Massachusetts, United States, 02130-4817
      • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
      • Contact: Ronald H Goldstein, MD; Phone Number: 617-323-7700; Email: ronald.goldstein@va.gov
      • Contact: Eric Garshick; Phone Number: 6173237700; Email: eric.garshick@va.gov
  • Nebraska
    • Omaha, Nebraska, United States, 68105-1850
      • Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
      • Contact: Ruxana Sadikot, MD; Phone Number: 402-346-8800; Email: ruxana.sadikot2@va.gov
      • Contact: Kristina Bailey, MD; Phone Number: 4023468800; Email: kristina.bailey@va.gov
  • Rhode Island
    • Providence, Rhode Island, United States, 02908-4734
      • Providence VA Medical Center, Providence, RI
      • Contact: Matthew D Jankowich, MD; Phone Number: 401-273-7100; Email: matthew.jankowich@va.gov
      • Contact: Gaurav Choudhary, MD; Phone Number: 12029 (401) 273-7100; Email: Gaurav.Choudhary@va.gov
      • Principal Investigator: Sharon I Rounds, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Encapsulated placebo one or 2 encapsulated tablets po QD	Drug: Placebo; one or two encapsulated tablets of placebo po QD
Active Comparator: tadalafil; one or 2 encapsulated tablets of encapsulated tadalafil (20MG) po QD	Drug: Tadalafil; one or 2 encapsulated tablets of encapsulated tadalafil (20MG) po QD; Other Names: Adcirca, Cialis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
severity of patient-reported dyspnea	Assessed by the University of California-San Diego Shortness of Breath Questionnaire (UCSD-SOBQ). Score range = 0-120 with higher scores indicating worse outcomes. Minimum score for inclusion in the study is 10.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
physical activity	assessed by objective average daily step count using actigraphy	6 months
clinically important deterioration	Defined as the presence or absence of at least one of the following: increase > 4U in the total health-related quality of life (St. George's Respiratory Questionnaire, SGRQ), decreased FEV1 of > 100mL, or moderate-severe acute exacerbation of COPD	6 months
functional exercise capacity	6 minute walk distance, defined as the distance walked in meters in 6 minutes	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary artery to aorta diameter ratio	measured on low dose CT scan	6 months
Estimated PA systolic pressure in mm Hg	measured by echocardiography	6 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: VA Eastern Colorado Health Care System; Atlanta VA Medical Center; VA Boston Healthcare System; VA Nebraska Western Iowa Health Care System
• Investigators: Principal Investigator: Sharon I Rounds, MD, Providence VA Medical Center, Providence, RI

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: June 27, 2023
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 10, 2023

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: physical activity; lung; COPD; echocardiography; spirometry; dyspnea; chest CT; cigarette smoke; clinically important deterioration
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease Attributes; Signs and Symptoms, Respiratory; Chronic Disease; Hypertension; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Hypertension, Pulmonary; Dyspnea; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: PULM-002-22F; I01CX002543 (Other Grant/Funding Number: VA CSRD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Publications of results will be available to the public.; The principal investigator will share de-identified datasets, statistics, and results collected from this proposal by depositing these data at the National Library of Medicine (NLM) PubMed Central website repository as this is a VA supported data repository. Additional documentation including metadata that will include information about the methodology and study procedures used to collect the data, details about code, definition of variables will also be included.
• IPD Sharing Time Frame: Above will be shared upon approval of the study.
• IPD Sharing Access Criteria: Individual participant data will be shared within one year of publication of results.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes