TADA-PHILD: Tadalafil for Pulmonary Hypertension Due to Chronic Lung Disease

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01862536
• Collaborator: (none)
• Enrollment: 44
• Locations: 5
• Arms: 2
• Actual Duration (Months): 71
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The functional, social, and economic burden of chronic obstructive lung disease (COPD) on the healthcare system is extraordinary. COPD is the fourth leading cause of death in the United States, and some estimates attribute up to $33.2 billion in health care costs to COPD-associated morbidity and mortality annually. The burden of COPD to the VA Healthcare system parallels these findings. According to the VA HSR&D Health Economics Resource Center, COPD ranks 5th among the 40 most common chronic clinical conditions in the U.S. Veteran patient population, is responsible for >14,000 VA hospital admission annually, and increases by $1,051/patient the total annual health care cost burden on the VA Healthcare system. Importantly, COPD is associated with frequent emergency room visitation and/or hospitalization patients. Pulmonary hypertension is a common co-morbid condition that worsen morbidity and mortality in patients with COPD. This study will examine the potential for tadalafil, a phosphodiesterase type-5 (PDE-5) inhibitor to improve functional status by decreasing pulmonary hypertension. Results from this study are expected to define the potential use of PDE-5 inhibitors in COPD-induced pulmonary hypertension. If successful, this treatment option may improve quality of life and outcomes for the large number of Veterans afflicted with PH due to COPD.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension; Chronic Obstructive Pulmonary Disease (COPD)	Drug: Tadalafil; Drug: placebo	Phase 2

Detailed Description

Project Summary/Abstract This VA CSR&D Merit Review Award for a Clinical Trial proposal describes a 5-year program to support a prospective, placebo-controlled, randomized clinical trial (RCT) evaluating the effect of phosphodiesterase type-5 (PDE-5) inhibition with tadalafil at 40 mg daily over 12 months on exercise capacity in patients with at least moderate pulmonary hypertension (PH) PH (mean pulmonary artery pressure (mPAP) > 25 mm Hg, pulmonary vascular resistance (PVR)>3.0 Woods units, pulmonary capillary wedge pressure (PCWP) <18 mm Hg) due to chronic obstructive pulmonary disease (COPD) GOLD stage II or higher, FEV1FVC <70). PDE-5 inhibitors are recommended for World Health Organization (WHO) Category 1 PH but there is no evidence based recommendation supporting the use of these inhibitors in COPD-induced PH (WHO Category 3). In order to ensure maximum patient enrollment and to increase the clinical and demographic diversity of patients included in this study, the proposed research will be conducted at four VA sites: Boston VA Healthcare System, Providence VA Medical Center, the Greater Los Angeles VA Healthcare System , Atlanta VA and Denver VA. The research team includes senior investigators with extensive experience in the clinical management of patients with COPD and PH. The principal investigators (PI) for this study is Dr. Ronald H. Goldstein (Chief, Pulmonary Medicine at the Boston Healthcare System) and Dr Sharon Rounds (Chief, Medical Service, Providence VA). Dr Shelley Shapiro will serve as site PI at the Greater Los Angeles VA Healthcare System.

Within the Veteran population, COPD ranks among the most common chronic diseases and inflicts a substantial clinical and economic burden on the VA Healthcare System. Importantly, the vast majority of COPD-associated mortality and morbidity, including hospital admissions, is derived from a relatively select subpopulation of patients. There is emerging evidence to suggest that clinically evident PH is a key determinate of risk in COPD for exacerbations and progression of disease. The investigators found that moderate or severe PH is associated with significantly increased rates of COPD-related hospital readmission as compared to similar Veterans with COPD and only mild PH. Moreover, this trend was not influenced by differences in conventional measures of COPD disease severity (i.e., forced expiratory volume in 1 second [FEV1]) and was irrespective of supplemental oxygen status. These observations are in support of previously established clinical observations from others demonstrating that traditional COPD therapies, including supplemental oxygen, are ineffective at modulating sustained improvements to cardiopulmonary hemodynamics in patients with COPD and PH. It is established in specific forms of PH in which hypoxia is not the central mediator of disease progression that restoration of NO--dependent signaling in pulmonary vascular tissue is effective at attenuating pulmonary vascular remodeling to improve cardiopulmonary hemodynamics, exercise tolerance, and quality of life. The extent to which therapies that preserve NO--dependent signaling in pulmonary vascular tissue are effective in PH due to chronic lung disease, however, is not known.

