Fast Induced Remodeling in Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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FIRE-HFpEF is a multi-center, prospective, randomized, single-blinded, clinical feasibility study. This study will enroll up to 105 subjects with heart failure with preserved ejection fraction in the United States. Data will be collected to evaluate whether pacing therapies can lead to improvements in exercise capacity and health status of subjects.

Detailed Description
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After enrollment, baseline data will be collected, and subjects will then have a pacemaker implanted. Subjects will then be randomized 1:1 to either the Atrial Ventricular Node Stimulation (AVNS) therapy or the control group, that will be applied for 24 hours and discontinued at the end of the 24-hour period. Serum biomarkers will be collected and analyzed. After 6 weeks, subjects will be randomized to either the full pacing therapy (TRT + PLR on) or the control group. At 7 months therapy modifications will be made based on initial pacing randomization assignment (full pacing therapy or modified pacing therapy), and a new randomization which applies pacing therapies (either full pacing therapy or modified pacing therapy) to all subjects will be applied. At 10 months all pacing therapy will have a final adjustment and subjects will be evaluated for their final visit at 12-months and exited from the study. Echocardiographic, functional, and health status endpoints will be collected and analyzed to assess therapy efficacy.

Official Title
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Fast Induced Remodeling in Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure With Preserved Ejection Fraction, Concentric Hypertrophy

Intervention / Treatment
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* Device: Pacemaker PLR + TRT ON
* Device: Pacemaker PLR ON


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Heart Failure, Left Ventricular Ejection Fraction (LVEF) ≥ 55% (this and other measurements must be made within the last year). New York Heart Association (NYHA) Functional Class I-III Stable on guideline-directed medical therapy (GDMT) heart failure medications as determined by the investigator, for at least 1 month, with the exception of loop diuretic therapy. GDMT should be in accordance with current American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) Guidelines and include consideration of Sodium/glucose cotransporter-2 inhibitors (SGLT2i) therapy. V End Diastolic Volume indexed to body surface area (BSA) ≤ 80 mL/m^2. Concentric remodeling or concentric hypertrophy defined as at least one of the following criteria: Left ventricular (LV) posterior or lateral wall thickness > 11mm Relative wall thickness (RWT) > 0.42 Male and LV mass indexed to BSA ≥115 g/m2 Male and LV mass indexed to height ≥ 49.2 g/m2.7 Female and LV mass indexed to BSA ≥ 95 g/m2 Female and LV mass indexed to height ≥ 46.7 g/m2.7 Exclusion Criteria: Unable or unwilling to undergo contrast MRI. Class I indication for permanent pacing, except for symptomatic chronotropic incompetence Current permanent or persistent Atrial fibrillation (A-fib) Structural heart disease requiring intervention Aortic valve replacement procedure less than 12 months prior to enrollment Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy Severe aortic or mitral valve disease, defined as severe regurgitation or a valve area < 1cm^2 Exertional angina Severe pulmonary disease including severe Chronic obstructive pulmonary disease (COPD) (i.e., requiring home oxygen, chronic nebulizer therapy, or chronic oral steroid therapy or hospitalized for pulmonary decompensation within 12 months) Estimated glomerular filtration rate (eGFR) < 25 ml/min/1.73m^2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula Uncontrolled blood pressure, defined as systolic pressure outside the range of 100 to 160 mmHg despite anti-hypertensive medication.

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: Factorial Assignment
Interventional Model Description: Eligible subjects will be randomized after baseline assessment and implanted with RAMware modified implantable pulse generator (IPG). Randomization will be 1:1 Atrial Ventricular Node Stimulation (AVNS) therapy versus control therapy (no pacing) after implant. After 6 weeks of no treatment for all subjects, subjects will be randomized 3:1 on-therapy versus off-therapy, over the first 7 months. On- therapy subjects will be further randomized 2:1 to a full pacing therapy arm or a modified pacing therapy arm for 3 months. Subjects originally randomized to the off-therapy group will start modified therapy pacing at 7 months. At 10 months, all pacing therapy will have a final adjustment and subjects will be exited as applicable at 12 months and the durability of the treatment will be tested.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pacemaker with multiple pacing therapies enabled<br>Device will be programmed for personalized lower rate pacing (PLR) and tachycardiac remodeling pacing (TRT). | Device: Pacemaker PLR + TRT ON<br>* RAMware modified implantable pulse generator (IPG) with personalized lower rate (PLR) and tachycardia remodeling therapy (TRT) on<br>Device: Pacemaker PLR ON<br>* RAMware modified implantable pulse generator (IPG) with personalized lower rate (PLR) on<br>|
| Active Comparator: Pacemaker with modified pacing therapy on<br>Device will be programmed for personalized lower rate pacing (PLR). | Device: Pacemaker PLR + TRT ON<br>* RAMware modified implantable pulse generator (IPG) with personalized lower rate (PLR) and tachycardia remodeling therapy (TRT) on<br>Device: Pacemaker PLR ON<br>* RAMware modified implantable pulse generator (IPG) with personalized lower rate (PLR) on<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular volumes as assessed by cardiac MRI compared from baseline to 7,10, and 12-month follow-up visits. |  | Through study completion, projected for three years until last subject last 12-month visit. | 
| Characterize the effect of pacing therapies on health status, defined as change in the Minnesota Living with Heart Failure Questionnaire (MLHFQ) from baseline to 3, 7, 10, and 12 months. | The Minnesota Living with Heart Failure Questionnaire (MLHFQ) is a validated patient-oriented measure of the adverse effects of heart failure on a patient's life. Each of the 21 questions are scored on a 6-point Likert Scale (0 to 5), the total score could range from 0 to 105, with higher scores indicating more significant impairment in health-related quality of life. | Through study completion, projected for three years until last subject last 12-month visit. | 
| Characterize the effect of pacing therapies on functional status, defined as change in 6-minute walk test from baseline to 7, 10, and 12 months. |  | Through study completion, projected for three years until last subject last 12-month visit. | 
| Characterize the effect of pacing therapies on functional status, defined as change in device-measured accelerometer data from baseline to 3, 7, 10, and 12 months. |  | Through study completion, projected for three years until last subject last 12-month visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize durability of changes in cardiac structure and/or health & functional status following the modification or cessation of pacing therapies at 7, 10, and 12 months. | Assess the number of crossovers and/or patients with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events v4.0 (CTCAE). | Through study completion, projected for three years until last subject last 12-month visit. | 
| Characterize the impact of AVNS therapy on changes in serum biomarkers: Tumor Necrosis Factor (TNF-α), Interleukin 6 (IL-6) Interleukin 1 beta (IL-1β) from pre-implant to 0 hours, 4 hours, 24 hours and 6 weeks post-implant. |  | From pre-implant to 0 hours, 4 hours, 24 hours and 6 weeks post-implant |