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Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure (HARPS)

This study has been terminated.
(No longer could obtain clenbuterol)
Sponsor:
Collaborators:
Georgetown University
Montefiore Medical Center
Northwestern University
Ohio State University
Texas Heart Institute
University of Minnesota - Clinical and Translational Science Institute
University of Pennsylvania
Thoratec Corporation
Information provided by (Responsible Party):
Francis D. Pagani, University of Michigan
ClinicalTrials.gov Identifier:
NCT00585546
First received: December 26, 2007
Last updated: November 22, 2016
Last verified: November 2016
  Purpose
The purpose of this study is to evaluate whether patients with chronic heart failure not due to coronary artery disease who require use of a left ventricular assist device (LVAD) for refractory heart failure can recover sufficient heart function to allow the pump to be explanted. The study aims to avoid the need for transplantation in these patients by using standard heart failure medications to reduce the size of the left ventricle and then using the investigational drug, clenbuterol, to further improve left ventricular function.

Condition Intervention
Heart Failure
Dilated Cardiomyopathy
Drug: clenbuterol

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Harefield Recovery Protocol Study (HARPS): A Nonrandomized, Open Label, Multicenter Evaluation of Potential Recovery of Heart Function in Patients With Refractory Chronic Heart Failure by Treatment With Combination of Left Ventricular Assist Device (LVAD), Drugs to Induce Maximal Reverse Remodeling and the Beta-2 Adrenergic Receptor Agonist Clenbuterol.

Resource links provided by NLM:


Further study details as provided by University of Michigan:

Primary Outcome Measures:
  • Percent of subjects who experience LVAD removal and subsequent freedom from mechanical circulatory support or heart transplantation for 1-year after explantation [ Time Frame: One year after LVAD explant or until transplant or death (if not explanted) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The number of evaluable subjects meeting explant criteria and subsequently explanted [ Time Frame: Maximum 16 months after LVAD implantation ] [ Designated as safety issue: No ]
  • Number of subjects who received maximum target dose of clenbuterol [ Time Frame: Up to 16 months after LVAD implantation ] [ Designated as safety issue: Yes ]
  • Median time to device explant for subjects meeting explant criteria defined in the protocol [ Time Frame: Time to explant (but not to be followed for more than 16 months) ] [ Designated as safety issue: No ]
  • Change in left ventricular ejection fraction from explant to one year following device explant [ Time Frame: 1 year after explantation ] [ Designated as safety issue: No ]
  • Absolute percent change in serum creatinine and aspartate transaminase (AST) from baseline to week 8 post implant and week 8 post clenbuterol [ Time Frame: Up to 24 weeks after LVAD implantation ] [ Designated as safety issue: Yes ]
  • Mean change in EuroQoL visual analog scale (EQ5D-VAS) from baseline to 6 months and 1 year following device implant [ Time Frame: 1 year following LVAD implantation ] [ Designated as safety issue: No ]
    Scale 0 - 100 where 0 is worst possible health state and 100 is perfect health.

  • Mean change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) from baseline to 6 months and 1 year following device implant [ Time Frame: 12 months following LVAD implantation ] [ Designated as safety issue: No ]
    Scale 0 - 105 (0- 5 on 21 items) where 0 means heart failure has not limited daily life at all and high scores mean that daily functions are greatly limited.

  • Mean change in left ventricular ejection fraction from device implant to completion of clenbuterol therapy [ Time Frame: up to 16 months, variable based on length of time receiveing clenbuterol ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: July 2007
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LVAD and Clenbuterol Drug: clenbuterol
Clenbuterol 20 mcg tablets uptitrated from 20 mcg PO TID to a maximally tolerated dose not to exceed 700 mcg PO TID. Patients will then be switched to the equivalent dose of clenbuterol liquid 59 mcg/ml PO TID. Clenbuterol will be administered for a minimum of 3 months and a maximum of 12 months.
Other Name: Spiropent

Detailed Description:

The hypothesis of this study is that patients with dilated nonischemic cardiomyopathy who require support with an implanted left ventricular assist device (LVAD) for chronic refractory heart failure can, with a specific two-staged medical regimen designed to enhance maximal reverse remodeling (an angiotensin converting enzyme inhibitor, beta blocker, angiotensin receptor blocker, aldosterone antagonist and digoxin [stage 1]) and prevent/reverse myocardial atrophy (the β2 agonist clenbuterol [stage 2]), recover adequate left ventricular systolic function to allow LVAD explantation and subsequent intermediate-term survival without need for mechanical circulatory support or heart transplantation.

