Clinical trial NCT01862536
Conditions: Pulmonary Hypertension Chronic Obstructive Pulmonary Disease (COPD)
Keywords: Randomized trial COPD tadalafil Phosphodiesterase inhibitor Pulmonary hypertension
Sponsor: VA Office of Research and Development
Start date: 2013-10-01; Completion date: 2019-08-31
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: Placebo tablet arm 2: Daily use of tadalafil (study drug) at 40 mg orally.
Interventions: intervention 1: Tadalafil intervention 2: placebo
Intervention descriptions: intervention 1: Daily use of study drug to treat pulmonary hypertension. intervention 2: Daily use in double blind study.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Tadalafil for Pulmonary Hypertension Associated with Chronic 
Lung Disease 
PI: Ronald Goldstein, MD 
Boston VA 
Co-PI: Sharon Rounds, MD 
Providence VA 
Site-PIs: Shelley Shapiro, MD 
Los Angeles VA 
Ruxana Sadikot, MD 
Atlanta VA 
Edward Dempsey, MD 
Denver VA 
The Boston site and the PI (Ronald H. Goldstein, M.D.) will serve as the 
coordinating center for the clinical trial. The primary operation of the 
coordinating center will be to provide coordination and oversight for the study. 
The Boston site study coordinator(s) will be responsible for maintaining records, 
organizing the monthly telephone conference agendas and maintaining minutes 
for these calls. The coordinating center will also serve as the primary statistical 
and data management center for the trial. All sites will immediately report all 
SAE's to the VA CSRD Data Monitoring Committee as well as the Coordinating 
Center. 
Rationale: 
Chronic obstructive pulmonary disease (COPD) is a critical contributor to 
the clinical, social, and economic profile of the VA Healthcare system. In 
particular, COPD patients with right ventricular (RV) dysfunction due to 
untreated pulmonary hypertension (PH) constitute a patient subgroup at 
elevated risk for COPD-associated morbidity and mortality. Classical 
pharmacotherapeutic treatment strategies to attenuate clinically evident PH in 
COPD, including supplemental oxygen, are largely ineffective at maintaining 
normal cardiopulmonary hemodynamics and/or preventing right heart failure. A 
preponderance of basic science, translational, and clinical data accounts for this 
observation 
by 
demonstrating 
that 
i) 
hypoxia-mediated 
pulmonary 
vasoconstriction is not exclusively responsible for the clinical expression of PH in 
COPD and ii) hypoxia-mediated upregulation of signaling pathways that increase 
inflammation and/or oxidant stress results in maladaptive histopathophenotypic 
changes to pulmonary arterioles. In addition, specific oxidant stress and/or 
inflammation mediated perturbations to NO- dependent signaling pathways in 
the pulmonary artery endothelial and smooth muscle cells exposed to chronic 
hypoxia promote pulmonary vascular remodeling. In turn, interventions that aim 
to restore bioavailable levels of NO- in the pulmonary vasculature, including 
PDE-5 inhibitors, are associated with improvements in cardiopulmonary 
hemodynamics and functional capacity in various forms of PH. To date, however, 
the role of PDE-5 inhibition in improving pulmonary vascular function and 
exercise tolerance in patients with COPD and clinically evident PH is unresolved 
March 25, 2019 
Page 1 


and PDE-5 inhibitors are not currently considered a standard treatment for PH 
associated with COPD. 
Hypothesis: 
Pharmacological inhibition of PDE-5 will improve functional capacity in 
patients with COPD-induced moderate to severe PH. 
Specific Aims: 
This proposal describes a prospective, double-blind, placebo-controlled 
randomized clinical trial in 64 subjects to address this hypothesis. 
Primary Aim: To study the effect of PDE-5 inhibition with Tadalafil on exercise 
capacity over 12 months as measured by 6MWT in patients with COPD and 
moderate or severe PH. 
Secondary Aims: To determine the effect of Tadalafil on maximal VO2 at 12 
months, and pulmonary vascular resistance (PVR) and mean pulmonary artery 
pressure (mPAP) will be assessed at 6 months. 
We will also assess the effect of Tadalafil therapy on dyspnea, health 
related quality of life (HRQL), COPD exacerbations and hospital admissions over 
the 12 month study period. 
Relevance to VA: 
The functional, social, and economic burden of chronic obstructive lung 
disease (COPD) on the healthcare system is extraordinary. According to the VA 
HSR&D Health Economics Resource Center, COPD ranks Stn  among the 40 most 
common chronic clinical conditions in the U.S. Veteran patient population and is 
responsible for >14,000 VA hospital admission annually. Importantly, COPD is 
associated 
with 
frequent 
emergency 
room 
visitation and/or 
patient 
hospitalizations. Pulmonary hypertension (PH) is a common comorbid condition 
that worsens 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 PH. 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: 
We propose a prospective randomized, double blind, placebo-controlled 
clinical trial to test our hypothesis that PDE-5 inhibition is an effective treatment 
strategy in patients with COPD and moderate to severe PH. 
