Clinical trial NCT01910389: Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure
Official title: Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Heart Failure
Pulmonary Hypertension
Keywords: Heart failure
Pulmonary hypertension
tadalafil
Phosphodiesterase Type 5 Inhibition
Lead sponsor: Carelon Research
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Massachusetts General Hospital
First posted: 2013-07-29
Enrollment: 23
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a multi-center, prospective, randomized, double blind, placebo-controlled clinical trial. Subjects in the study will be adults with New York Heart Association (NYHA) Class II-IV heart failure (HF) due to left ventricular systolic dysfunction (LVSD), left ventricular ejection fraction (LVEF) \<0.40, and secondary pulmonary hypertension (PH). The purpose of the study is to evaluate the safety, effectiveness, and effects of tadalafil compared to placebo on the subjects' functional capacity / quality of life.


Eligibility criteria: Inclusion Criteria:

* Male or female age 21 years or older.
* NYHA Class II-IV HF with LVSD (most recent LVEF \< 0.40).
* At high risk of future clinical instability, indicated by EITHER:

a hospitalization for the primary reason of decompensated HF within the 12 months prior to screening; OR a plasma B-type Natriuretic Peptide (BNP) level ≥ 300 pg/ml or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥1800pg/ml measured during a period of clinical stability in the 3 months prior to screening.

* Documented secondary PH within the last 6 months
* Medication and device treatment according to current American Heart Association/American College of Cardiology (AHA/ACC) guidelines.
* Stable medical therapy for 30 days prior to randomization
* African-American patients intolerant of or otherwise unable or unwilling to utilize isosorbide dinitrate/hydralazine therapy will be included.
* Willingness to comply with protocol, attend follow-up appointments, complete all study assessments and provide written informed consent.

Exclusion Criteria:

* Concurrent or anticipated nitrate use for any reason, or nitrate use within the 14 days prior to screening through the day of randomization.
* Known allergy, hypersensitivity (anaphylaxis), or adverse reaction to tadalafil or other Phosphodiesterase Type 5 (PDE5) inhibitor
* Erectile dysfunction treated with a PDE5 inhibitor.
* Severe renal dysfunction defined as an estimated glomerular filtration rate (GFR) \< 30 ml/min/1.73 m\^2 or requiring chronic dialysis
* Current use of alpha antagonists (except carvedilol or tamsulosin) or use of cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, erythromycin, or cimetidine). Patients who have used a protease inhibitor that is a P450 3A4 inhibitor for longer than one week can be enrolled.
* Pulmonary arterial hypertension (World Health Organization (WHO) Group I, III-V) for which PDE5 inhibitor therapy may be indicated
* Severe pulmonary disease requiring home oxygen therapy
* Comorbidities including clinically significant valvular stenosis (aortic valve area \< 0.8 cm\^2 or a mitral valve area \<1.0 cm\^2), uncontrolled hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg) or hypotension (systolic blood pressure \<85 mmHg)
* Chronic intravenous inotrope therapy
* Non-arteritic anterior ischemic optic neuropathy (NAION)
* ST elevation MI (STEMI) within 90 days prior to screening
* Coronary Artery Bypass Grafting (CABG) or mitral valve surgery, initiation of cardiac resynchronization (CRT) or initiation of β-blocker therapy within the 6 months prior to screening
* Infiltrative or inflammatory myocardial disease (e.g. amyloid, sarcoid)
* Heart transplant recipient
* United Network Organ Sharing (UNOS) status 1A or 1B
* Mechanical circulatory support (MCS) use or planned MCS use at time of consent
* Active malignancy (except non-melanoma skin cancer) requiring therapy other than observation.
* Severe non-cardiac illness resulting in life expectancy judged less than three years
* Known chronic hepatic disease defined as aspartate aminotransferase (AST) and alanine transaminase (ALT) levels \> 3.0 times the upper limit of normal
* Inability to walk even a few steps due to non-cardiac (e.g. orthopedic) reasons
* Participation in any clinical trial within the last 30 days (with exception of observational study)
* Previous randomization in PITCH-HF

