Heart Failure, Pulmonary Hypertension
Conditions
Keywords
Heart failure, Pulmonary hypertension, tadalafil, Phosphodiesterase Type 5 Inhibition
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.
Interventions
DRUGTadalafil
DRUGPlacebo for tadalafil
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Massachusetts General Hospital
Carelon Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 |
| Cardiovascular Mortality | Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject |
| 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 |
| Change in 6 Minute Walk Distance From Baseline to 3 Months | Randomization to 3 months |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 15 |
| Placebo 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. | 8 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study Closed | 13 | 8 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Tadalafil | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 4 Participants | 14 Participants |
| Age, Continuous | 62.6 years | 63.3 years | 62.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 8 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 13 Participants | 7 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 15 | 0 / 8 |
| serious Total, serious adverse events | 4 / 15 | 2 / 8 |
Outcome results
Primary
Composite Outcome of Cardiovascular (CV) Mortality or Heart Failure (HF) Hospitalization
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
All-cause Mortality
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Cardiovascular Mortality
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Change in 6 Minute Walk Distance From Baseline to 18 Months
Time frame: Randomization to 18 months
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Change in 6 Minute Walk Distance From Baseline to 3 Months
Time frame: Randomization to 3 months
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score From Baseline to 18 Months
Time frame: Randomization to 18 months
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Change in MLHFQ Score From Baseline to 3 Months
Time frame: Randomization to 3 months
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Composite Outcome of All-cause Mortality or CV Hospitalization (Myocardial Infarction, Acute Coronary Syndrome, Stroke, Arrhythmia, or Heart Failure)
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Frequency of CV Hospitalizations
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Frequency of HF Hospitalizations
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Heart Failure Hospitalization
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 3 years per subject
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Trend in 6 Minute Walk Distance From Baseline Through 18 Months
Time frame: Randomization to 18 months
Population: Trial was terminated early. Data for outcome not obtained.
Secondary
Trend in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score From Baseline Through 18 Months
Time frame: Randomization to 18 months
Population: Trial was terminated early. Data for outcome not obtained.