AC6 Gene Transfer for CHF

Sponsor

Hammond, H. Kirk, M.D. (Other)

Overall Status

Completed

CT.gov ID

NCT00787059

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH), Renova Therapeutics (Industry)

Enrollment

Locations

Arms

88.5

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure	Drug: Ad5.hAC6 Drug: Sucrose (3%)	Phase 1/Phase 2

Detailed Description

Study Design

Study Type:

Interventional

Actual Enrollment :

56 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2010

Actual Primary Completion Date :

Jan 1, 2015

Actual Study Completion Date :

Nov 16, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ad5.hAC6 Will receive intracoronary adenovirus encoding human adenylyl cyclase type 6	Drug: Ad5.hAC6 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
Placebo Comparator: sucrose solution Will receive intracoronary sucrose solution	Drug: Sucrose (3%)

Arm

Intervention/Treatment

Experimental: Ad5.hAC6

Will receive intracoronary adenovirus encoding human adenylyl cyclase type 6

Drug: Ad5.hAC6

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

Placebo Comparator: sucrose solution

Will receive intracoronary sucrose solution

Drug: Sucrose (3%)

Outcome Measures

Primary Outcome Measures

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

Symptoms (KCCQ); hemodynamics; ICD discharge frequency [Before, 4w, 12 w]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92037
2	VA San Diego Healthcare System	San Diego	California	United States	92161
3	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
4	Minneapolis Heart Institute Foundation	Minneapolis	Minnesota	United States	55407
5	University of Utah Health Care, Utah	Salt Lake City	Utah	United States	84132
6	Fletcher Allen Health Care	Burlington	Vermont	United States	05401
7	University of Wisconsin-Madison	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

Hammond, H. Kirk, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
Renova Therapeutics

Investigators

Study Director: H. Kirk Hammond, MD, UCSD; VA San Diego Healthcare System; Veterans Medical Research Foundation
Principal Investigator: William Penny, MD, UCSD; VA San Diego Healthcare System; Veteran's Medical Research Foundation
Principal Investigator: Jay H Traverse, MD, Minneapolis Heart Institute Foundation
Principal Investigator: Clyde W Yancy, MD, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital
Principal Investigator: Matthew W Watkins, MD, Fletcher Allen Health Care, University of Vermont
Principal Investigator: Eric D Adler, MD, University of California, San Diego
Principal Investigator: David R Murray, MD, University of Wisconsin, Madison
Principal Investigator: Amit Patel, MD, University of Utah Health Care, Utah