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

• ClinicalTrials.gov Identifier: NCT00585546
• Recruitment Status: Terminated
• First Posted: January 3, 2008
• Results First Posted: December 15, 2017
• Last Update Posted: December 15, 2017
• Sponsor: Francis D. Pagani
• Collaborators: Georgetown University; Montefiore Medical Center; Northwestern University; Ohio State University; Texas Heart Institute; University of Minnesota; University of Pennsylvania; Thoratec Corporation
• Information provided by (Responsible Party): Francis D. Pagani, University of Michigan

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Heart Failure; Dilated Cardiomyopathy	Drug: clenbuterol	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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.
• Study Start Date: July 2007
• Actual Primary Completion Date: March 2010
• Actual Study Completion Date: March 2010

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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) ]

Secondary Outcome Measures :

1. The Number of Evaluable Subjects Meeting Explant Criteria and Subsequently Explanted [ Time Frame: Maximum 12 months after LVAD implantation ]
2. Number of Subjects Who Received Maximum Target Dose of Clenbuterol [ Time Frame: Up to 16 months after LVAD implantation (12 months after beginning clenbuterol) ]
3. 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) ]
   Time from LVAD placement to explant for the single participant who achieved explant
4. Absolute Change in Left Ventricular Ejection Fraction From Explant to 18 Months Following Device Explant [ Time Frame: 18 months after explantation ]
5. Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Implant [ Time Frame: Up to 8 weeks after LVAD implantation ]
6. 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 ]
   Scale 0 - 100 where 0 is worst possible health state and 100 is perfect health.
7. Mean Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to 6 Months [ Time Frame: 6 months following LVAD implantation ]
   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.
8. 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 ]
9. Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Clenbuterol [ Time Frame: baseline to week 8 post clenbuterol ]
10. Mean Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to 1 Year Following Device Implant [ Time Frame: 1 year ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

United States, District of Columbia

Georgetown Hospital

Washington, D.C., 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

The 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

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:

Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, Banner NR, Khaghani A, Yacoub MH. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med. 2006 Nov 2;355(18):1873-84. doi: 10.1056/NEJMoa053063.

• Responsible Party: Francis D. Pagani, Professor of Cardiac Surgery, University of Michigan
• ClinicalTrials.gov Identifier: NCT00585546
• Obsolete Identifiers: NCT00701116
• Other Study ID Numbers: HARPS
• First Posted: January 3, 2008
• Results First Posted: December 15, 2017
• Last Update Posted: December 15, 2017
• Last Verified: May 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Francis D. Pagani, 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; Laminopathies; Genetic Diseases, Inborn; 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