AC6 Gene Transfer for CHF

Congestive Heart Failure Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00787059
• Other study ID #: 365
• Secondary ID: P01HL066941
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: November 6, 2008
• Last updated: February 6, 2018
• Start date: July 2010
• Est. completion date: November 16, 2017

Study information

• Verified date: August 2017
• Source: Hammond, H. Kirk, M.D.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: November 16, 2017
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Congestive Heart Failure
• Heart Failure

Intervention

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
• Sucrose (3%)

Locations

Country	Name	City	State
United States	Fletcher Allen Health Care	Burlington	Vermont
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	University of Wisconsin-Madison	Madison	Wisconsin
United States	Minneapolis Heart Institute Foundation	Minneapolis	Minnesota
United States	University of Utah Health Care, Utah	Salt Lake City	Utah
United States	University of California, San Diego	San Diego	California
United States	VA San Diego Healthcare System	San Diego	California

Sponsors (3)

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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Symptoms (KCCQ); hemodynamics; ICD discharge frequency		Before, 4w, 12 w