Under physiological conditions, the enzyme phosphodiesterase type-5 (PDE-5) functions to maintain pulmonary vascular tone by degrading cGMP a key signaling intermediary involved in NO--dependent signaling. However, in PH due to lung disease, pulmonary vascular levels of NO- are diminished while PDE-5 levels are increased. This raises the possibility that PDE-5 inhibition is a potential strategy by which to increase NO- bioavailability and attenuate PH in patients with COPD, and sets the framework for the central hypothesis of the current proposal is that pharmacological inhibition of PDE-5 will improve functional capacity as assessed by 6 minute walk test in patients with COPD-induced moderate to severe PH. The secondary outcome measures will assess whether this change in functional status is accompanied by an improvement in maximal oxygen uptake during cardiopulmonary testing (VO2) and changes in vascular remodeling as assessed by cardiopulmonary hemodynamics. To test this hypothesis, a RCT will be conducted using tadalafil (40 mg orally daily) or placebo. The primary outcome measurements will be the six minute walk test. The secondary outcome measures will be functional assessment using peak volume of oxygen consumption (VO2) and the hemodynamic measures of PVR and mPAP. Additional information will be obtained related to the non-invasive assessment of pulmonary artery systolic pressure and right ventricular (RV) function including tricuspid annular plane systolic excursion, pulmonary artery acceleration time, and changes to the pulmonary outflow tract Doppler envelope, dyspnea, health related quality of life assessed by validated standardized questionnaires and the frequency of COPD exacerbations after 12 months. Results from this study are expected to define the potential use of PDE-5 inhibitors in COPD-induced PH. If successful, this treatment option may improve quality of life and outcomes for the large number of Veterans afflicted with PH due to COPD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Tadalafil for Pulmonary Hypertension Associated With Chronic Lung Disease
• Actual Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Aug 31, 2019
• Actual Study Completion Date: Aug 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo tablet	Drug: placebo; Daily use in double blind study.
Experimental: Tadalafil Daily use of tadalafil (study drug) at 40 mg orally.	Drug: Tadalafil; Daily use of study drug to treat pulmonary hypertension.; Other Names: Cialis

Outcome Measures

Primary Outcome Measures

1. Change in 6 Minute Walk Test [The change in distance walked when assessed at 3 months following trial initiation as compared to baseline, similarly at 6 months compared to baseline, at 9 months compared to baseline and at 12 months compared to baseline.]

   Change from baseline in distance walked in 6 minutes.

Secondary Outcome Measures

1. Maximum VO2 [12 months]

   Measure of aerobic fitness on exercise assessed by cardiopulmonary exercise test.

2. Pulmonary Vascular Resistance [6 months]

   Pulmonary vascular resistance assessed on right heart catheterization is a hemodynamic measurement of pulmonary vascular remodeling.

3. Mean Pulmonary Artery Pressure [6 months]

   Mean pulmonary artery pressure assessed by right heart catheterization is a hemodynamic measurement of pulmonary hypertension severity.

4. Tricuspid Annular Plane Excursion (TAPSE) [12 months]

   The tricuspid annular plane excursion is an echocardiographic measurement of right ventricular systolic dysfunction.

5. St. George's Respiratory Questionnaire, Dyspnea and Health Related Quality of Life [12 months]

   Disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. There are 50 items, 2 parts, (3 components). Each item is accorded a weight determined by the degree of distress accorded to each symptom or state described. Scores range from 0-100, with higher scores indicating more limitations

6. N-type Brain Natriuretic Peptide (BNP) Concentration [12 months]

   Plasma BNP concentration is a biochemical marker that correlates positively with pulmonary hypertension severity.