Primary outcomes:
measure: Composite Outcome of Cardiovascular (CV) Mortality or Heart Failure (HF) Hospitalization
timeFrame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Secondary outcomes:
measure: Cardiovascular Mortality
timeFrame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
measure: Heart Failure Hospitalization
timeFrame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
measure: All-cause Mortality
timeFrame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
measure: Composite Outcome of All-cause Mortality or CV Hospitalization (Myocardial Infarction, Acute Coronary Syndrome, Stroke, Arrhythmia, or Heart Failure)
timeFrame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
measure: Frequency of CV Hospitalizations
timeFrame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
measure: Frequency of HF Hospitalizations
timeFrame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
measure: Change in 6 Minute Walk Distance From Baseline to 3 Months
timeFrame: Randomization to 3 months
measure: Change in MLHFQ Score From Baseline to 3 Months
timeFrame: Randomization to 3 months
measure: Change in 6 Minute Walk Distance From Baseline to 18 Months
timeFrame: Randomization to 18 months
measure: Trend in 6 Minute Walk Distance From Baseline Through 18 Months
timeFrame: Randomization to 18 months
measure: Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score From Baseline to 18 Months
timeFrame: Randomization to 18 months
measure: Trend in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score From Baseline Through 18 Months
timeFrame: Randomization to 18 months
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Heart Center Inc - Research
state: Alabama
city: Little Rock
country: United States
facility: Baptist Health Transplant Institute
state: Arkansas
city: Fountain Valley
country: United States
facility: Allianz Medical and Research Center
state: California
city: Newark
country: United States
facility: Christiana Care Health System
state: Delaware
city: Ft. Lauderdale
country: United States
facility: Broward Health
state: Florida
city: Miami
country: United States
facility: Miller School of Medicine University of Miami
state: Florida
city: Orlando
country: United States
facility: Orlando Health
state: Florida
city: Port Charlotte
country: United States
facility: Charlotte Heart Group Research Center
state: Florida
city: Rockledge
country: United States
facility: Brevard Cardiovascular Research Associates
state: Florida
city: Augusta
country: United States
facility: University Cardiology Associates LLC
state: Georgia
city: Fort Gordon
country: United States
facility: Eisenhower Army Medical Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois Hospital
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Group Cardiology
state: Illinois
city: Louisville
country: United States
facility: Baptist Hospital East
state: Kentucky
city: Owensboro
country: United States
facility: Research Integrity LLC
state: Kentucky
city: New Orleans
country: United States
facility: LSU Health Sciences Center
state: Louisiana
city: Auburn
country: United States
facility: Maine Research Associates
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Ayer
country: United States
facility: Primary Care Cardiology Research, Inc.
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Waltham
country: United States
facility: MGH West
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Dearborn
country: United States
facility: Oakwood Hospital and Medical Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Saginaw
country: United States
facility: Covenant Center for the Heart
state: Michigan
city: Duluth
country: United States
facility: Essentia Health East
state: Minnesota
city: Minneapolis
country: United States
facility: Metropolitan Heart and Vascular Institute
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Columbia
country: United States
facility: Missouri Cardiovascular Specialists
state: Missouri
city: Kansas City
country: United States
facility: St. Luke's Health System
state: Missouri
city: Kalispell
country: United States
facility: Glacier View Research Institute
state: Montana
city: Bridgewater
country: United States
facility: Advanced Heart Care, LLC
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Somerset
country: United States
facility: Heart & Vascular Center of NJ/Cardio Metabolic Institute
state: New Jersey
city: Bronx
country: United States
facility: Bronx - Lebanon Hospital Center
state: New York
city: Brooklyn
country: United States
facility: New York Methodist Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Schenectady
country: United States
facility: Cardiology Associates of Schenectady
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Hospital
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Greensboro
country: United States
facility: LeBauer Cardiovascular Research Foundation
state: North Carolina
city: Cincinnati
country: United States
facility: The Lindner Center for Research & Education at The Christ Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dayton
country: United States
facility: Dayton VA Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma City VA
state: Oklahoma
city: Tulsa
country: United States
facility: Warren Cancer Research Foundation
state: Oklahoma
city: Lancaster
country: United States
facility: Lancaster Heart and Stroke Foundation
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Sellersville
country: United States
facility: Grand View - Lehigh Valley Health Service
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: Germantown
country: United States
facility: Stern Cardiovascular Foundation, Inc.
state: Tennessee
city: Dallas
country: United States
facility: CIVA/CArdiovascular Research Institute of Dallas
state: Texas
city: Houston
country: United States
facility: Michael E. Debakey VA Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Milwaukee
country: United States
facility: Aurora St. Luke's Medical Center
state: Wisconsin
city: Wausau
country: United States
facility: Aspirus Wausau Hospital
state: Wisconsin
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
Study officials:
affiliation: Massachusetts General Hospital
name: Marc J. Semigran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: New England Research Institutes, Inc.
name: Susan F Assmann, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: New England Research Institutes, Inc.
name: Flora S Siami, MPH
role: PRINCIPAL_INVESTIGATOR
References: