MIRACLE EF Clinical Study

Study Overview
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Brief Summary
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This study is looking at whether the electrical treatment provided by a special type of pacemaker called a Cardiac Resynchronization Therapy (CRT) pacemaker may keep a patient's heart failure from getting worse. When the lower heart chambers (i.e. ventricles) are electrically paced to beat together by the CRT pacemaker, blood may be pumped to the body more efficiently. The CRT pacemaker being studied in this clinical trial is approved by the US Food and Drug Administration (FDA) for patients with moderate to severe heart failure, whose hearts pump blood inefficiently. In the MIRACLE EF study, patients who have heart failure with slightly less inefficient hearts will be observed to see if the electrical pacing treatment is better than not getting the treatment. This study is being conducted to support FDA approval of this type of pacemaker for people whose heart failure is less inefficient.

Detailed Description
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Medtronic, Inc. is sponsoring the MIRACLE EF study, a prospective, randomized, controlled, double-blinded, global multi-center, Cardiac Resynchronization Therapy (CRT) in Heart Failure (HF) clinical study. The purpose of this study is to evaluate market released CRT pacemaker (CRT-P) devices in symptomatic HF patients with less severe left ventricular systolic dysfunction, specifically patients with reduced left ventricular ejection fraction (LVEF) in the range of 36% to 50%. This study will support expansion of indications for CRT worldwide. The outcome of this study is expected to support modification of existing U.S. and Japanese labeling for Medtronic's implantable CRT-P devices and to provide further evidence to support changes to cardiology practice guidelines (ACC/AHA, ESC guidelines) regarding the use of CRT in patients with mild to moderate HF. Following enrollment and the baseline assessment, eligible subjects will be implanted with a CRT-P system and randomized in a 2:1 fashion to either treatment (CRT-P ON) or control (CRT-P OFF) groups. Study subjects will be followed for a minimum of 24 months or until study closure, and will remain in their randomized groups until their 60 month visit or until the study is stopped, whichever comes first. The effectiveness of CRT-P in this population will be assessed using a composite endpoint of time to first event, with event defined as All-cause mortality or HF Event. To assess the safety of CRT-P in this population, the primary safety endpoint will measure freedom from system-related complications at 6 months post-implant.

Official Title
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MIRACLE EF Clinical Study

Conditions
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Congestive Heart Failure, Left Bundle Branch Block, Systolic Heart Failure