7. Resting Hypoxemia [Early (4 hours and 3 days following treatment) and late (1, 3, 6, 9, 12 months following treatment)]

   Changes to resting peripheral oxyhemoglobin saturation levels will be used to assess the safety of the study drug in patients with chronic lung diseases.

8. Exercise-induced Hypoxemia [12 months]

   Changes to peripheral oxyhemoglobin saturation levels on exercise will be used to assess the safety of the study drug in patients with chronic lung diseases.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female U.S. Veteran patients 40-85 years old, with Gold Stage II COPD by pulmonary function testing (FEV1/FVC <0.70; performed within 6 months of recruitment.

• Eligible subjects must have PH documented on transthoracic echocardiogram within 6 months of baseline visit demonstrating an RV systolic pressure >40mmHg. To confirm the presence of PH, a right-heart catheterization will be performed, with subjects randomized to treatment only if catheterization shows a:

• mPAP >25 mm Hg

• PVR >2.5 Wood units

• pulmonary artery capillary wedge pressure 18 mm Hg or less at rest

• PH belonging to the following subgroup of the updated Dana Point Clinical

Classification:

• Group 3 (PH associated with lung disease and/or hypoxemia) specifically, Group 3.1 (chronic obstructive pulmonary disease [COPD]) as the major criteria. Patients may also have minor clinical features associated with 3.2 (Interstitial disease) (such as mild fibrosis on high resolution chest CT, but total lung capacity>80% predicted) and 3.3 (sleep disordered breathing) (AHI <15 or 20/hour).

• 6-minute walk distance between 50-450 meters at screening visit.

Exclusion Criteria:

• PH belonging to the following subgroups of the updated Dana Point Clinical

Classification:

Group 1

• Idiopathic

• heritable

• drug or toxin-induced

• Associated Pulmonary Arterial Hypertension (APAH) with:

• connective tissue disease

• congenital heart disease

• or HIV

Group 2

• left atrial hypertension

Group 4

• chronic thromboembolic PH

• or other forms of PH not associated with primary lung disease

Also

• Patients with a history of systemic hypotension in the ambulatory setting (reproducible measurements of systolic blood pressure <89 mmHg) on chart review.

• Patients with moderate or severe hepatic impairment (Child-Pugh B and C)

• Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2)

• Severe aortic stenosis (aortic valve area <1.0 cm2)

• Patients with any acute or chronic impairment:

• (other than dyspnea), limiting the ability to comply with the study requirements, including the 6-minute walk test and right heart catheterization.

• Patients with a recent stroke

• Patients with untreated hypoxemia (SaO2 <92%) at rest

• Patients with untreated moderate or severe obstructive sleep apnea (AHI>15)

• Patients with any coagulopathy

• Patients requiring nitrate therapy for any clinical indication

• Patients with an active prescription for pulmonary vasodilator medication other than oxygen

• Patients with a history of nonarteritic anterior ischemic optic neuropathy

• Contraindication to tadalafil use including allergy to:

• any PDE-5 inhibitor

• anatomical deformations of the penis

• sickle cell anemia

• multiple myeloma

• leukemia

• bleeding disorders

• active peptic ulcer disease

• retinitis pigmentosa or other retinal disorders.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Greater Los Angeles Healthcare System, West Los Angeles, CA	West Los Angeles	California	United States	90073
2	VA Eastern Colorado Health Care System, Denver, CO	Denver	Colorado	United States	80220
3	Atlanta VA Medical and Rehab Center, Decatur, GA	Decatur	Georgia	United States	30033
4	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts	United States	02130
5	Providence VA Medical Center, Providence, RI	Providence	Rhode Island	United States	02908

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Ronald H Goldstein, MD, VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 25, 2019

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01862536
• Other Study ID Numbers: CLIN-008-12F
• First Posted: May 24, 2013
• Last Update Posted: Mar 9, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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.: No
• Keywords provided by VA Office of Research and Development: Randomized trial; COPD; tadalafil; Phosphodiesterase inhibitor; Pulmonary hypertension
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Hypertension, Pulmonary; Hypertension; Tadalafil

