Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure

Phase 3

Terminated

Conditions: Heart Failure
Pulmonary Hypertension

Interventions: Drug: Placebo for tadalafil
Drug: Tadalafil

Registration Number: NCT01910389

Lead Sponsor: Carelon Research

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 23

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo for tadalafil	Placebo of tadalafil. Subjects will take one tablet once per day and will be titrated to two tablets once per day after one week. Subjects are on study drug for the duration of the trial.
Tadalafil	Tadalafil	Tadalafil is supplied in 20 mg tablets. Subjects will take 20 mg (one tablet) once per day and will be titrated to 40 mg (two tablets once per day) after one week. Subjects are on study drug for the duration of the trial.

Primary Outcome Measures

Name	Time	Method
Composite Outcome of Cardiovascular (CV) Mortality or Heart Failure (HF) Hospitalization	Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject

Secondary Outcome Measures

Name	Time	Method
Cardiovascular Mortality	Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Heart Failure Hospitalization	Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
All-cause Mortality	Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Composite Outcome of All-cause Mortality or CV Hospitalization (Myocardial Infarction, Acute Coronary Syndrome, Stroke, Arrhythmia, or Heart Failure)	Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Frequency of CV Hospitalizations	Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Frequency of HF Hospitalizations	Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Change in 6 Minute Walk Distance From Baseline to 3 Months	Randomization to 3 months
Change in MLHFQ Score From Baseline to 3 Months	Randomization to 3 months
Change in 6 Minute Walk Distance From Baseline to 18 Months	Randomization to 18 months
Trend in 6 Minute Walk Distance From Baseline Through 18 Months	Randomization to 18 months
Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score From Baseline to 18 Months	Randomization to 18 months
Trend in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score From Baseline Through 18 Months	Randomization to 18 months

Trial Locations

Locations (63): Heart Center Inc - Research
🇺🇸
Huntsville, Alabama, United States
Baptist Health Transplant Institute
🇺🇸
Little Rock, Arkansas, United States
Allianz Medical and Research Center
🇺🇸
Fountain Valley, California, United States
Christiana Care Health System
🇺🇸
Newark, Delaware, United States
Broward Health
🇺🇸
Ft. Lauderdale, Florida, United States
Miller School of Medicine University of Miami
🇺🇸
Miami, Florida, United States
Orlando Health
🇺🇸
Orlando, Florida, United States
Charlotte Heart Group Research Center
🇺🇸
Port Charlotte, Florida, United States
Brevard Cardiovascular Research Associates
🇺🇸
Rockledge, Florida, United States
University Cardiology Associates LLC
🇺🇸
Augusta, Georgia, United States
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Heart Center Inc - Research
🇺🇸Huntsville, Alabama, United States