Inclusion criteria 
1. Male and female U.S. Veteran patients 40-85 years old, with Gold Stage >_ II 
COPD by pulmonary function testing (FEV,/FVC <0.70) performed within 12 
months of recruitment. 
March 25, 2019 
~_-__----~ 
-___ Page 2 


2. Eligible subjects must have PH defined for this study as a mean pulmonary 
artery pressure >25 mm Hg, pulmonary vascular resistance >2.5 Wood units, and 
pulmonary artery capillary wedge pressure :518 mm Hg at rest on right heart 
catheterization performed within 6 months of study enrollment. 
Exclusion Criteria 
I. 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 3 PH 
not due to COPD, Group 4 (chronic thromboembolic PH) or other forms of PH 
not associated with primary lung disease. 
2. Patients with a history of systemic hypotension in the ambulatory setting 
(reproducible measurements of systolic blood pressure <89 mmHg) on chart 
review. 
3.Patients with moderate or severe hepatic impairment (Child-Pugh B and Q. 
4.Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2). 
5.Severe aortic stenosis (aortic valve area <1.0 cm2). 
6. Patients with any acute or chronic impairment (other than dyspnea), limiting 
the ability to comply with the study requirements. 
7.Patients with current unstable angina, recent myocardial infarction or recent 
stroke (within 6 months). 
8. Patients with untreated hypoxemia (SaO2 <92%) at rest. 
9.Patients with any known coagulopathy. 
10.Patients requiring nitrate therapy for any clinical indication. 
11.Patients with an active prescription for any PDE-5 inhibitor or any other 
pulmonary vasodilator medication other than oxygen. 
12. Patients with a history of nonarteritic anterior ischemic optic neuropathy. 
13.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. 
14.The use or anticipated use of any of the following drugs: any nitrate, protease 
inhibitor, anti-fungal agent (oral only), and/or rifampin, or doxazosin. 
15.Pregnant or breastfeeding women. 
16. Patients with a known 6-minute walk distance of less than 50 meters on prior 
testing. 
17.Patients with veno-occlusive disease. 
Source of Participants and Participant Recruitment: 
Patient recruitment will occur by 2 mechanisms at the Boston site. . 
1. Database Search: A population of potential study patients will be generated by 
looking at the echocardiography patient database (Xcelera). This database 
provides sufficient information to enable ready identification of patients meeting 
pulmonary artery systolic pressure for study enrollment. 
Subsequently, a chart review will be performed on potential patients to 
evaluate for inclusion and exclusion criteria including review of available clinical 
March 25, 2019 
_ 
Page 3 


studies in CPRS to categorize the patient's pulmonary hypertension (such as 
laboratory data--liver function tests, HIV, renal function; heart catherization; 
pulmonary function tests; CT scan of the thorax; sleep study; echocardiography 
and V/Q scan or chest CT angiography). 
Potential subjects (name, last 4 digits of SSN) will be temporarily recorded 
in a password protected "screening spreadsheet" kept in a restricted access folder 
on a VA secure server which only the PI and research staff have access to. After 
subjects are identified by screening of our database and chart review, subjects 
will be recruited by mailings that provide i) information regarding the study, ii) 
the reason for which patients were contacted, and iii) simple methods by which to 
declare or decline interest in study participation. Interested subjects will be asked 
to contact our study staff by telephone and/or the mailing will include a postcard 
for patients to return indicating an interest or indicating a wish not to be further 
contacted. If patients return the postcard indicating a wish not to be contacted 
further, no further contact will take place. Patients who do not respond to the 
mailing by telephone or returning the postcard will be contacted by telephone 
approximately 2 weeks after the mailing to be invited to participate. Information 
of patients who decline participation by mail or after telephone contact will be 
deleted from the "Screening Spreadsheet". 
Patients who are interested in 
participating will be scheduled for a screening visit. 
2. In-clinic Referral. Study patients may also be identified during routine clinical 
practice that involves PH and COPD patients in the Cardiology, PH and 
Pulmonary medicine longitudinal clinics. 
Providers in the Pulmonary, 
Cardiology, and PH clinics will be educated about the study and the 
inclusion/exclusion criteria. Providers will inform patients about the study, and 
provide them with contact information for the study coordinator/investigators. 
Patients who contact the study coordinator/investigators and express interest in 
the study will have a chart review conducted as above, and will be scheduled for a 
screening visit if potentially eligible. 
Studv visits (Total of 8 Studv Visits and 8 Teleuhone Calls 
1. Screening visit. 
At the screening visit, the study will be explained to the patient. Inclusion 
and exclusion criteria will be reviewed. If patients meet eligibility criteria and do 
not have any exclusion criteria, and are willing to participate in the study, written 
informed consent will be obtained. 
