Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure (PITCH-HF)

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.

Study Overview

• Status: Terminated
• Conditions: Heart Failure; Pulmonary Hypertension
• Intervention / Treatment: Drug: Tadalafil; Drug: Placebo for tadalafil

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada
      • Jewish General Hospital
• United States
  • Alabama
    • Huntsville, Alabama, United States
      • Heart Center Inc - Research
  • Arkansas
    • Little Rock, Arkansas, United States
      • Baptist Health Transplant Institute
  • California
    • Fountain Valley, California, United States
      • Allianz Medical and Research Center
  • Delaware
    • Newark, Delaware, United States
      • Christiana Care Health System
  • Florida
    • Ft. Lauderdale, Florida, United States
      • Broward Health
    • Miami, Florida, United States
      • Miller School of Medicine University of Miami
    • Orlando, Florida, United States
      • Orlando Health
    • Port Charlotte, Florida, United States
      • Charlotte Heart Group Research Center
    • Rockledge, Florida, United States
      • Brevard Cardiovascular Research Associates
  • Georgia
    • Augusta, Georgia, United States
      • University Cardiology Associates LLC
    • Fort Gordon, Georgia, United States
      • Eisenhower Army Medical Center
  • Illinois
    • Chicago, Illinois, United States
      • Northwestern University
    • Chicago, Illinois, United States
      • University of Illinois Hospital
    • Peoria, Illinois, United States
      • Methodist Medical Group Cardiology
  • Kentucky
    • Louisville, Kentucky, United States
      • Baptist Hospital East
    • Owensboro, Kentucky, United States
      • Research Integrity LLC
  • Louisiana
    • New Orleans, Louisiana, United States
      • LSU Health Sciences Center
  • Maine
    • Auburn, Maine, United States
      • Maine Research Associates
  • Maryland
    • Baltimore, Maryland, United States
      • Johns Hopkins Hospital
  • Massachusetts
    • Ayer, Massachusetts, United States
      • Primary Care Cardiology Research, Inc.
    • Boston, Massachusetts, United States
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States
      • Brigham and Women's Hospital
    • Waltham, Massachusetts, United States
      • MGH West
  • Michigan
    • Ann Arbor, Michigan, United States
      • University of Michigan Health System
    • Dearborn, Michigan, United States
      • Oakwood Hospital and Medical Center
    • Detroit, Michigan, United States
      • Henry Ford Hospital
    • Royal Oak, Michigan, United States
      • William Beaumont Hospital
    • Saginaw, Michigan, United States
      • Covenant Center for the Heart
  • Minnesota
    • Duluth, Minnesota, United States
      • Essentia Health East
    • Minneapolis, Minnesota, United States
      • Metropolitan Heart and Vascular Institute
    • Rochester, Minnesota, United States
      • Mayo Clinic
  • Missouri
    • Columbia, Missouri, United States
      • Missouri Cardiovascular Specialists
    • Kansas City, Missouri, United States
      • St. Luke's Health System
  • Montana
    • Kalispell, Montana, United States
      • Glacier View Research Institute
  • New Jersey
    • Bridgewater, New Jersey, United States
      • Advanced Heart Care, LLC
    • Hackensack, New Jersey, United States
      • Hackensack University Medical Center
    • Newark, New Jersey, United States
      • Newark Beth Israel Medical Center
    • Somerset, New Jersey, United States
      • Heart & Vascular Center of NJ/Cardio Metabolic Institute
  • New York
    • Bronx, New York, United States
      • Bronx - Lebanon Hospital Center
    • Brooklyn, New York, United States
      • New York Methodist Hospital
    • New York, New York, United States
      • Columbia University Medical Center
    • New York, New York, United States
      • Mount Sinai Medical Center
    • Schenectady, New York, United States
      • Cardiology Associates of Schenectady
    • Stony Brook, New York, United States
      • Stony Brook University Hospital
    • Syracuse, New York, United States
      • Suny Upstate Medical University
  • North Carolina
    • Greensboro, North Carolina, United States
      • LeBauer Cardiovascular Research Foundation
  • Ohio
    • Cincinnati, Ohio, United States
      • The Lindner Center for Research & Education at The Christ Hospital
    • Cleveland, Ohio, United States
      • Cleveland Clinic
    • Dayton, Ohio, United States
      • Dayton VA Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Oklahoma City VA
    • Tulsa, Oklahoma, United States
      • Warren Cancer Research Foundation
  • Pennsylvania
    • Lancaster, Pennsylvania, United States
      • Lancaster Heart and Stroke Foundation
    • Philadelphia, Pennsylvania, United States
      • Drexel University College of Medicine
    • Philadelphia, Pennsylvania, United States
      • Temple University
    • Sellersville, Pennsylvania, United States
      • Grand View - Lehigh Valley Health Service
    • Wynnewood, Pennsylvania, United States
      • Lankenau Medical Center
  • Tennessee
    • Germantown, Tennessee, United States
      • Stern Cardiovascular Foundation, Inc.
  • Texas
    • Dallas, Texas, United States
      • CIVA/CArdiovascular Research Institute of Dallas
    • Houston, Texas, United States
      • Michael E. DeBakey VA Medical Center
  • Utah
    • Salt Lake City, Utah, United States
      • University of Utah
  • Wisconsin
    • Milwaukee, Wisconsin, United States
      • Aurora St. Luke's Medical Center
    • Wausau, Wisconsin, United States
      • Aspirus Wausau Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 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.	Drug: Placebo for tadalafil
Active Comparator: 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.	Drug: Tadalafil; Other Names: Adcirca

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: HealthCore-NERI
• Collaborators: Massachusetts General Hospital; National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Marc J. Semigran, MD, Massachusetts General Hospital; Principal Investigator: Susan F Assmann, PhD, New England Research Institutes, Inc.; Principal Investigator: Flora S Siami, MPH, New England Research Institutes, Inc.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: July 25, 2013
• First Submitted That Met QC Criteria: July 25, 2013
• First Posted (Estimate): July 29, 2013

Study Record Updates

• Last Update Posted (Estimate): May 4, 2015
• Last Update Submitted That Met QC Criteria: April 16, 2015
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Heart failure; Pulmonary hypertension; tadalafil; Phosphodiesterase Type 5 Inhibition
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: U01HL105463 (U.S. NIH Grant/Contract)