Intervention / Treatment
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* Device: CRT-P Implant
* Device: CRT-P OFF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has diagnosis of chronic heart failure > 90 days in duration Has left ventricular ejection fraction (LVEF) between 36% and 50%, inclusive, as documented at baseline or within 30 days prior to enrollment Is either: (a) NYHA Class III at enrollment or at baseline OR (b) NYHA Class II at enrollment or at baseline, with a documented hospitalization for HF in the 12 months prior to enrollment OR (c) NYHA Class II at enrollment or at baseline, without a documented hospitalization for HF in the prior 12 months, but with BNP ≥250 pg/ml or NT-proBNP ≥1000 pg/ml Has documented left bundle branch block (LBBB) with QRS ≥130ms at baseline or within 30 days prior to enrollment. Is in sinus rhythm at time of enrollment or at the baseline visit. Has had no additions to or subtractions from non-diuretic heart failure medical therapy within 30 days prior to enrollment Is on maximum tolerated (guideline) dosages of medications in ACC/AHA guidelines for HF, Ischemic Heart Disease, Hypertension and AF as appropriate. Has signed and dated the study informed consent. Is able to receive a pectoral CRT-P implant. Is expected to remain available for follow-up visits. Is willing and able to comply with the Clinical Investigation Plan. Exclusion Criteria: Requires permanent cardiac pacing. Indicated for implantable cardioverter defibrillator (ICD), such as for secondary prevention of prior sudden cardiac arrest, related to prior history of ventricular tachycardia and/or ventricular fibrillation. Less than 18 years of age, or under a higher minimum age requirement as defined by local law. Unstable angina or an acute MI within 40 days prior to enrollment. Coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) within the 90 days prior to enrollment. Chronic (permanent) atrial arrhythmias. Chronic (permanent) atrial arrhythmias are defined as cases of long-standing atrial fibrillation (e.g., greater than 1 year) in which cardioversion has not been indicated or attempted. Cardioversion for atrial fibrillation within 30 days prior to enrollment. Treatable pericardial constraint within 30 days prior to enrollment. Restrictive (infiltrative) cardiomyopathies, such as amyloidosis, sarcoidosis, or hemochromatosis. Enrolled in a concurrent study, with the exception of a study-manager approved study that is strictly observational in nature and does not confound the results of this study (e.g. registries). Life expectancy of less than 24 months due to non-cardiac conditions. Pregnant, or of childbearing potential and not on a reliable form of birth control. CRT-P, pacemaker, ICD or CRT-D device implanted previously, or currently. Restrictive, hypertrophic, or reversible cardiomyopathy. Mechanical right heart valve. Primary valvular disease and is indicated for valve repair or replacement. Heart transplant, or is currently on a heart transplant list. Significant renal dysfunction, as manifested by serum creatinine level >2.5 mg/dl or ≥275 μmol/L or estimated glomerular filtration rate (GFR) ≤30 mL/min/1.73 m2, which is documented within the 30 days prior to enrollment or at baseline. Significant hepatic dysfunction, as evidenced by a hepatic function panel (serum) > 3 times upper limit of normal, which is documented within the 30 days prior to enrollment or at baseline. Chronic or treatment-resistant severe anemia (hemoglobin <10.0 g/dL), which is documented within the 30 days prior to enrollment or at baseline. On intravenous inotropic drug therapy.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CRT-P ON<br>CRT-P Implant CRT-P ON | Device: CRT-P Implant<br>* The Medtronic Consulta CRT-P (models C3TR01, C4TR011) dual chamber implantable pacemaker with cardiac resynchronization therapy (CRT-P) is a multi-programmable cardiac device that monitors and regulates the patient's heart rate by providing single or dual chamber rate-responsive bradycardia pacing, and sequential biventricular pacing. The device senses the electrical activity of the patient's heart using the electrodes of the implanted atrial and right ventricular leads. It then analyzes the heart rhythm based on selectable detection parameters. The device responds to bradyarrhythmias by providing bradycardia pacing therapy. Simultaneous or sequential biventricular pacing is used to provide patients with cardiac resynchronization therapy. The device also provides diagnostic and monitoring information that assists with system evaluation and patient care.<br>* Other names: C4TR01;|
| Placebo Comparator: CRT-P OFF<br>CRT-P Implant CRT-P OFF | Device: CRT-P Implant<br>* The Medtronic Consulta CRT-P (models C3TR01, C4TR011) dual chamber implantable pacemaker with cardiac resynchronization therapy (CRT-P) is a multi-programmable cardiac device that monitors and regulates the patient's heart rate by providing single or dual chamber rate-responsive bradycardia pacing, and sequential biventricular pacing. The device senses the electrical activity of the patient's heart using the electrodes of the implanted atrial and right ventricular leads. It then analyzes the heart rhythm based on selectable detection parameters. The device responds to bradyarrhythmias by providing bradycardia pacing therapy. Simultaneous or sequential biventricular pacing is used to provide patients with cardiac resynchronization therapy. The device also provides diagnostic and monitoring information that assists with system evaluation and patient care.<br>* Other names: C4TR01;Device: CRT-P OFF<br>* Device programmed to minimal pacing at 40 beats/minute. Device and arrhythmia diagnostics may remain enabled.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality or Heart Failure Morbidity | Primary Efficacy Endpoint: The time to first event, with event defined as: All-cause mortality, or HF Event, defined as either: Inpatient hospitalization for HF, or Outpatient event requiring invasive clinical intervention and management for HF (i.e. IV diuretics, ultrafiltration, or equivalent) and overnight stay Note: No endpoints were reached, so this objective was not analyzed | From date of randomization to date of event, assessed for a minimum of 24 months and up to 60 months | 
| System-related Complication | Primary Safety Endpoint: Time to first system-related complication in subjects with a successful implant. Note: Because of the small number of subjects, number of complications was noted between arms and a time to event analysis was not performed. Complication is defined as: An adverse event that results in death, involves any termination of significant device function, or requires an invasive intervention | From the date of implant to the date of 6 month follow-up visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Time to death between the study groups Note: No endpoints were reached, so this objective was not analyzed | From date of randomization to date of death, for a minimum of 24 months and up to 60 months | 
| Mortality or Heart Failure Morbidity or Worsening Systolic Function | Secondary Composite Efficacy Endpoint: The time to first event, with event defined as: All-cause mortality HF Event, defined as either: Inpatient hospitalization for HF, or Outpatient event requiring invasive clinical intervention and management for HF (i.e. IV diuretics, ultrafiltration, or equivalent) and overnight stay, or Worsening systolic function meeting an ICD/CRT-D indication, defined as: A drop in LVEF to 35% or below, with an absolute decrease of greater than or equal to 10%, after maximum tolerated doses of guideline HF medications have been established Note: No endpoints were reached, so this objective was not analyzed | From date of randomization to date of event, assessed for a minimum of 24 months and up to 60 months | 
| Recurrent HF Events | The frequency of HF events between the study groups Note: No endpoints were reached, so this objective was not analyzed - HF Event, defined as either: Inpatient hospitalization for HF, or Outpatient event requiring invasive clinical intervention and management for HF (i.e. IV diuretics, ultrafiltration, or equivalent) and overnight stay | From date of randomization to date of event, assessed for a minimum of 24 months and up to 60 months | 
| Quality of Life (QoL) | The quality of life between study groups and the change in quality of life over time between study groups using clinically accepted quality of life measures. Note: No subjects completed 24 months of follow-up, so this objective could not be analyzed. Two QOL questionnaires were used in the study. EQ-5D: scores typically range from 0-1, where higher scores reflect better quality of life KCCQ: scores range from 0-100, where higher scores reflect better quality of life | Assessed from baseline visit to 24-month follow-up visit | 
| Reverse Remodeling by Echocardiography | The change in LVEF between study groups. Note: No subjects completed 24 months of follow-up, so this objective could not be analyzed. | Assessed from baseline visit to 24-month follow-up visit |