The informed consent process will be undertaken by study investigators 
who have been trained in human subject protection and are credentialed by the 
VA to conduct the informed consent process. The investigator will explain the 
study to the potential participants and answer any questions that they may have 
regarding the study protocol. The investigator will make it clear that the protocol 
is research as well as voluntary and that declining participation will in no way 
affect further evaluation or access to clinical care. Participants will also be 
informed that they may withdraw their consent at any point throughout the study. 
March 25, 2019 
Page 4 


Patients will be given adequate time to read the consent form and discuss its 
contents with research personnel before signing the consent form. Participants 
will then be asked to sign an IRB-approved written consent document and health 
insurance portability and accountability act (HIPAA) agreement, which will allow 
data pertinent to the study to be collected. 
Following the completion of informed consent, the test dose visit will be 
scheduled. 
2. Test dose visit: 
At this visit, the subjects will undergo a history and physical exam. Blood. 
will be drawn at the clinical phlebotomy lab for BNP measurement. They will be 
asked to fill out the Shortness of Breath, St. George's Respiratory and Veterans 
Rand 36 Item Health Survey (VR-36) questionnaires. A six minute walk test will 
be performed. 
., 
Next, we will randomize the patients: 
Randomization: The randomization process will occur by computer generated 
number assignment. The study investigator, after entering an order for study 
drug in the CPRS system, will bring the assigned number as well as a, copy of the 
informed consent to the pharmacy. The Boston research pharmacist will then 
match the number to the appropriate test dose medication (study drug or 
placebo) based on the randomization, identical aside from number labeling. The 
Boston research pharmacist will distribute placebo/Tadalafil to all study sites, 
(Boston, Providence, Los Angeles, Denver and Atlanta). 
Any enrolled women of childbearing potential will have to have had a 
documented negative pregnancy test and must be using adequate contraception 
prior to receiving test dose. 
Test dose protocol: Following at least 10 minutes of quiet rest after the 6 
minute walk test, blood pressure will be measured by sphygmomanometer and 
oxygen level will be assessed by a fingertip probe. Subjects will then receive a test 
dose of the study medication (Tadalafil 201ng or placebo by mouth) if the 
baseline systolic blood pressure is greater than 9ommHg AND the 
oxyhemoglobin saturation is greater than 92% on room air or on the patient's 
typical flow rate of supplemental oxygen at rest. The subject will be observed and 
the blood pressure and oxygen level will be re-measured and recorded at baseline, 
30 minutes post baseline, 1 hour post baseline and then 2 hours post baseline 
after the test dose to ensure that the blood pressure and oxygen levels are not 
adversely affected by the medication. If at any time point in the 2 hours following 
the test dose a subject develops hypotension (systolic blood pressure < 9ommHg, 
or a drop in systolic blood pressure of greater than 2ommHg accompanied by 
symptoms such as dizziness, lightheadedness, or syncope), or if the patient 
experiences significant hypoxemia (a decrease in oxyhemoglobin saturation to 
less than 9o% on room air or, for subjects on supplemental oxygen, a decrease in 
March 25, 2019 
Page 5 


oxyhemoglobin saturation that requires an increase in supplemental oxygen to 
greater than 41pm at rest to maintain a oxyhemoglobin saturation of 90%), that 
subject will not participate further in the study. 
Subjects experiencing 
hypotension or worsened hypoxemia as above will receive appropriate 
monitoring and clinical care, potentially including hospital admission, 
supplemental oxygen, IV fluids, etc., until their blood pressure and oxygenation 
improve. 
Subjects who tolerate the test dose will be scheduled for a baseline study visit. 
In the situation whereby another clinical service intends to start prazosin in a 
patient already on the study, we propose the administration of the first dose of 
prazosin in the pulmonary clinic with clinical monitoring and will follow the test 
dose protocol described above. If hypotension developed as per the protocol the 
subject will not participate further in the research study. 
3. Baseline Visit: 
At the baseline visit, a brief interview will be conducted to assess for any 
recent changes in health status. Echocardiogram and cardiopulmonary exercise 
testing will be performed. (Patients requiring supplemental oxygen will not have 
a cardiopulmonary exercise test.) The study medication will be prescribed after 
these tests at this visit. The research pharmacist will provide the patient with a 
numbered box containing either placebo or study drug. The patient will be 
provided with a supply of 20 mg Tadalafil tablets or identical placebo tablets. 
Women of childbearing potential will have to have a documented negative 
pregnancy test and must be using adequate contraception during the study 
treatment phase and for 9 months afterward. Monthly pregnancy tests will be 
done, and compliance with contraception use will be documented at the 
telephone and clinic follow up visits. Should a female become pregnant at any 
time during the study, the study medication will be discontinued at that time. 
The patients will be instructed to take 1 tablet daily for three days 
beginning the following morning (day 1). After telephone contact with a study 
team member on day 3, assuming no adverse effects are noted, the patient will be 
instructed to take two tablets per day. Patients who describe new symptoms, 
particularly dizziness, lightheadedness, or increased dyspnea, will be evaluated in 
clinic and blood pressure and peripheral oxygen saturation levels will be assessed 
before advancing therapy. 
