title: Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.
abstract: Gene transfer has rarely been tested in randomized clinical trials.
  
  
  
  To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure.
  
  
  
  A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt) and decline (-dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization.
  
  
  
  Intracoronary administration of Ad5.hAC6 (3.2 × 109 to 1012 virus particles) or placebo.
  
  
  
  Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4 + 5).
  
  
  
  Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P = .27; 12 weeks, P = .47, respectively). The D4 + 5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n = 21; P < .004), but not 12 weeks (+3.0 [2.4] EF units; n = 21; P = .16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks. Exercise duration showed no between-group differences (4-week change from baseline: placebo, 27 [36] seconds; D4 + 5, 44 [25] seconds; P = .27; 12-week change from baseline: placebo, 44 [28] seconds; D4 + 5, 58 [29 seconds, P = .47). AC6 gene transfer increased basal left ventricular peak -dP/dt (4-week change from baseline: placebo, +93 [51] mm Hg/s; D4 + 5, -39 [33] mm Hg/s; placebo [n = 21]; P < .03); AC6 did not increase arrhythmias. The admission rate for patients with heart failure was 9.5% (4 of 42) in the AC6 group and 28.6% (4 of 14) in the placebo group (relative risk, 0.33 [95% CI, 0.08-1.36]; P = .10).
  
  
  
  AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted.
  
  
  
  clinicaltrials.gov Identifier: NCT00787059.
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: William F
authors.initials: WF
authors.lastname: Penny
authors.affiliation: Minneapolis Heart Institute, Minneapolis, Minnesota.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Traverse
authors.affiliation: Minneapolis Heart Institute, Minneapolis, Minnesota4now with Cedars Sinai Heart Institute, Los Angeles, California.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Henry
authors.affiliation: Department of Medicine, University of Vermont, Burlington.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Watkins
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Clyde W
authors.initials: CW
authors.lastname: Yancy
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ranya N
authors.initials: RN
authors.lastname: Sweis
authors.affiliation: Department of Medicine, University of California, San Diego.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Adler
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City.
authors.forename: Amit N
authors.initials: AN
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Wisconsin, Madison.
authors.forename: David R
authors.initials: DR
authors.lastname: Murray
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: Valmik
authors.initials: V
authors.lastname: Bhargava
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: Alan
authors.initials: A
authors.lastname: Maisel
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: Denise D
authors.initials: DD
authors.lastname: Barnard
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.affiliation: Department of Medicine, University of California, San Diego.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.affiliation: Department of Biostatistics, UCLA (University of California at Los Angeles).
authors.forename: Martin L
authors.initials: ML
authors.lastname: Lee
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego10now with School of Medicine, Stanford University, Palo Alto, California.
authors.forename: Sanjiv M
authors.initials: SM
authors.lastname: Narayan
authors.affiliation: Department of Medicine, University of California, San Diego.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Blanchard
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego California2Department of Medicine, University of California, San Diego.
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000262:Adenylyl Cyclases / Q000008:administration & dosage* / Q000627:therapeutic use; D000368:Aged; D006328:Cardiac Catheterization / Q000379:methods; D004452:Echocardiography; D005080:Exercise Test / Q000379:methods; D005260:Female; D018014:Gene Transfer Techniques / Q000639:trends*; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010343:Patient Admission / Q000706:statistics & numerical data; D013318:Stroke Volume / Q000187:drug effects*; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6