Within one year of this study's start, a new LVAD became the standard of care for implantation, so the study device became an inferior standard of care shortly thereafter. By 2012 the trial was stopped for futility in enrollment. Thus, certain original outcomes have been deleted, specifically because there was only a single subject explanted, multivariate analysis for sustainability of reverse remodeling following LVAD explantation and predictors of recovery of left ventricular function/remodeling and of LVAD removal could not be done.

Similarly, and for lack of funding, biobank components were not collected; therefore no data exists to present biochemical, structural, cellular and molecular changes in the myocardium resulting from the HARPS protocol interventions, changes in systemic inflammation, circulating progenitor cells and growth factors, or DEXA scan based data: changes in body mass, lean muscle mass, muscle strength and maximal and submaximal exercise capacity. All remaining outcome measures have been edited to more precisely show the outcome measures intended.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients with refractory symptomatic heart failure (NYHA Class IV, or Stage D) due to dilated, non-ischemic cardiomyopathy who meet the following criteria:

  • Severe clinical heart failure with associated haemodynamic compromise resistant to intensive medical therapy and requiring LVAD implantation
  • Duration of heart failure symptoms to be ≥ 12 months prior to LVAD implant
  • Documentation of LVEF ≤ 40% at least 1 year prior to LVAD implantation
  • LVEF ≤ 30% and cardiomegaly at the time of LVAD implantation as documented by radionuclide or contrast ventriculography or by echocardiography
  • Nonischemic etiology confirmed by coronary angiography within two years of enrollment
  • Listed for heart transplantation or plan to list for heart transplantation pending successful LVAD implantation in one of the participating centers, as per usual transplant listing policy at each participating center
  • >= 18 years of age
  • Body surface area >= 1.5 m2
  • Have an implantable defibrillator in place or a commitment to implant an ICD prior to hospital discharge
  • Have undergone insertion within prior 2 weeks or will be inserted with a Heartmate XVE LVAD with use of antimicrobial prophylaxis and drive line restraining belt

Exclusion Criteria:

  • Not a heart transplant candidate
  • Evidence of active acute myocarditis
  • Pulmonary Vascular Resistance > 6 Wood Units
  • History of previous CVA resulting in significant fixed motor deficit limiting ability to perform exercise testing
  • Previous prosthetic replacement of aortic and/or mitral valve(s)
  • Hypertrophic obstructive cardiomyopathy
  • LVIDD < 5 cm by surface echocardiogram (restrictive cardiomyopathy)
  • Irreversible multi-organ failure
  • Underlying bleeding disorder, or platelet count < 75,000, INR > 2.5 (without Coumadin), or Hgb < 8.0.
  • Pregnant or lactating women or unwilling to utilize two reliable methods of birth control for women of childbearing age
  • Receipt of other investigational drug therapy during LVAD support
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00585546

Locations
United States, District of Columbia
Georgetown Hospital
Washington, District of Columbia, United States, 20010
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Michigan
University of Michigan Health System
Ann Arbor, Michigan, United States, 48109
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19014
United States, Texas
Texas Heart Institute
Houston, Texas, United States, 77030
Sponsors and Collaborators
Francis D. Pagani
Georgetown University
Montefiore Medical Center
Northwestern University
Ohio State University
Texas Heart Institute
University of Minnesota - Clinical and Translational Science Institute
University of Pennsylvania
Thoratec Corporation
Investigators
Principal Investigator: Leslie W. Miller, MD Georgetown University
Study Director: Keith D. Aaronson, MD, MS University of Michigan
Study Director: Francis D. Pagani, MD, PhD University of Michigan
  More Information

Publications:
Responsible Party: Francis D. Pagani, Professor of Cardiac Surgery, University of Michigan
ClinicalTrials.gov Identifier: NCT00585546     History of Changes
Obsolete Identifiers: NCT00701116
Other Study ID Numbers: HARPS 
Study First Received: December 26, 2007
Last Updated: November 22, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Michigan:
heart failure
dilated cardiomyopathy
heart assist device
clenbuterol
adrenergic beta agonists
heart transplantation

Additional relevant MeSH terms:
Heart Failure
Cardiomyopathies
Cardiomyopathy, Dilated
Heart Diseases
Cardiovascular Diseases
Cardiomegaly
Clenbuterol
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Sympathomimetics

ClinicalTrials.gov processed this record on December 07, 2016