Study Drug: Tadalafil is an oral PDE-5 inhibitor that was approved by the Food 
and Drug Administration (FDA) in 2009 for use in treating pulmonary arterial 
hypertension (WHO Group I). It is administered as a standard dose of 40 mg (2, 
20 mg pills). In WHO group I patients, it has been shown to be effective in 
improving distance achieved on the 6MWT and time to clinical worsening, as well 
as mean pulmonary pressure and PVR. The half-life of Tadalafil is 15-35  hours, 
which enables the proposed dosing strategy. Compliance will be assessed by 
March 25, 2019 
Page 6 


monitoring return pills and pill counts with the assistance of the research 
pharmacist. 
Days Telephone Follow-up 
Following initiation of therapy, study staff will make telephone contact 
with each participant at post-randomization day 3 to identify any early problems 
with treatment adherence and to ascertain any early adverse events. The 
participant will be asked a series of questions to ensure that the patient remains 
active and performing normal activities of daily living. If no adverse events or 
symptoms are reported, the patient will be instructed to increase the dose of 
study drug or placebo to 2 tablets (40mg) by mouth per day the following 
morning. 
Subsequent monthly follow up phone calls will occur between clinic visits 
Follow up visits. 
Patients will undergo routine follow up visits as outlined in Table 1 to 
assess compliance with medication use, changes in symptoms, development of 
adverse reactions and further data collection. At all study visits, history and 
physical exam, medication compliance, exacerbation history and 6 minute walk 
tests will be performed. The patient will also complete the Shortness of Breath, 
St. George's Respiratory and Veterans Rand 36 Item Health Survey (VR-36) 
questionnaires. In addition, adverse event monitoring, interim ED visits and 
hospitalizations will be assessed and recorded. Any exacerbations of COPD, 
defined as an acute worsening of respiratory symptoms, including dyspnea, 
cough, sputum production, requiring either ED visit, hospitalization, and/or 
therapy with antibiotics or corticosteroids, will be recorded. If in follow up, 
patients develop gastroesophageal reflux symptoms, a known side effect of 
Tadalafil, then proton pump inhibitor therapy (omeprazole 20 mg per day) will 
be offered. 
Summary of follow up visits is as follows: 
4. One month visit: history and physical examination, Shortness of Breath, St. 
George's Respiratory and Veterans Rand 36 Item Health Survey (VR-36) 
questionnaires, 6MWT. 
5) Three month visit: history and physical examination, Shortness of Breath, St. 
George's Respiratory and Veterans Rand 36 Item Health Survey (VR-36) 
questionnaires, 6MWT. 
6) Six month visit: history and physical examination, Shortness of Breath, St. 
George's Respiratory and Veterans Rand 36 Item Health Survey (VR-36) 
questionnaires, 6MWT, blood sample for BNP drawn in clinic lab, and right heart 
catheterization will be performed. 
March 25, 2019 
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7) Nine month visit: history and physical examination, Shortness of Breath, St. 
George's Respiratory and Veterans Rand 36 Item Health Survey (VR-36) 
questionnaires, 6MWT. 
8) Twelve month visit: history and physical examination, Shortness of Breath, St. 
George's Respiratory and Veterans Rand 36 Item Health Survey (VR-36) 
questionnaires, 
6MWT, 
blood 
sample 
for 
BNP, 
echocardiogram, 
cardiopulmonary exercise study. 
Randomization/ 
Baseline 
Telephone 
Month 
Month 
Month 
Month 
Month 
Test Dose Visit 
Visit 
calls* 
1 
3 
6 
9 
12 
Contact 
Clinic 
Clinic 
Tel 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Medical History/Physical 
X 
X 
X 
X 
X 
X 
Assess medication 
X 
X 
X 
X 
X 
X 
compliance 
6-Minute Walk Test 
X 
X 
X 
X 
X 
X 
Echocardiogram 
X 
X 
CPET** 
X 
X 
Shortness of Breath , 
X 
X 
X 
X 
X 
X 
St. George's 
Respiratory and 
Veterans Rand 36 Item 
Health Survey (VR-36) 
questionnaires 
BNP 
X 
X 
X 
RHC 
X 
Exacerbation History 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring 
Table 1. Follow-up Clinic Visits, telephone calls and schedule of studies Tel, telephone contact; 
CPET, cardiopulmonary exercise stress test; BNP, N-terminal brain natriuretic peptide; RHC, right heart 
catheterization 
*Day 3, Month 2, 4, 5, 7, 8, 10, 11 
—Patients requiring supplemental oxygen will not have a CPET 
Subjects will receive $50 for each clinic visit for their time and effort. 
Study procedures that occur at each study visit are described below. 
Specific Study Procedures: 
Questionnaires: The Shortness of Breath Questionnaire will be the dyspnea 
questionnaire used and the St. George's Respiratory Questionnaire will be used to 
assess quality of life. The Veterans Rand 36 Item Health Survey questions your 
views about your health. 
