Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial

Abstract

Importance: Gene transfer has rarely been tested in randomized clinical trials.

Objective: To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure.

Design, setting, and participants: 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.

Interventions: Intracoronary administration of Ad5.hAC6 (3.2 × 109 to 1012 virus particles) or placebo.

Main outcomes and measures: 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).

Results: 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).

Conclusions and relevance: AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted.

Trial registration: clinicaltrials.gov Identifier: NCT00787059.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hammond reported being a founder, board member, and unpaid consultant for Renova Therapeutics, a start-up private biotechnology company. Renova had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Dr Lee reported receiving financial support from Renova Therapeutics. Dr Narayan reported equity interest in Topera, a paid consultancy with Abbott, and receiving honoraria from Medtronic, Boston Scientific, St Jude Medical Inc, and Biotronik. No other disclosures were reported.

Figures

Figure 1. Flow Diagram of Enrollment, Randomization, Follow-up, and Analysis

CVA indicates cerebrovascular accident; D4 + 5, doses 4 and 5; dP/dt, rate of left ventricular (LV) pressure development and decay; EF, ejection fraction; ETT, exercise treadmill test; and IC, intracoronary.

Figure 2. Effects of Intracoronary Administration of Adenovirus 5 Encoding Adenylyl Cyclase 6 on Left Ventricular (LV) Ejection Fraction (EF) and Exercise Duration

A, Placebo participants (baseline, n = 14; 4 and 12 weeks, n = 13) did not show significantly increased EF at 4 weeks (mean [SE] +4.1 [2.2] EF units; P = .08) or at 12 weeks (+0.8 [1.2] EF units; P = .48). Dose 4 and 5 (D4 + 5) participants (baseline, n = 23; 4 and 12 weeks, n = 21) showed increased EF at 4 weeks (+5.5 [1.7] EF units; P < .004) but less increase at 12 weeks (+3.5 [2.3] EF units; P = .16). Between-group findings for D4 + 5 and placebo were not significant (4 weeks, P = .59; 12 weeks, P = .42). B, Placebo participants (baseline, n = 14; 4 weeks, n = 13; 12 weeks, n = 12) did not have increased exercise treadmill test (ETT) duration at 4 weeks, but did at 12 weeks (P = .03). D4 + 5 participants (baseline, n = 19; 4 and 12 weeks, n = 17) showed no significant increases in ETT duration at 4 weeks (P = .10) or 12 weeks (P = .06). Error bars denote SE. Between-group findings for D4 + 5 and placebo were not significant (4 weeks, P = .70; 12 weeks, P = .94). AC6 indicates adenylyl cyclase 6.

Figure 3. Left Ventricular (LV) Pressure Development (+dP/dt), LV Decline (−dP/dt), and Symptom Scores

A, LV peak −dP/dt decreased (LV pressure decline more rapid) in D4 + 5 participants (n = 22) compared with placebo participants (n = 14) 4 weeks after treatment. This between-group difference was statistically significant (P < .03). B, There was no between-group difference in LV peak +dP/dt between 14 placebo and 21 D4 + 5 participants (P = .42). C, D4 + 5 participants (baseline, n = 22; 4 weeks, n = 23; 12 weeks, n = 22) had reduced symptoms 12 weeks after randomization (P = .0005); no significant changes were noted in the placebo group (baseline, n = 13; 4 weeks, n = 14; 12 weeks, n = 13) (P = .16). Error bars denote SE. There was no between-group difference in symptom scores between D4 + 5 and placebo at 4 weeks (P = .85) and 12 weeks (P = .24). AC6 indicates adenylyl cyclase 6.