Study Results

Participant Flow

Pre-assignment Detail	The discrepancy between the enrollment number (44) and number in the participant flow module (36) was due to participant drop out. Of the 44 consented, 3 declined to participate, 3 did not complete the test dose trial, 1 had a medication conflict and 1 died prior to trial initiation.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo tablet placebo: Daily use in double blind study.	Daily use of tadalafil (study drug) at 40 mg orally. Tadalafil: Daily use of study drug to treat pulmonary hypertension.
Period Title: Overall Study
STARTED	13	23
COMPLETED	10	16
NOT COMPLETED	3	7

Baseline Characteristics

Arm/Group Title	Placebo	Tadalafil	Total
Arm/Group Description	Placebo tablet placebo: Daily use in double blind study.	Daily use of tadalafil (study drug) at 40 mg orally. Tadalafil: Daily use of study drug to treat pulmonary hypertension.	Total of all reporting groups
Overall Participants	13	23	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 46.2%	8 34.8%	14 38.9%
>=65 years	7 53.8%	15 65.2%	22 61.1%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	13 100%	23 100%	36 100%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	13 100%	23 100%	36 100%
6 Minute Walk Test (Meters walked in 6 minutes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Meters walked in 6 minutes]	243.50	249.35	246.425

Outcome Measures

1. Primary Outcome

Title	Change in 6 Minute Walk Test
Description	Change from baseline in distance walked in 6 minutes.
Time Frame	The change in distance walked when assessed at 3 months following trial initiation as compared to baseline, similarly at 6 months compared to baseline, at 9 months compared to baseline and at 12 months compared to baseline.

Outcome Measure Data

Analysis Population Description

.The Overall Number of Participants Analyzed differs with the number in the Participant Flow because of subject drop out over the study period

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo tablet placebo: Daily use in double blind study.	Daily use of tadalafil (study drug) at 40 mg orally. Tadalafil: Daily use of study drug to treat pulmonary hypertension.
Measure Participants	13	19
Change in 6 MWT from baseline to 3 months	7.00	16.60
Change in 6 MWT from baseline to 6 months	16.00	4.90
Change in 6 MWT from baseline to 9 months	-18.00	8.93
Change in 6 MWT from baseline to 12 months	21.00	16.76

2. Secondary Outcome

Title	Maximum VO2
Description	Measure of aerobic fitness on exercise assessed by cardiopulmonary exercise test.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed differs with the number in the Participant Flow because of subject drop out and patients who required supplemental oxygen did not have a cardiopulmonary exercise test performed.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo tablet placebo: Daily use in double blind study.	Daily use of tadalafil (study drug) at 40 mg orally. Tadalafil: Daily use of study drug to treat pulmonary hypertension.
Measure Participants	0	3
Median (Inter-Quartile Range) [mL/kg/min]	13.6

3. Secondary Outcome

Title	Pulmonary Vascular Resistance
Description	Pulmonary vascular resistance assessed on right heart catheterization is a hemodynamic measurement of pulmonary vascular remodeling.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed differs with the number in the Participant Flow because these participants refused to have a RHC procedure at the 12 month timepoint and therefore the PVR data was not available for analysis.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo Tablet	Daily use of tadalafil (study drug) at 40 mg. orally
Measure Participants	12	17
Median (Inter-Quartile Range) [mmHg]	4.26	2.69

4. Secondary Outcome

Title	Mean Pulmonary Artery Pressure
Description	Mean pulmonary artery pressure assessed by right heart catheterization is a hemodynamic measurement of pulmonary hypertension severity.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed differs with the number in the Participant Flow because these participants refused to have a RHC procedure at the 12 month timepoint and therefore the mPAP data was not available for analysis.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo tablet placebo: Daily use in double blind study.	Daily use of tadalafil (study drug) at 40 mg orally. Tadalafil: Daily use of study drug to treat pulmonary hypertension.
Measure Participants	12	17
Median (Inter-Quartile Range) [Wood units]	33.00	29.00