March 25, 2019 
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Echocardiogram: Transthoracic echocardiography is a routine medical 
procedure using ultrasound waves to assess heart structure and function. 
Echocardiography will be performed in the semi recumbent position. 
Measurements to be collected include: left ventricular ejection fraction; left 
ventricular wall thickness; relative wall thickness (as calculated by 2 x posterior 
wall thickness in diastole/left ventricular diastolic diameter); left ventricular 
outflow tract minimum diameter, left ventricular outflow tract Doppler flow, 
ratio of peak mitral Doppler inflow velocities (E/A ratio); diastolic myocardial 
relaxation velocity of the lateral mitral annulus (E'); and the ratio of mitral inflow 
velocity to annular relaxation velocity (E/E'), right ventricular dimensions 
including maximal minor axis (Si), ejection time, myocardial performance index, 
and function, tricuspid annular motion, and velocity of the tricuspid regurgitant 
jet, tricuspid inflow velocity, right ventricular outflow velocity. 
Cardiopulmonary exercise test: Cardiopulmonary exercise testing is a test 
of a subject's maximal exercise capacity. This test will be performed on a bicycle 
in the presence of a physician. The subject will wear nose clips, and will breathe 
through a mouthpiece connected to a metabolic machine, which will measure 
factors including oxygen consumption, CO2 production, volume of air per breath, 
and respiratory rate. 
The patient will also be monitored by EKG leads 
demonstrating the heart rate and rhythm. The patient will then exercise at 
increasing levels of resistance (increasing intensity of exercise) according to a 
protocol until the protocol is completed or the patient can no longer exercise. 
The maximal value for oxygen consumption (VO2 max) will be recorded, along 
with other exercise parameters such as maximal heart rate achieved, the 
respiratory quotient (ratio of 02 consumption to CO2 production), and the dead 
space to tidal volume ratio. Patients requiring supplemental oxygen will not have 
a cardiopulmonary exercise test. 
Phlebotomy: Phlebotomy is a commonly performed medical procedure in 
which blood samples are drawn from a vein, typically in the forearm, after 
venipuncture, and which will be performed by a trained laboratory phlebotomist. 
Phlebotomy will be performed at the initial study visit and the twelve month 
follow- up study visit. 
Right heart catheterization: Right heart catheterization will be performed 
according to standard guidelines. The patient is continuously monitored by a 
registered nurse during the procedure. Technicians are also present to assist in 
recording of hemodynamics. After sterile preparation and draping, ultrasound 
guidance is used to identify a vein in the neck, subclavian region, or groin. Local 
anesthesia is provided to minimize discomfort prior to accessing the appropriate 
vein. Then, a sheath is placed in the vein. A hemodynamic balloon-tipped flow-
guided catheter is then passed through the sheath and into the central veins, right 
heart chambers, and then into the pulmonary artery. The catheter is advanced 
until wedged in a small pulmonary artery. Fluoroscopy is used as needed during 
the procedure for additional guidance. Continuous hemodynamic recordings are 
March 25, 2019 
Page 9 


made throughout the procedure, including measurements of blood pressure and 
cardiac output. A sample of 5m1 of blood will be drawn via the catheter from the 
pulmonary artery. After completion of recording, the catheter is removed. The 
sheath is then removed from the vein and pressure applied until hemostasis is 
ensured. Total radiation dose is monitored and documented. A post-procedure 
chest x-ray is performed to assess for any complications. A bandage is applied to 
the vein access site. The patient is monitored in the post-procedure unit by 
nursing staff. When standard parameters are met, the patient is discharged. 
Arterial blood gas: An arterial blood gas will be drawn at the time of the right 
heart catheterization. This test involves puncturing an artery in the arm or leg 
with a needle and collecting a sample of 2m1 blood. 
Six minute walk test: 
Six-minute walk testing will be performed on a 
measured circuit according to standards published by the American Thoracic 
Society. 
Patient safety: 
Human Subjects Research 
This Human Subjects Research meets the definition of "Clinical Research". 
This study is a clinical trial, and will be registered on Clinicaltrials.gov. 
Protection of human subjects 
Potential risks 
Questionnaires and record keeping
 There is no specific physical risk to 
completing the dyspnea and quality of life questionnaires. All records will be 
kept confidential, kept in locked cabinets, and identified by study code only in the 
working databases. 
Phlebotomy  Phlebotomy for blood drawing is associated with temporary pain at 
the site and may result in bruising at the needle insertion site. Risks of the 
procedure include: vasovagal reaction during needle puncture; bruising at the 
phlebotomy site; and the possibility of skin or soft tissue infection at the needle 
puncture site. 
Echocardiogram
 Standard 
approaches 
to 
performing 
transthoracic 
echocardiography will be utilized, which may induce transient discomfort as the 
ultrasound probe is pressed against the upper chest. 
