AC6 Trial

Principal Investigator: Craig Selzman
Keywords: Gene Therapy , Heart Failure , Cardiomyopathy Department: Cardiothoracic Division
IRB Number: 00070250 Co Investigator: Anwar  Tandar
Specialty: Cardiothoracic Surgery, Cardiothoracic Surgery
Sub Specialties: Heart Stem Cell Therapy, Heart Failure
Recruitment Status: Active, not recruiting

Contact Information

Matthew  Brobeck
matthew.brobeck@hsc.utah.edu
801.581.5328

Brief Summary

Specific Aim: To test the hypothesis that intracoronary delivery of an adenovirus encoding AC6 will improve heart function and reduce symptoms in patients with Class II/III/IV CHF.

The initial clinical trial will be a randomized, double‑blinded, placebo‑controlled study to evaluate the safety, tolerability and clinical effectiveness of ascending doses of human adenovirus-5 (E1/E3-deleted, replication defective) encoding human AC6  (Ad5.hAC6) in patients with stable but severe congestive heart failure (CHF).  The vector will be delivered by intracoronary injection simultaneously with intracoronary nitroprusside, used to increase gene transfer efficiency.  We also will evaluate the effects of Ad5.hAC6 on exercise tolerance, symptom severity and right heart pressures and cardiac output measured by right heart catheterization, and by left heart pressure development before and during dobutamine infusion.  This will be predominantly a Phase 1 trial (safety and dose selection).  Patients in the highest dose groups may show evidence of reaching efficacy endpoints, but the small sample size may not provide sufficient power to establish this with certainty.

Detailed Description

The initial clinical trial will be a randomized, double‑blinded, placebo‑controlled study to evaluate the safety, tolerability and clinical effectiveness of ascending doses of human adenovirus-5 (E1/E3-deleted, replication defective) encoding human AC6 (Ad5.hAC6) in patients with stable but severe congestive heart failure (CHF). The vector will be delivered by intracoronary injection simultaneously with intracoronary nitroprusside, used to increase gene transfer efficiency. We also will evaluate the effects of Ad5.hAC6 on exercise tolerance, symptom severity and right heart pressures and cardiac output measured by right heart catheterization, and by left heart pressure development before and during dobutamine infusion. This will be predominantly a Phase 1 trial (safety and dose selection). Patients in the highest dose groups may show evidence of reaching efficacy endpoints, but the small sample size may not provide sufficient power to establish this with certainty.

Inclusion Criteria

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

  1. ≥3-month history of heart failure
  2. Compensated (stable) CHF not on intravenous inotropes, vasodilators or diuretics, on optimal medical and device therapy as defined by AHA/ACC Guidelines
  3. LV ejection fraction (on optimal therapy) of ≤40%
  4. Implanted cardiac defibrillator
  5. At least one major coronary artery (or graft) with <50% proximal obstruction

7.   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.

8.   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