AC6 Gene Transfer for CHF

NCT ID: NCT00787059

Last Updated: 2018-02-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-07-31
• Study Completion Date: 2017-11-16

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.

Detailed Description

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.

Conditions

Congestive Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ad5.hAC6

Will receive intracoronary adenovirus encoding human adenylyl cyclase type 6

Group Type: EXPERIMENTAL

Ad5.hAC6

Intervention Type: DRUG

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

sucrose solution

Will receive intracoronary sucrose solution

Group Type: PLACEBO_COMPARATOR

Sucrose (3%)

Intervention Type: DRUG

Interventions

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

Intervention Type: DRUG

Sucrose (3%)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Male or non-pregnant female patients aged 18-80 years of age

2. ≥3-month history of heart failure

3. Compensated (stable) CHF not on intravenous inotropes, vasodilators or diuretics, on optimal medical and device therapy as defined by AHA/ACC Guidelines

4. LV ejection fraction (on optimal therapy) no greater than 40%

5. Implanted cardiac defibrillator

6. At least one major coronary artery (or graft) with <50% proximal obstruction

7. Patients unable to walk (spinal injury, orthopedic problems) can be enrolled if all other criteria are met.

8. 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.

9. Subjects willingly provide informed consent consistent with ICH-GCP guidelines

Exclusion Criteria

1. Unstable or Class IV angina

2. Coronary revascularization planned or predicted in next 6 months

3. 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.

4. ≥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.

5. 2° AV Block (Mobitz 2) or 3° AV block unless pacemaker is present

6. Hospitalization for CHF requiring intravenous inotropes or vasodilators in the past 4 weeks

7. History of biopsy proven myocarditis

8. Myocardial infarction in previous 6 months

9. Restrictive, hypertrophic or infiltrative cardiomyopathy or chronic pericarditis

10. Previous or planned organ transplant recipient or donor.

11. Thrombocytopenia (<100,000 platelets/µl) or bleeding diathesis

12. COPD requiring supplemental oxygen at home

13. 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.

14. 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.

15. CVA or TIA <6 months prior to enrollment

16. Patients who are immunosuppressed by medicines (corticosteroids, methotrexate, cyclophosphamide, cyclosporine), illnesses (AIDS, HIV), or neutrophil count <1000/mm3

17. Patients receiving other investigational drug therapy within 30 days of enrollment including gene transfer

18. Patients with diseases other than CHF that, in the opinion of the investigator, put the subject at risk or adversely affect the results

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Renova Therapeutics

INDUSTRY

Sponsor Role: collaborator

Hammond, H. Kirk, M.D.

INDIV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

H. Kirk Hammond, MD

Role: STUDY_DIRECTOR

UCSD; VA San Diego Healthcare System; Veterans Medical Research Foundation

William Penny, MD

Role: PRINCIPAL_INVESTIGATOR

UCSD; VA San Diego Healthcare System; Veteran's Medical Research Foundation

Jay H Traverse, MD

Role: PRINCIPAL_INVESTIGATOR

Minneapolis Heart Institute Foundation

Clyde W Yancy, MD

Role: PRINCIPAL_INVESTIGATOR

Bluhm Cardiovascular Institute, Northwestern Memorial Hospital

Matthew W Watkins, MD

Role: PRINCIPAL_INVESTIGATOR

Fletcher Allen Health Care, University of Vermont

Eric D Adler, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Diego

David R Murray, MD

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Amit Patel, MD

Role: PRINCIPAL_INVESTIGATOR

University of Utah Health Care, Utah

Locations

University of California, San Diego

San Diego, California, United States

VA San Diego Healthcare System

San Diego, California, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Minneapolis Heart Institute Foundation

Minneapolis, Minnesota, United States

University of Utah Health Care, Utah

Salt Lake City, Utah, United States

Fletcher Allen Health Care

Burlington, Vermont, United States

University of Wisconsin-Madison

Madison, Wisconsin, United States

Countries

United States

References

Hammond HK, Penny WF, Traverse JH, Henry TD, Watkins MW, Yancy CW, Sweis RN, Adler ED, Patel AN, Murray DR, Ross RS, Bhargava V, Maisel A, Barnard DD, Lai NC, Dalton ND, Lee ML, Narayan SM, Blanchard DG, Gao MH. Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial. JAMA Cardiol. 2016 May 1;1(2):163-71. doi: 10.1001/jamacardio.2016.0008.

Reference Type: DERIVED

PMID: 27437887 (View on PubMed)

Other Identifiers

P01HL066941

Identifier Type: NIH

Identifier Source: secondary_id

View Link

365

Identifier Type: -

Identifier Source: org_study_id