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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Heart Failure; Dilated Cardiomyopathy
• Intervention / Treatment: Drug: clenbuterol

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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20010
      • Georgetown Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • New York
    • The Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19014
      • University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Heart Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Spiropent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent of Subjects Who Experience LVAD Removal and Subsequent Freedom From Mechanical Circulatory Support or Heart Transplantation for 1-year After Explantation	One year after LVAD explant or until transplant or death (if not explanted)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Evaluable Subjects Meeting Explant Criteria and Subsequently Explanted		Maximum 12 months after LVAD implantation
Number of Subjects Who Received Maximum Target Dose of Clenbuterol		Up to 16 months after LVAD implantation (12 months after beginning clenbuterol)
Time to Device Explant for Subjects Meeting Explant Criteria Defined in the Protocol	Time from LVAD placement to explant for the single participant who achieved explant	Time to explant (but not to be followed for more than 16 months)
Absolute Change in Left Ventricular Ejection Fraction From Explant to 18 Months Following Device Explant		18 months after explantation
Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Implant		Up to 8 weeks after LVAD implantation
Mean Change in EuroQoL Visual Analog Scale (EQ5D-VAS) From Baseline to 6 Months and 1 Year Following Device Implant	Scale 0 - 100 where 0 is worst possible health state and 100 is perfect health.	1 year following LVAD implantation
Mean Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to 6 Months	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.	6 months following LVAD implantation
Mean Change in Left Ventricular Ejection Fraction From Device Implant to Completion of Clenbuterol Therapy		up to 16 months, variable based on length of time receiveing clenbuterol
Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Clenbuterol		baseline to week 8 post clenbuterol
Mean Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to 1 Year Following Device Implant	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.	1 year

Collaborators and Investigators

• Sponsor: Francis D. Pagani
• Collaborators: University of Pennsylvania; Northwestern University; Georgetown University; Montefiore Medical Center; Ohio State University; University of Minnesota; Thoratec Corporation; Texas Heart Institute
• 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

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: December 26, 2007
• First Submitted That Met QC Criteria: December 26, 2007
• First Posted (Estimate): January 3, 2008

Study Record Updates

• Last Update Posted (Actual): December 15, 2017
• Last Update Submitted That Met QC Criteria: May 16, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: heart failure; dilated cardiomyopathy; heart transplantation; heart assist device; clenbuterol; adrenergic beta agonists
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Heart Failure; Cardiomyopathies; Cardiomyopathy, Dilated; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-Agonists; Sympathomimetics; Clenbuterol
• Other Study ID Numbers: HARPS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No