Evaluate Safety and Efficacy of the OPTIMIZER® System in Subjects With Moderate-to-Severe Heart Failure: FIX-HF-5C

Study Overview
=================
Brief Summary
-----------------
The objective of this investigation is to evaluate the safety and effectiveness of the OPTIMIZER® System in subjects with medically refractory moderate-to-severe heart failure.

Detailed Description
-----------------
The Impulse Dynamics FIX-HF-5C Study is a prospective, multicenter, randomized study to evaluate the safety and efficacy of cardiac contractility modulation (CCM) signals delivered by the implantable OPTIMIZER System in patients with NYHA class III and IV heart failure and an ejection fraction 25-45%. The study will involve the recruitment of 160 subjects at a total of up to 60 sites. Those subjects who fulfill all inclusion and exclusion criteria based upon baseline test results will be randomly assigned in a 1:1 ratio to either the OPTIMIZER System plus optimal medical therapy (OMT) or to a control group receiving OMT alone. All randomized subjects will be followed for 24 weeks and shall receive the same study related assessments throughout the course of the study. In addition, all subjects will continue to receive OMT for the treatment of their heart failure. Mortality will be reported out to 2 years.

Official Title
-----------------
Evaluation of the Safety and Efficacy of the OPTIMIZER® System in Subjects With Moderate-to-Severe Heart Failure With Ejection Fraction Between 25% and 45%: FIX-HF-5C

Conditions
-----------------
NYHA Class III Heart Failure, NYHA Class IV Heart Failure

Intervention / Treatment
-----------------
* Device: Optimizer System
* Other: No intervention: Optimal medical therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who are 18 years of age or older Subjects who are either male or female. Females of childbearing potential must be using a medically approved method of birth control and must agree to continue to use birth control throughout the study, or must be surgically sterilized (tubal ligation, hysterectomy) or post-menopausal for at least 1 year. Condition Subjects who have a baseline ejection fraction greater than or equal to 25% and less than or equal to 45% by echocardiography determined by the echocardiography core laboratory. Subjects who have been treated for heart failure for at least 90 days (including treatment with a β-blocker for at least 90 days unless the subject is intolerant) and are in New York Heart Association functional Class III and IV at the time of enrollment. Subjects receiving appropriate, stable medical therapy during the 30 days prior to enrollment for treatment of heart failure according to the region- specific guideline recommendations. For patients with EF≤35%, this regimen shall consist of the appropriate doses of diuretics, ACE-inhibitor or angiotensin II receptor blocker and β-blocker. Stable is defined as no more than a 100% increase or 50% decrease in dose. Subjects who, in the opinion of the Principal Investigator (based on the current guidelines for clinical practice ), have a clinical indication for an implanted cardiac defibrillator (ICD, e.g., EF≤35%) and/or pacemaker, must have an existing device or agree to undergo implantation of such a device unless the patient refuses to undergo the implantation of such device for personal reasons. Subjects who are willing and able to return for all follow-up visits. Exclusion Criteria: Subjects whose baseline peak VO2 is <9 or >20 ml O2/min/kg. Subjects who have a potentially correctible cause of heart failure, such as valvular heart disease or congenital heart disease. Subjects who have clinically significant angina pectoris, consisting of angina during daily life (i.e., Canadian Cardiovascular Society Angina score of II or more), an episode of unstable angina within 30 days of enrollment, or angina and/or ECG changes during exercise testing performed during baseline evaluation. Subjects who have been hospitalized for heart failure which required the use of inotropic support within 30 days of enrollment. Subjects who have a clinically significant amount of ambient ectopy, defined as more than 8,900 PVCs per 24 hours on baseline Holter monitoring. Subjects having a PR interval greater than 375 ms. Subjects who have chronic (permanent or persistent) atrial fibrillation or atrial flutter or those cardioverted within 30 days of enrollment. Subjects whose exercise tolerance is limited by a condition other than heart failure (e.g., angina, COPD, peripheral vascular disease, orthopedic or rheumatologic conditions) or who are unable to perform baseline stress testing. Subjects who are scheduled for a CABG or a PTCA procedure, or who have undergone a CABG procedure within 90 days or a PTCA procedure within 30 days of enrollment. Subjects who have a biventricular pacing system, an accepted indication for such a device, or a QRS width of 130ms or greater. Subjects who have had a myocardial infarction within 90 days of enrollment. Subjects who have mechanical tricuspid valve. Subjects who have a prior heart transplant. Subjects on dialysis. Subjects who are participating in another experimental protocol. Subjects who are unable to provide informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>The treatment group receives the OPTIMIZER System implant and continues with optimal heart failure medical therapy. | Device: Optimizer System<br>* The OPTIMIZER System delivers non-excitatory cardiac contractility modulating (CCM) electrical signals to the heart muscle. Treatment group subjects receive five non-contiguous one-hour periods of CCM signals per day.<br>* Other names: CCM therapy;|
| Other: Control<br>The Control group will not receive the OPTIMIZER System and will continue with optimal heart failure medical therapy. | Other: No intervention: Optimal medical therapy<br>* The control group receives optimal medical therapy only.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak VO2 | Exercise tolerance quantified by peak VO2 measured with cardiopulmonary exercise stress testing (CPX) and evaluated by a blinded core lab. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minnesota Living With Heart Failure (MLWHF) Questionnaire | Change in quality of life at 24 weeks compared to baseline, as assessed by the Minnesota Living with Heart Failure (MLWHF) Questionnaire. The MLWHFQ score could range from 0 to 105, with higher scores indicating more significant impairment in health-related quality of lif | 24 weeks | 
| Peak VO2 With Respiratory Exchange Ratio (RER) | Peak VO2 with change in respiratory exchange ratio (RER) included as a covariate, as measured by a blinded core lab. | 24 weeks | 
| NYHA | Heart failure class, as assessed by the New York Heart Association (NYHA) classification. | 24 weeks | 
| Peak VO2 With a Peak RER of ≥1.05 | Peak VO2 in an analysis that only includes tests with a peak RER of ≥1.05. | 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart Failure, Congestive Heart Failure, Chronic heart disease, Cardiac contractility modulation, CCM, CHF