Cardiopulmonary exercise testing.  The testing may cause shortness of breath, 
fatigue, muscle discomfort, and very rarely (<1:1,000) may be associated with 
heart attack or death. 
March 25, 2019 
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Right heart catheterization  This is an invasive procedure. Discomfort may result 
from the needle stick to provide local anesthesia (i.e., most often 1% lidocaine) for 
placement of the catheter. The discomfort is generally mild and resolves 
spontaneously within 30 seconds. More serious complications of this procedure 
such as, but not limited to, air in the pleural space (pneumothorax), major 
infection, major bleeding, clotting around the catheter, air embolism, arrhythmia, 
myocardial infarction (heart attack), stroke, and/or death occur in <i% of all 
right heart catheterization procedures. 
Arterial blood gas  This involves a needle puncture of an artery. Discomfort may 
occur from the needle stick. This is usually mild and resolves within 5 minutes. 
Complications include hematoma formation, infection and bleeding. Rarely, 
permanent damage or clot in the artery occurs, which can result in tissue damage 
to the hand or leg. 
Theraueutic risks 
Treatment with Tadalafil 
Although Tadalafil has been taken by many people, it has not been tested 
as a treatment for pulmonary hypertension caused by chronic lung disease. Side 
effects that have been most commonly reported by people who have taken 
Tadalafil include headache, upset stomach, back pain (sometimes severe), muscle 
ache, stuffy nose, and flushing. When treatment was needed, most headaches 
and back and muscle pains were relieved by medicines like Tylenol or ibuprofen. 
Less common side effects reported include dizziness, vomiting, swollen eyelids, 
eye pain, blurred vision, and irritated eyes. Side effects that have been very rarely 
reported include rash, hives, face swelling, serious skin reactions (which may be 
life threatening), heart attack (including fatal ones), stroke, chest pain, skipped 
heart beats, fast heart rate, high blood pressure, fainting, abdominal pain, 
heartburn, sweating, and partial loss of vision. 
Risks in Men: 
Priapism (prolonged erection) has been reported with medications for 
erectile dysfunction, including Tadalafil. If priapism is not treated immediately, 
lasting damage can happen to the penis, including the inability to have erections. 
Other PDES inhibitors should not be taken while participating in this study. 
Serious health problems could result. In animal studies, dogs were given 
Tadalafil at doses that exposed them to about the same level of Tadalafil that 
subjects may be exposed to if taking the highest dose in this study (40 mg). After 
6- and 12-months of taking Tadalafil every day, the dogs had some damage to 
their testicle tissues which made them produce less or no sperm. It is not known 
if the damage to the dogs' testicles would get better after dosing was stopped. 
The damage may be permanent. The effect of reduced sperm count may include, 
but is not be limited to, an inability of a spouse or partner to become pregnant. 
Similar findings have not been seen in human studies designed to assess this risk, 
but those studies have not been conducted with doses of Tadalafil as high as 
those given in the present study. 
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Risks in Women: 
Studies in animals showed that Tadalafil did not affect the reproductive 
cycles of females or their ability to become pregnant. However, there may be 
unknown risks for pregnant women taking Tadalafil; for their developing embryo, 
fetus, or unborn child; or for infants breast-fed by women taking Tadalafil. 
Tadalafil has not been tested in pregnant women. 
Risk of low blood oxygen: 
Individuals with chronic lung disease may have low blood oxygen or 
require oxygen treatment. There are small numbers of reports of patients with 
chronic lung disease whose blood oxygen decreased when they were given a 
medication similar to Tadalafil. Subjects will be tested for this effect by giving a 
test dose. Oxygen prescriptions will be adjusted, if needed. 
Adequacy of protection from risk 
Protection against risk 
Study personnel will be fully trained and credentialed in human subject 
protection. Study ID numbers will not include PHI. All research data which will 
be kept in locked cabinets or password protected files on VA servers. 
Risks from cardiopulmonary exercise testing will be minimized by 
supervision of testing by an attending physician which is to be performed by 
trained technicians at Boston VA with emergency equipment readily available. 
Patients will be encouraged to exercise to their symptomatic limits, if there are 
any signs of medical instability; the physician will end the test before the 
symptomatic endpoint is achieved. 
The risks from right heart catheterization will be minimized by 
performance by trained physicians in a fully equipped angiography suite with 
readily available emergency equipment and personnel. 
Phlebotomy will be performed by trained phlebotomists. 
Potential benefits of research to human subjects and others 
There may be no direct clinical benefits to the subjects. The medication 
may increase walking capacity, decrease cardiopulmonary hemodynamic 
measurements of PH, and/or improve quality of life. If the medication is not 
successful at modulating these anticipated beneficial responses, then our results 
will provide evidence to establish that PDE-5 inhibition is not a valid therapy in 
the large number of patients with COPD and PH. 