5. Secondary Outcome

Title	Tricuspid Annular Plane Excursion (TAPSE)
Description	The tricuspid annular plane excursion is an echocardiographic measurement of right ventricular systolic dysfunction.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed differs with the number in the Participant Flow because these participants did not complete an ECHO procedure and therefore TAPSE data was not available for analysis.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo Tablet	Daily use of tadalafil (study drug) at 40 mg. orally
Measure Participants	8	14
Median (Inter-Quartile Range) [mm]	2.08	2.12

6. Secondary Outcome

Title	St. George's Respiratory Questionnaire, Dyspnea and Health Related Quality of Life
Description	Disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. There are 50 items, 2 parts, (3 components). Each item is accorded a weight determined by the degree of distress accorded to each symptom or state described. Scores range from 0-100, with higher scores indicating more limitations
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo Tablet	Daily use of tadalafil (study drug) at 40 mg. orally
Measure Participants	10	16
Median (Inter-Quartile Range) [score on a scale]	49.34	44.64

7. Secondary Outcome

Title	N-type Brain Natriuretic Peptide (BNP) Concentration
Description	Plasma BNP concentration is a biochemical marker that correlates positively with pulmonary hypertension severity.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The Overall Number of Participants Analyzed differs with the number in the Participant Flow because these participants did not show up for the lab test and therefore the data was not available for analysis.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo Tablet	Daily use of tadalafil (study drug) at 40 mg. orally
Measure Participants	9	14
Median (Inter-Quartile Range) [pg/mL]	37.50	47.81

8. Secondary Outcome

Title	Resting Hypoxemia
Description	Changes to resting peripheral oxyhemoglobin saturation levels will be used to assess the safety of the study drug in patients with chronic lung diseases.
Time Frame	Early (4 hours and 3 days following treatment) and late (1, 3, 6, 9, 12 months following treatment)

Outcome Measure Data

Analysis Population Description

Measurements were not obtained

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo Tablet	Daily use of tadalafil (study drug) at 40 mg. orally
Measure Participants	0	0

9. Secondary Outcome

Title	Exercise-induced Hypoxemia
Description	Changes to peripheral oxyhemoglobin saturation levels on exercise will be used to assess the safety of the study drug in patients with chronic lung diseases.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Measurements were not obtained

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo Tablet	Daily use of tadalafil (study drug) at 40 mg. orally
Measure Participants	0	0

Adverse Events

Time Frame	1 year
Arm/Group Title	Placebo		Tadalafil
Arm/Group Description	Placebo tablet placebo: Daily use in double blind study.		Daily use of tadalafil (study drug) at 40 mg orally. Tadalafil: Daily use of study drug to treat pulmonary hypertension.
All Cause Mortality
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		5/23 (21.7%)
Serious Adverse Events
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/13 (30.8%)		4/23 (17.4%)
Blood and lymphatic system disorders
hemoptysis	0/13 (0%)	0	1/23 (4.3%)	1
Cardiac disorders
chest pain	1/13 (7.7%)	1	2/23 (8.7%)	2
Eye disorders
eye floaters	0/13 (0%)	0	1/23 (4.3%)	1
Gastrointestinal disorders
bowel obstruction	0/13 (0%)	0	1/23 (4.3%)	1
General disorders
heartburn, dizziness, inability to swallow	1/13 (7.7%)	1	4/23 (17.4%)	5
Respiratory, thoracic and mediastinal disorders
COPD exacerbation	4/13 (30.8%)	4	4/23 (17.4%)	4
Skin and subcutaneous tissue disorders
cellulitis	0/13 (0%)	0	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/23 (0%)

Limitations/Caveats

This trial did not reach its enrollment goals. Enrollment was limited because of the unexpected frailty of patients with advanced COPD and evidence of elevated pulmonary artery pressure as assessed by cardiac echo. In addition we found that many potential candidates were found to have features of both group II and group III PH.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.