Study to Evaluate the Safety and Efficacy of JVS-100 Administered to Adults With Ischemic Heart Failure

Study Overview
=================
Brief Summary
-----------------
A phase I/II study to evaluate the safety and efficacy of JVS-100 administered by retrograde delivery to cohorts of adults with Ischemic Heart Failure.

Detailed Description
-----------------
72 subjects with ischemic cardiomyopathy. The Phase I portion (n=12 subjects) will be open label. In the first cohort, six subjects will receive a single dose of 30 mg of JVS-100 with a minimum of 3 days between each enrollment. After seven days following the enrollment of the last patient of cohort 1, a safety assessment by the DSMC will be performed. Upon DSMC approval, the second cohort of six subjects will receive a single dose of 45 mg of JVS-100 with a minimum of 3 days between each enrollment. After seven days following the enrollment of the last patient of cohort 2, a safety assessment by the DSMC will be performed. Upon DSMC approval, up to 60 subjects will be randomized (1:1:1) to receive a single dose of 30 mg or 45 mg of JVS-100 or matching placebo.

Official Title
-----------------
A Phase I/II Study to Evaluate the Safety and Efficacy of JVS-100 Administered by Retrograde Delivery to Cohorts of Adults With Ischemic Heart Failure

Conditions
-----------------
Ischemic Heart Failure

Intervention / Treatment
-----------------
* Biological: Placebo
* Biological: 30 mg dose of JVS-100
* Biological: 45 mg dose of JVS-100


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing and able to sign informed consent Greater than or equal to 18 years of age Poor quality of life as measured by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ) Impaired 6 Minute Walk test Ischemic cardiomyopathy without an acute coronary syndrome within the last 6 months Residual well-demarcated region of LV systolic dysfunction defined as at least 3 consecutive segments of abnormal wall motion by echocardiography read at the echocardiography core laboratory LVEF less than or equal to 40% measured by echocardiography read at the echocardiography core laboratory Subject receiving stable optimal pharmacological therapy defined as: ACE inhibitor and/or ARB, and Beta-blocker for 90 days with stable dose* for 30 days unless contraindicated Diuretic in subjects with evidence of fluid retention ASA unless contraindicated Statin unless contraindicated Aldosterone antagonist per physician discretion Subject must not have a permanent device placed in the coronary sinus at the time of enrollment *As defined as no more than 50% change in dose Exclusion Criteria: Planned revascularization within 30 days following enrollment Note: if an angiographic study has been performed within the last year and the subject is enrolled, the angiography study report should be included as part of the subject's file Estimated Glomerular Filtration Rate < 30 ml/min* Signs of acute heart failure within 24 hours of scheduled infusion History of aortic valve regurgitation classified as moderate-severe or worse Patients will be excluded who have: Known prior trauma to the coronary sinus In dwelling instrumentation that may hamper coronary venous catheterization, including a biventricular pacing coronary sinus lead Mitral regurgitation defined as severe measured by echocardiography at the clinical site Patients with planned mitral valve repair or replacement surgery Any patient with a history of cancer will be excluded unless: The cancer was limited to curable non-melanoma skin malignancies and/or The cancer was removed by a successful tumor resection, with or without radiation or chemotherapy treatment, 5 years or more prior to enrollment in this study without recurrence. Subjects with persistent (per ACC/AHA/EEC guidelines)53, defined as recurrent AF episodes lasting longer than 7 days) or chronic atrial fibrillation will be excluded unless: A stable, regular heart rate is maintained with a biventricular pacemaker A stable, regular heart rate is maintained with a univentricular pacemaker pacing less than or equal to 40% of the time Inability to undergo 6 minute walk or treadmill exercise test Previous solid organ transplant Subjects with greater than 40% univentricular RV Pacing Subjects with uncontrolled diabetes defined as HbA1c >10 % Participation in an experimental clinical trial within 30 days prior to enrollment Life expectancy of less than 1 year Positive pregnancy test (serum βHCG) in women of childbearing potential and/or unwillingness to use contraceptives or limit sexual activity as described in Section 8.2.1 below Unwillingness of men capable of fathering a child to agree to use barrier contraception or limit sexual activity as described in Section 8.2.1 below Subjects who are breast feeding Subjects with a positive test results for hepatitis B/C and/or HIV will be excluded unless: The subject is a carrier for hepatitis B/C but has never had an active flare Subjects with a history of Systemic Lupus Erythematosus (SLE) flare Total Serum Bilirubin >4.0 mg/dl Aspartate aminotransferase (AST) > 120 IU/L Alanine aminotransferase (ALT) > 135 IU/L Alkaline phosphatase (ALP): >300 IU/L Clinically significant elevations in PT or PTT relative to laboratory norms at day 0 Critical limb ischemia that limits the patients from completing 6 minute walk or treadmill testing Subjects with severe chronic obstructive pulmonary disease (COPD) Severe defined as having been hospitalized for COPD within the last 12 months Any subject requiring home oxygen use for treatment of the symptoms of COPD History of drug or alcohol abuse within the last year A subject will be excluded if he/she is unfit for the trial based on the discretion of the site Principal Investigator

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Biological: 30 mg dose of JVS-100<br>* Coronary Sinus Delivery<br>Biological: 45 mg dose of JVS-100<br>* Coronary Sinus Delivery<br>|
| Experimental: 30 mg dose of JVS-100<br> | Biological: Placebo<br>* Coronary Sinus Delivery<br>Biological: 45 mg dose of JVS-100<br>* Coronary Sinus Delivery<br>|
| Experimental: 45 mg dose of JVS-100<br> | Biological: Placebo<br>* Coronary Sinus Delivery<br>Biological: 30 mg dose of JVS-100<br>* Coronary Sinus Delivery<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of JVS-100 delivery on 6 minute walk distance at 4 month follow-up | To investigate the impact of single doses of JVS-100 (either 30 or 45 mg) delivered retrograde via the coronary sinus through the Oscor Venos Occlusion Balloon catheter on 6 minute walk distance compared to placebo at 4 months post dosing. | 4 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of JVS-100 delivery on heart failure symptoms compared to placebo at 4 and/or 12 month follow-up | To assess the impact of a single dose of JVS-100 on heart failure symptoms compared to placebo at 4 and/or 12 months post-dosing. | 4 and/or 12 months |