Importance of knowledge gained 
The societal benefits to the study include the generation of pivotal data 
regarding the treatment of COPD-induced PH. If PDE-5 inhibitor therapy is 
effective in this patient population, the study provides for the first time complete 
March 25, 2019 
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evidence to demonstrate this as a novel treatment for COPD-induced PH. If the 
therapy is ineffective in this patient population, then our results will provide 
evidence against the systematic and/or empiric use of these medications for this 
disorder. Depending on our findings, the downstream consequences of the 
proposed work are to reduce VA healthcare costs by decreasing hospital 
admissions rates in COPD patients or attenuate the use of PDE-5 inhibitors in 
clinical practice for this patient population. 
Data and safety monitoring 
As described above, frequent contact will be maintained with participants 
throughout their participation in this study, with telephone contact at 3 days and 
monthly as well as clinic visits at 1, 3, 6, 9 and 12 months after randomization to 
ascertain dyspnea, hospitalizations, illnesses or other adverse events as outlined 
in Table 1. The PI and staff will meet on a weekly basis to review study progress 
and adverse events. The PI will, on a weekly basis, review all data collected to 
assure that no physiological (e.g., blood pressure) findings warrant immediate 
intervention. If so, the participant will be contacted and advised of the findings 
and offered assistance with appropriate referrals. Data from the echocardiogram 
and cardiopulmonary exercise testing procedures will be reviewed by the 
investigators and any unusual or adverse findings will be communicated to the 
participant's primary care physician. Adverse events (classified by severity and 
unexpected/expected) will be defined and reported to the IRB in accordance with 
the rules regulating each severity class (expected vs. unexpected, serious vs. other, 
related vs. unrelated). A DMSB has been established—see below. 
Follow up  visits. Patients will undergo routine follow up visits as outlined in 
Table 1 to assess compliance with medication use, changes in symptoms, 
development of adverse reactions and further data collection. 
Monitoring for Adverse Events (AEs) 
At the baseline clinic visit and each follow-up contact, subjects are to 
notify study staff if they experience any change in their medical condition or 
medications, or have urgent care visits, emergency room visits, or 
hospitalizations. Study staff will also monitor for interim emergency room visits 
or hospitalizations through patient notification system in CPRS to ensure timely 
reporting. 
The investigator will contact participants if any reported adverse 
event suggests clinical deterioration warranting immediate medical attention. 
During the study, if a subject experiences medical problems or hospitalization, 
the study medication will be continued unless complicated by hypotension or new 
or worsened hypoxemia. If discontinued, it would be resumed once baseline 
clinical status is confirmed, assuming the event was not felt to be related to the 
study medication itself. 
Any AE that are immediately life-threatening, cause permanent or lasting 
harm, or require a hospitalization will receive a "serious" classification. All 
serious AEs and unanticipated problems will be reported to the IRB and DSMB 
as soon as possible, but no later than 5 days from notification. If an event is 
March 25, 2019 
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possibly, probably or definitely related to the intervention, it will be classified as 
intervention-related. 
In the event of an emergency medical situation, the patient's treatment 
assignment can be unblinded. In such a situation, the treating physician can 
contact the pharmacy, who will have emergency access to the unblinding 
information. 
We have convened an independent, external Data and Safety Monitoring 
Board (DSMB) to review recruitment, follow-up rates, and protocol adherence 
and safety results. 
They will monitor the rates of AEs and SAEs and 
unanticipated problems. The DSMB is composed of experienced experts in 
clinical studies of pulmonary hypertension and includes Dr. Raed Dweik, a 
Professor of Medicine at the Cleveland Clinic and Director of the Pulmonary 
Vascular Program, Dr. Nicholas Hill, Chief of Pulmonary and Professor of 
Medicine at Tufts Medical Center and an expert in PH and Dr. Steven Kawut, 
Associate Professor of Medicine at University of Pennsylvania and Director of the 
Pulmonary Vascular Disease Program. They will meet every 6 months, and as 
needed, by telephone conference. 
Data Collected: 
Data collection will include demographics, interview and questionnaire 
data, history and physical exam data, medications, hospitalization and emergency 
department records, acute outpatient care records during study period, 
laboratory data (baseline labs from chart including arterial and venous blood gas 
values, blood chemistries--chem 7/basic metabolic panel, complete blood count, 
BUN, creatinine, rheumatological serologies, HIV testing, liver function tests, 
thyroid studies, coagulation studies, c-reactive protein, troponin, as well as BNP 
levels), pulmonary function data, radiological studies including chest x-rays, 
chest CT scans, ventilation-perfusion lung scans, echocardiography data, heart 
catheterization data, cardiopulmonary exercise testing and 6 minute walk data. 
Data Analysis Plan 
The data will be entered into an Access (Microsoft Corp) database, and 
SAS 9.2, (SAS Institute; Cary, NC) used for analysis. We will compare baseline 
characteristics between groups (e.g., age, %-predicted FEV1, including 
pulmonary hemodynamics, exercise capacity, dyspnea score, and quality of life). 
We will conduct analyses using available data based on an intention to treat 
strategy, and we will also assess subjects completing the 12 month trial. 
