Tadalafil for Pulmonary Hypertension Due to Chronic Lung Disease
Information source: Department of Veterans Affairs
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pulmonary Hypertension; Chronic Obstructive Pulmonary Disease (COPD)
Intervention: Tadalafil (Drug); placebo (Drug)
Phase: N/A
Status: Recruiting
Sponsored by: Department of Veterans Affairs Official(s) and/or principal investigator(s): Ronald Howard Goldstein, MD, Principal Investigator, Affiliation: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
Overall contact: Ronald H Goldstein, MD, Phone: (857) 203-6578, Email: Ronald.Goldstein@va.gov
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.
Clinical Details
Official title: Tadalafil for Pulmonary Hypertension Associated With Chronic Lung Disease
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Change in 6 minute walk test
Secondary outcome: Maximum volume of oxygen extraction on exercise testingPulmonary vascular resistance Mean pulmonary artery pressure Tricuspid annular plane excursion (TAPSE) Dyspnea and health related quality of life (HRQL) N-type brain natriuretic peptide (BNP) concentration Resting Hypoxemia Exercise-induced hypoxemia
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) > 30 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 and FEV1 <79% ). 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 three VA sites: Boston VA
Healthcare System, Providence VA Medical Center, and the Greater Los Angeles VA Healthcare
System. 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.
Eligibility
Minimum age: 40 Years.
Maximum age: 85 Years.
Gender(s): Both.
Criteria:
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; FEV1 <79%) 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 >30 mm Hg
- PVR >2. 5 Wood units
- pulmonary artery capillary wedge pressure 18 mm Hg 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.
- DlCO less than 30% of predicted
Locations and Contacts
Ronald H Goldstein, MD, Phone: (857) 203-6578, Email: Ronald.Goldstein@va.gov
VA Greater Los Angeles Healthcare System, West Los Angeles, CA, West Los Angeles, California 90073, United States; Recruiting Shelley Shapiro, Phone: 310-268-4314, Email: shelley.shapiro@va.gov
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA, Boston, Massachusetts 02130, United States; Recruiting Paul R Conlin, MD, Phone: (857) 203-5111, Email: Paul.Conlin@va.gov Terence M Keane, PhD, Phone: (857) 364-4551, Email: terry.keane@va.gov Ronald Howard Goldstein, MD, Principal Investigator
Providence VA Medical Center, Providence, RI, Providence, Rhode Island 02908, United States; Recruiting Sharon I Rounds, Phone: 401-457-3020, Email: sharon.rounds@va.gov
Additional Information
Starting date: October 2013
Last updated: June 4, 2015
|