Dilated Cardiomyopathy, Heart Failure
Conditions
Keywords
heart failure, dilated cardiomyopathy, heart assist device, clenbuterol, adrenergic beta agonists, heart transplantation
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.
Interventions
DRUGclenbuterol
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.
Sponsors
Georgetown University
Montefiore Medical Center
Northwestern University
Ohio State University
Texas Heart Institute
University of Minnesota
University of Pennsylvania
Thoratec Corporation
Francis D. Pagani
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 | 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 | — |
| The Number of Evaluable Subjects Meeting Explant Criteria and Subsequently Explanted | Maximum 12 months after LVAD implantation | — |
| Mean Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to 6 Months | 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 | 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 | 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. |
| Mean Change in EuroQoL Visual Analog Scale (EQ5D-VAS) From Baseline to 6 Months and 1 Year Following Device Implant | 1 year following LVAD implantation | Scale 0 - 100 where 0 is worst possible health state and 100 is perfect health. |
Countries
United States
Participant flow
Pre-assignment details
Of 19 consented, 1 was a screen fail and did not enter the study protocol.
Participants by arm
| Arm | Count |
|---|---|
| LVAD and Clenbuterol 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. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Clenbuterol Treatment - up to 12 Months | Adverse Event | 3 |
| Clenbuterol Treatment - up to 12 Months | Death | 1 |
Baseline characteristics
| Characteristic | LVAD and Clenbuterol |
|---|---|
| Age, Continuous | 57 years |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 18 |
| other Total, other adverse events | 11 / 18 |
| serious Total, serious adverse events | 13 / 18 |
Outcome results
Primary
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LVAD and Clenbuterol | Percent of Subjects Who Experience LVAD Removal and Subsequent Freedom From Mechanical Circulatory Support or Heart Transplantation for 1-year After Explantation | 5.6 percentage of participants |
Secondary
Absolute Change in Left Ventricular Ejection Fraction From Explant to 18 Months Following Device Explant
Time frame: 18 months after explantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LVAD and Clenbuterol | Absolute Change in Left Ventricular Ejection Fraction From Explant to 18 Months Following Device Explant | -.09 absolute change in ejection fraction |
Secondary
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
Population: baseline data is based on 19 participants, but different subsequent data collections had different numbers of evaluable subjects listed below
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LVAD and Clenbuterol | Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Clenbuterol | creatinine from baseline to week 8 of clenbuterol | -15.8 percent change | Standard Deviation 13.3 |
| LVAD and Clenbuterol | Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Clenbuterol | AST from baseline to week 8 on clenbuterol | 15.6 percent change | Standard Deviation 14.3 |
Secondary
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
Population: Because data only is available for 15 participants for 8 week post implant AST value, it has a different participants analyzed value
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LVAD and Clenbuterol | Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Implant | Creatinine | 17.2 percent change | Standard Deviation 15.2 |
| LVAD and Clenbuterol | Absolute Percent Change in Serum Creatinine and Aspartate Transaminase (AST) From Baseline to Week 8 Post Implant | aspartate transaminase (AST) | 25 percent change | Standard Deviation 19.7 |
Secondary
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.
Time frame: 1 year following LVAD implantation
Population: While baseline data was available for 13 participants at baseline, (start of clenbuterol), different numbers of participants provided evaluable data At six months post implant and 12 months, so the mean changes are based on the actual population that provided both data points as listed below
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LVAD and Clenbuterol | Mean Change in EuroQoL Visual Analog Scale (EQ5D-VAS) From Baseline to 6 Months and 1 Year Following Device Implant | 6 months post implant | 46 units on a scale | Standard Deviation 35 |
| LVAD and Clenbuterol | Mean Change in EuroQoL Visual Analog Scale (EQ5D-VAS) From Baseline to 6 Months and 1 Year Following Device Implant | 12 months post implant | 51 units on a scale | Standard Deviation 30 |
Secondary
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
Population: data is available for 9 evaluable subjects at end of clenbuterol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LVAD and Clenbuterol | Mean Change in Left Ventricular Ejection Fraction From Device Implant to Completion of Clenbuterol Therapy | 0.16 ejection fraction | Standard Deviation 0.1 |
Secondary
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.
Time frame: 1 year
Population: Data is not available for Minnesota Living with Heart Failure Questionnaire at the 12 month time point.
Secondary
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.
Time frame: 6 months following LVAD implantation
Population: Only 11 participants provided usable data at the six month time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LVAD and Clenbuterol | Mean Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) From Baseline to 6 Months | 28.3 units on a scale | Standard Deviation 19.7 |
Secondary
Number of Subjects Who Received Maximum Target Dose of Clenbuterol
Time frame: Up to 16 months after LVAD implantation (12 months after beginning clenbuterol)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LVAD and Clenbuterol | Number of Subjects Who Received Maximum Target Dose of Clenbuterol | 13 Participants |
Secondary
The Number of Evaluable Subjects Meeting Explant Criteria and Subsequently Explanted
Time frame: Maximum 12 months after LVAD implantation
Population: Because only 13 began Clenbuterol, only 13 are evaluable for this purpose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LVAD and Clenbuterol | The Number of Evaluable Subjects Meeting Explant Criteria and Subsequently Explanted | 1 Participants |
Secondary
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 frame: Time to explant (but not to be followed for more than 16 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LVAD and Clenbuterol | Time to Device Explant for Subjects Meeting Explant Criteria Defined in the Protocol | 28 weeks |