Aim 1: The primary outcome will be the difference in distance performed 
on a 6MWT between baseline and 12 months [06MWT], which will be assessed 
using a two-sample t-test for independent samples. We will also assess 
longitudinal change in the 6 repeated measures of 6MWT using mixed linear 
models that take into consideration the correlated nature of repeated 
measurements (PROC MIXED in SAS), and the effects will be adjusted for age 
and %-predicted FEV1 using the same model. 
Secondary Aims: The change in maximal VO2 during exercise between 
baseline and at 12 months [OVO2] will also be assessed using a t-test for 
March 25, 2019 
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independent samples. For multivariate analyses, we will use general linear 
models (PROC GLM in SAS) to assess if this difference is influenced by 
adjustment for age and %-predicted FEV1. 
We will calculate the mean difference in PVR and mPAP at 6 months 
compared to baseline value in each group [OPVR and OmPAP]. For crude analysis, 
we will use a t-test for independent samples; we will then compare OPVR and 
OmPAP in the two groups. For multivariate analyses, we will use general linear 
models (PROC GLM in SAS) to assess if this difference is influenced by 
adjustment for age and %-predicted FEV1. 
Additional outcome measures: Differences in cardiac echo derived indices 
of RV function will be compared similarly as noted for OPVR and OmPAP. There 
will also be 6 measures of dyspnea score and quality of life. Assessment of the 
differences in these measures between groups based on these longitudinal 
assessments will be performed as was done with 06MWT above. 
Predictors of acute exacerbations and hospitalizations will be assessed 
using a generalized linear model (assuming a negative binomial distribution) 
with the logarithm of observation time as an offset variable (PROC GENMOD in 
SAS). In addition to assessing each group as a predictor of exacerbations and 
hospitalizations, we will adjust for %-predicted FEV1, age, and a history of 
previous exacerbations in the past year. 
Data storage and sharing: Data will be acquired by the PI and recorded on a 
Microsoft ExcelTM spreadsheet. All data will be collected using a study code that 
does not identify the patient. The cross-link matching the patient with the code 
will be saved in a password-protected file, separate from the rest of the data files 
and stored on the secure VA server that only the PI and research staff have access 
to. Consent forms are being stored in a locked cabinet in Dr. Ronald Goldstein's 
office. Paper data such as data abstraction sheets (without patient identifiers) will 
be kept in a locked cabinet in the locked office of the investigator. No VA 
sensitive data will be transmitted outside the VA. Only VA non-sensitive data will 
be transmitted electronically via internet for discussion during study meetings 
and collaboration with off-site co-investigator/ collaborators. 
Study data will also be collected and managed using REDCap electronic 
data capture tools hosted at the Department of Veterans Affairs.1 REDCap 
(Research Electronic Data Capture) is a secure, Web application designed to 
support data capture for research studies, providing: 1) an intuitive interface for 
validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to 
common statistical packages; and 4) procedures for importing data from external 
sources 
(URL http://vaww.viree.research.va.gov/REDCap/Overview.htm) 
1 Paul A. Harris, Robert Taylor, Robert Thielke, Jonathon Payne, Nathaniel 
Gonzalez, Jose G. Conde, Research electronic data capture (REDCap) - A 
metadata-driven methodology and workflow process for providing translational 
research informatics support, J Biomed Inform. 2oog Apr; 42(2):377-81. 
March 25, 2019 
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Data collected from this study will be used for research purposes. No 
patient identifiable information will be released or published without written 
permission unless required to do so by law. Records will be maintained in 
accordance with the Department of Veterans Affairs Record Control Schedule lo-
1. In the event that theft, loss of other unauthorized access of sensitive data or 
storage devices and non-compliance with security controls occur, study staff have 
been instructed to follow Boston VA's standard operating procedure on incidence 
reporting. Electronic access to research study data and protected electronic 
folder will be revoked by informing the OUT personnel for the study personnel 
who are no longer part of the research team. Access to paper data will be revoked 
by the PI by not providing access to the storage cabinets and room. 
Data analysis using deidentified data will be performed using SAS statistical 
program. 
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Lewis GD, Shah R, Shahzad K, et al.: Sildenafil improves exercise capacity and 
quality of life in patients with systolic heart failure and secondary pulmonary 
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Warwick G, Thomas PS, Yates DH: Biomarkers in pulmonary hypertension. 
The European respiratory journal : official journal of the European Society for 
Clinical Respiratory Physiology. 2008:32:503-512. 
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Nagaya N, Nishikimi T, Uematsu M, et al.: Plasma brain natriuretic peptide as 
a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 
2000:102:865-870. 
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Minai OA, Chaouat A, Adnot S: Pulmonary hypertension in COPD: 
epidemiology, significance, and management: pulmonary vascular disease: the 
global perspective. Chest. 2010:137:39S-51S. 
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Galie N, Ghofrani HA, Torbicki A, et al.: Sildenafil citrate therapy for 
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