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

Tracking Information
First Submitted Date ICMJE	December 26, 2007
First Posted Date ICMJE	January 3, 2008
Results First Submitted Date	March 25, 2017
Results First Posted Date	December 15, 2017
Last Update Posted Date	December 15, 2017
Study Start Date ICMJE	July 2007
Actual Primary Completion Date	March 2010 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 27, 2008)	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) ]
Original Primary Outcome Measures ICMJE; (submitted: December 26, 2007)	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) ]
Change History	Complete list of historical versions of study NCT00585546 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: May 16, 2017)	The Number of Evaluable Subjects Meeting Explant Criteria and Subsequently Explanted [ Time Frame: Maximum 12 months after LVAD implantation ]; Number of Subjects Who Received Maximum Target Dose of Clenbuterol [ Time Frame: 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 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; Absolute Change in Left Ventricular Ejection Fraction From Explant to 18 Months Following Device Explant [ Time Frame: 18 months after explantation ]; 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 ]; 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.; 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.; 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 ]; 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 ]; 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.
Original Secondary Outcome Measures ICMJE; (submitted: December 26, 2007)	The proportion of evaluable subjects meeting explant criteria and subsequently explanted [ Time Frame: Maximum 16 months after LVAD implantation ]; Safety and tolerability of clenbuterol [ Time Frame: 16 months after LVAD implantation ]; To determine the time course of reverse remodeling on a left ventricular assist device during phase I (heart failure medications) and phase II (clenbuterol) of the HARPS protocol [ Time Frame: Up to 16 months after LVAD implantation ]; To determine the time course and sustainability of reverse remodeling remodeling following LVAD explantation [ Time Frame: 1 year after explantation ]; To assess the biochemical, structural, cellular and molecular changes in the myocardium resulting from the HARPS protocol interventions [ Time Frame: Up to 28 months following LVAD implantation (up to 16 months after LVAD implantation plus 1 year after explantation) ]; To determine predictors of recovery of left ventricular function/remodeling and of LVAD removal [ Time Frame: Up to 16 months following LVAD implantation ]; To assess changes in body mass, lean muscle mass, muscle strength and maximal and submaximal exercise capacity [ Time Frame: Up to 22 months following LVAD implantation (up to 16 months following LVAD implantation and 6 months following LVAD explantation) ]; To assess changes in renal function and hepatic enzymes [ Time Frame: Up to 28 months after LVAD implantation ]; To assess changes in quality of life, as measured by the EuroQoL (EQ5D) and Minnesota Living with Heart Failure Questionnaire (MLHFQ) questionnaires [ Time Frame: Up to 28 months following LVAD implantation ]; To assess changes in systemic inflammation, circulating progenitor cells and growth factors [ Time Frame: Up to 16 months following LVAD implantation ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure
Official Title ICMJE	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.
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.
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 ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Heart Failure; Dilated Cardiomyopathy
Intervention ICMJE	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
Study Arms	Experimental: LVAD and Clenbuterol; Intervention: Drug: clenbuterol
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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Terminated
Actual Enrollment ICMJE; (submitted: November 22, 2016)	18
Original Estimated Enrollment ICMJE; (submitted: December 26, 2007)	40
Actual Study Completion Date	March 2010
Actual Primary Completion Date	March 2010 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00585546
Other Study ID Numbers ICMJE	HARPS
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement	Not Provided
Responsible Party	Francis D. Pagani, University of Michigan
Study Sponsor ICMJE	Francis D. Pagani
Collaborators ICMJE	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 ICMJE	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
PRS Account	University of Michigan
Verification Date	May 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP