AC6 Gene Transfer for CHF

NCT00787059 | Completed Phase 1 DMC

• 2 other identifiers: 365P01HL066941
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 7

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.

Conditions

Congestive Heart Failure

Keywords

Adenylyl Cyclase; AC6; adenovirus; gene therapy; congestive heart failure; intracoronary; nitroprusside

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Symptoms (KCCQ); hemodynamics; ICD discharge frequency

  Before, 4w, 12 w

Study Arms (2)

Ad5.hAC6

EXPERIMENTAL

Will receive intracoronary adenovirus encoding human adenylyl cyclase type 6

Drug: Ad5.hAC6

sucrose solution

PLACEBO COMPARATOR

Will receive intracoronary sucrose solution

Drug: Sucrose (3%)

Interventions

Ad5.hAC6 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

Ad5.hAC6

Sucrose (3%) DRUG

sucrose solution

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• ° 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

Sponsors & Collaborators

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

Study Sites (7)

University of California, San Diego

San Diego, California, 92037, United States

Location

VA San Diego Healthcare System

San Diego, California, 92161, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Minneapolis Heart Institute Foundation

Minneapolis, Minnesota, 55407, United States

Location

University of Utah Health Care, Utah

Salt Lake City, Utah, 84132, United States

Location

Fletcher Allen Health Care

Burlington, Vermont, 05401, United States

Location

University of Wisconsin-Madison

Madison, Wisconsin, 53792, United States

Location

Related Publications (1)

• 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.

  PMID: 27437887 DERIVED

MeSH Terms

Conditions

Heart Failure; Adenoviridae Infections

Interventions

Sucrose

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; DNA Virus Infections; Virus Diseases; Infections

Intervention Hierarchy (Ancestors)

Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Study Officials

• H. Kirk Hammond, MD

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

  STUDY DIRECTOR

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDIV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 6, 2008
• First Posted: November 7, 2008
• Study Start: July 1, 2010
• Primary Completion: January 1, 2015
• Study Completion: November 16, 2017
• Last Updated: February 9, 2018

Record last verified: 2017-08

Locations

US (7)