AC6 Gene Transfer for CHF

Study Overview
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Brief Summary
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This research study is designed to determine: 1) whether gene transfer using an agent called Ad5.hAC6 (adenovirus-5 encoding human adenylyl cyclase type 6) can be given safely to patients with congestive heart failure (CHF) and 2) whether this agent may be of benefit in heart failure. Gene transfer is a process by which genes are introduced into cells and the cells then produce the specific protein that the gene directs, in this case, a protein known as adenylyl cyclase type 6 (AC6). The gene is carried into the heart cells by a modified virus. The virus that is modified is an adenovirus (Ad5), a virus that sometimes causes a brief cold. In extensive animal experiments, it was found that increased amounts of AC6 protein in heart cells appeared to make the heart pump more vigorously.

Detailed Description
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This research study is designed to determine: 1) whether gene transfer using an agent called Ad5.hAC6 (adenovirus-5 encoding human adenylyl cyclase type 6) can be given safely to patients with congestive heart failure (CHF) and 2) whether this agent may be of benefit in heart failure. Gene transfer is a process by which genes are introduced into cells and the cells then produce the specific protein that the gene directs, in this case, a protein known as adenylyl cyclase type 6 (AC6). The gene is carried into the heart cells by a modified virus. The virus that is modified is an adenovirus (Ad5), a virus that sometimes causes a brief cold. In extensive animal experiments, it was found that increased amounts of AC6 protein in heart cells appear to make the heart pump more vigorously.

Official Title
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Phase I/II Study AC6 Gene Transfer for Congestive Heart Failure

Conditions
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Congestive Heart Failure

Intervention / Treatment
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* Drug: Ad5.hAC6
* Drug: Sucrose (3%)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or non-pregnant female patients aged 18-80 years of age ≥3-month history of heart failure Compensated (stable) CHF not on intravenous inotropes, vasodilators or diuretics, on optimal medical and device therapy as defined by AHA/ACC Guidelines LV ejection fraction (on optimal therapy) no greater than 40% Implanted cardiac defibrillator At least one major coronary artery (or graft) with <50% proximal obstruction Patients unable to walk (spinal injury, orthopedic problems) can be enrolled if all other criteria are met. Women of child-bearing capacity must have a negative pregnancy test within 2 days of test substance administration, and female and male patients must be willing to use birth control during sex for 12w after test substance administration if the female partner is of child-bearing capacity. Subjects willingly provide informed consent consistent with ICH-GCP guidelines Exclusion Criteria Unstable or Class IV angina Coronary revascularization planned or predicted in next 6 months Ischemic myocardium in 3 or more regions of a single perfusion bed, as assessed by stress echocardiography or jeopardized viable myocardium >15% on perfusion imaging. ≥50% occlusion of an unprotected left main coronary artery. If arterial or venous conduits provide blood flow to the distal left coronary circulation (ie, patent bypass grafts) then left main disease is protected and such patients are not excluded. The cardiologist performing the cardiac catheterization will make these decisions. 2° AV Block (Mobitz 2) or 3° AV block unless pacemaker is present Hospitalization for CHF requiring intravenous inotropes or vasodilators in the past 4 weeks History of biopsy proven myocarditis Myocardial infarction in previous 6 months Restrictive, hypertrophic or infiltrative cardiomyopathy or chronic pericarditis Previous or planned organ transplant recipient or donor. Thrombocytopenia (<100,000 platelets/µl) or bleeding diathesis COPD requiring supplemental oxygen at home AST > 2 times upper limit of normal or chronic liver disease such as cirrhosis or Hepatitis C Virus (HCV). Patients with HCV are eligible only if both of two conditions are met: a) liver function tests are normal; AND b) liver biopsy is normal or shows only mild fibrosis. Current or predicted hemodialysis within 12 months or estimated glomerular filtration rate (EGFR) <30 ml/min. On online EGFR calculator that uses sex, age, body weight and serum creatinine is available at: www.kidney.org/professionals/kdoqi/gfr_calculator.cfm. Use the higher of two EGFR results, which are based upon MDRD and CKD-EPI formulas. CVA or TIA <6 months prior to enrollment Patients who are immunosuppressed by medicines (corticosteroids, methotrexate, cyclophosphamide, cyclosporine), illnesses (AIDS, HIV), or neutrophil count <1000/mm3 Patients receiving other investigational drug therapy within 30 days of enrollment including gene transfer Patients with diseases other than CHF that, in the opinion of the investigator, put the subject at risk or adversely affect the results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| Experimental: Ad5.hAC6<br>Will receive intracoronary adenovirus encoding human adenylyl cyclase type 6 | Drug: Ad5.hAC6<br>* Intracoronary delivery of test substance in 3:1 randomization (Ad5.hAC6 : placebo) with dose escalation, starting at 3.2 x 10^9 vp to 10^12 vp in 5 dose groups<br>|
| Placebo Comparator: sucrose solution<br>Will receive intracoronary sucrose solution | Drug: Sucrose (3%)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined: a) Exercise treadmill time; b) LV function by echocardiography before and during dobutamine infusion; c) Rate of LV pressure development and decline (dP/dt and -dP/dt) before and during dobutamine infusion. |  | Before, 4w, 12w | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptoms (KCCQ); hemodynamics; ICD discharge frequency |  | Before, 4w, 12 w | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenylyl Cyclase, AC6, adenovirus, gene therapy, congestive heart failure, intracoronary, nitroprusside