Assessment of CCM in HF With Higher Ejection Fraction

Study Overview
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Brief Summary
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The AIM HIGHer Clinical Trial will evaluate the safety and efficacy of Cardiac Contractility Modulation (CCM) therapy in patients with heart failure with LVEF ≥40% and ≤60%.

Detailed Description
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The AIM HIGHer Clinical Trial is a prospective, multi-center, randomized, quadruple-blind, sham-controlled, two-part embedded trial of the safety and efficacy of CCM therapy delivered via the OPTIMIZER Smart Mini System in subjects with heart failure and an LVEF ≥40% and ≤60%. Subjects will be enrolled at approximately 150 sites in the US and 75 sites OUS. All subjects will undergo screening and baseline testing; all eligible subjects will be implanted with the Optimizer System. Subjects will be randomized in a 2:1 ratio to either CCM ON (CCM group) or to CCM OFF (Sham group). The trial will be blinded to the treatment assignment of the device for 18-months. Subjects in the Sham group will have CCM turned ON after completion of the 18-month study visit. Subjects enrolled during Part I (450 subjects) of the trial will continue follow-up through the end of Part II (up to an additional 1,050) and contribute data to both parts of the trial. Each part of the trial is distinguished by a separate scientific purpose. The specific purpose of each part is: Part I - Establish safety and effectiveness based on functional capacity and health status. Part II - Establish safety and effectiveness based on clinical outcome data.

Official Title
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Assessment of Implantable CCM in the Heart Failure Group With Higher Ejection Fraction

Conditions
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Heart Failure, Heart Failure With Preserved Ejection Fraction, Heart Failure With Mid Range Ejection Fraction, Heart Failure With Moderately Reduced Ejection Fraction, Diastolic Heart Failure

Intervention / Treatment
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* Device: Cardiac Contractility Modulation Therapy via OPTIMIZER™ Smart Mini System
* Device: OPTIMIZER™ Smart Mini System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent form; Male or non-pregnant female, 18 years or older; Diagnosed with symptomatic heart failure; LVEF ≥40 and ≤60% (as assessed by echo core lab); A. Heart failure hospitalization within 12 months prior to study consent OR an urgent heart failure visit requiring IV therapy within 6 months prior to study consent, AND elevated BMI-adjusted natriuretic peptide values (Refer to Table A in Section 9.2.6) OR B. If there is no heart failure hospitalization within 12 months prior to study consent OR an urgent heart failure visit requiring IV therapy within 6 months prior to study consent, an elevated BMI-adjusted natriuretic peptide value must be achieved (Refer to Table B in Section 9.2.6) Subjects must be on stable, scheduled oral loop diuretic treatment (not only PRN) for at least 30 days prior to study consent, unless documented allergy/intolerance. Note: Stable is defined as no more than a 100% increase or 50% decrease in dose within the last 30 days. A one-time hold of diuretic dosing for 24 hours during the 30-day period is allowed and not an exclusionary event. Exclusion Criteria: Resting ventricular rate <50 or >110 bpm; Resting systolic blood pressure <100 or ≥160 mmHg; BMI greater than 46 Any severe valvular stenotic disease or any severe valvular regurgitation; Mechanical tricuspid valve; Complex congenital heart disease; Exercise tolerance limited by a condition other than heart failure that, in the opinion of the investigator, contributes significantly to the primary symptoms of shortness of breath and/or exercise intolerance; Unable to walk at least 100 meters or walks more than 450 meters during a 6MWT; A KCCQ CCS score higher than 85; Hypertrophic, infiltrative/restrictive or inflammatory cardiomyopathy; Unstable angina pectoris within 30 days prior to study consent; Acute, decompensated heart failure requiring IV therapy or ultrafiltration within 30 days prior to consent, in the hospital or an outpatient setting; Receiving cardiac resynchronization therapy (CRT); Scheduled for a cardiac surgery or a percutaneous cardiac intervention (PCI) or have undergone cardiac surgery within 90 days or a PCI procedure within 30 days prior to study consent; Myocardial infarction within 90 days prior to study consent; Prior heart transplant or ventricular assist device; Planning to become pregnant during the study; Dialysis (permanent) or GFR <20 ml/min/1.73m2; Participating in another investigational study; Currently undergoing active chemotherapeutic and/or radiation treatment for cancer or has a history of chemotherapy during the 2-year period prior to study consent; Expected lifespan of less than 18 months from time of study consent;

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
Interventional Model Description: Multicenter, multi-national, randomized, quadruple-blind, sham controlled, 2-part, embedded IDE clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CCM Group (CCM ON)<br>CCM therapy will be turned on in 2/3 of the subjects for the entire duration of the study. | Device: Cardiac Contractility Modulation Therapy via OPTIMIZER™ Smart Mini System<br>* The OPTIMIZER™ Smart Mini System will be implanted and CCM will be programmed ON for the first 18 months (blinded phase). CCM therapy will be programmed to deliver 7 one-hour phases of CCM therapy that are distributed equally over every 24-hour period. CCM will remain on following completion of the 18-month visit.<br>* Other names: CCM Group (CCM ON);|
| Sham Comparator: Sham Group (CCM OFF)<br>CCM therapy will be turned off in 1/3 of the subjects for the first 18 months of the study. After 18 months, CCM therapy will be turned on for the rest of the study duration. | Device: OPTIMIZER™ Smart Mini System<br>* The OPTIMIZER™ Smart Mini System will be implanted and CCM will be programmed OFF for the first 18 months (blinded phase). CCM will be turned on following completion of the 18-month visit.<br>* Other names: Sham Group (CCM OFF);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Efficacy Endpoint - Change in 6-minute walk distance (6MWD) from baseline to 6 months. | Demonstrate that CCM therapy improves functional capacity in subjects with symptomatic heart failure with LVEF ≥40% and ≤60%. Compare the changes in functional capacity, as measured by the 6-minute walk distance (6MWD), from baseline to 6-months following the randomization date between the two study groups. | 6 months | 
| Part 1 Efficacy Endpoint - Change in the health status from baseline to 6 months as assessed by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS). | Demonstrate that CCM therapy improves health status in subjects with symptomatic heart failure with LVEF ≥40% and ≤60%. Compare the changes in health status, as measured by the KCCQ CSS, from baseline to 6-months following the randomization date between the two study groups. | 6 months | 
| Part 1 Safety Endpoint - The incidence of Optimizer device- or procedure-related complications within the first 12 months after implant | Compare the composite incidence of Optimizer device-related and procedure-related SAEs (complications) for available data collected from implant to 12 months after the Optimizer implantation procedure to a performance goal of 75% free of complications. | 12 months | 
| Part 2 Endpoint - The hierarchical composite of mortality, morbidity, and health status outcomes (KCCQ CSS). | Demonstrate that CCM therapy improves a composite endpoint of cardiovascular mortality at 18-months, heart failure hospitalizations at 18-months, urgent heart failure visits requiring IV diuretics at 18-months and the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS) at 12-months. Comparison of a hierarchical composite endpoint between the two study groups will be based on the Finkelstein-Schoenfeld global rank method. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HFpEF, Heart failure, CCM, CCM therapy, cardiac contractility modulation, symptomatic heart failure, left ventricular ejection fraction, LVEF, Optimizer, Optimizer Smart Mini, Quality of Life