Clinical trial NCT00787059: AC6 Gene Transfer for CHF
Official title: Phase I/II Study AC6 Gene Transfer for Congestive Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Congestive Heart Failure
Keywords: Adenylyl Cyclase
AC6
adenovirus
gene therapy
congestive heart failure
intracoronary
nitroprusside
Lead sponsor: Hammond, H. Kirk, M.D.
Sponsor class: INDIV
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Renova Therapeutics
First posted: 2008-11-07
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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.
timeFrame: Before, 4w, 12w
Secondary outcomes:
measure: Symptoms (KCCQ); hemodynamics; ICD discharge frequency
timeFrame: Before, 4w, 12 w
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System
state: California
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Salt Lake City
country: United States
facility: University of Utah Health Care, Utah
state: Utah
city: Burlington
country: United States
facility: Fletcher Allen Health Care
state: Vermont
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
Study officials:
affiliation: UCSD; VA San Diego Healthcare System; Veterans Medical Research Foundation
name: H. Kirk Hammond, MD
role: STUDY_DIRECTOR
affiliation: UCSD; VA San Diego Healthcare System; Veteran's Medical Research Foundation
name: William Penny, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Minneapolis Heart Institute Foundation
name: Jay H Traverse, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bluhm Cardiovascular Institute, Northwestern Memorial Hospital
name: Clyde W Yancy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fletcher Allen Health Care, University of Vermont
name: Matthew W Watkins, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Eric D Adler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: David R Murray, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah Health Care, Utah
name: Amit Patel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.