Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Heart Failure, Dilated Cardiomyopathy

Intervention / Treatment
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* Drug: clenbuterol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LVAD and Clenbuterol<br> | Drug: clenbuterol<br>* 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.<br>* Other names: Spiropent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, dilated cardiomyopathy, heart assist device, clenbuterol, adrenergic beta agonists, heart transplantation