Beta-Interferon in Chronic Viral Cardiomyopathy - BICC — Presented at AHA 2008

Nov 11, 2008
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Trial Sponsor:
Bayer Healthcare
Date Presented:
01/01/2008
Date Updated:
11/11/2008
Original Posted Date:
11/11/2008
References

Description:

Idiopathic dilated cardiomyopathy is an important cause of heart failure. Chronic viral cardiomyopathy (CVC) represents a subset of these patients, where newer molecular diagnostic techniques have enabled the demonstration of detectable levels of viral genome by polymerase chain reaction in the myocardium. In these patients, virus persistence has been associated with adverse outcomes.

BICC was a phase II clinical trial that sought to evaluate the safety and efficacy of 2 doses of beta-interferon (IFNB)-1b in the treatment of patients with proven CVC on biopsy, with adenovirus, enterovirus, and/or parvovirus.

Hypothesis:

IFNB-1b would be associated with a reduction or elimination in the viral load in patients with proven CVC on biopsy, with adenovirus, enterovirus, and/or parvovirus.

Study Design

Study Design:

Patients Screened: 368
Patients Enrolled: 143
NYHA Class: II (62.2%), III/IV (35.7%)
Mean Follow Up: 24 weeks
Mean Patient Age: 50.6 years
Female: 64
Mean Ejection Fraction: 44%

Patient Populations:

  • Evidence of virus persistence ± inflammation on endomyocardial biopsy
  • Ejection fraction >25%
  • CHF history >6 months

Exclusions:

  • Suspicion of acute myocarditis
  • Severe episodes of CHF within the preceding 8 weeks
  • EF <25%
  • Any other cardiac disease, such as coronary artery disease, hypertension, and valvular disease
  • Ventricular or supraventricular arrhythmias, which could not be stabilized by drug or device
  • Patient on transplant list
  • Antiviral, immunomodulatory, or immunosuppressive medication within the past 6 months
  • Pregnancy
  • Drug or alcohol abuse
  • Decompensated liver disease
  • History of depression
  • Interferon-specific predefined neurologic and biochemical exclusion criteria

Primary Endpoints:

  • Viral load reduction or elimination at 24 weeks

Secondary Endpoints:

  • Change in NYHA class
  • Composite clinical endpoint consisting of NYHA functional class, patient global assessment, and major adverse events
  • Change in quality of life, as assessed by the MLHF scale
  • Echocardiographic assessment of LV function (LVEF) and dimensions
  • Improvements in 6-minute walk test

Drug/Procedures Used:

Patients were randomized in a 1:1:1 fashion to either 8 million IU IFNB-1b injection every other day subcutaneously (high dose), 4 million IU IFNB-1b injection every other day subcutaneously (low dose), or placebo for 24 weeks.

Principal Findings:

A total of 143 patients were randomized, 46 to high-dose IFNB-1b, 49 to low-dose IFNB-1b, and 48 to placebo. Baseline characteristics were fairly similar between the three groups. The majority of patients had New York Heart Association (NYHA) class II symptoms.

Baseline left ventricular ejection fraction (LVEF) was about 44%, and an EF ≤40% was present in about 35% of the patients. The mean LV end-systolic dimension was about 46 mm, and the mean LV end-diastolic dimension was about 59 mm.

There was a significant reduction in the primary endpoint of viral load reduction or elimination in the IFNB-1b groups versus placebo at the end of follow-up (approximately 32% vs. 17%, odds ratio 2.33, p = 0.048), although total virus elimination was observed in only a minority of the patients. There was no difference between the efficacy of the two doses of IFNB-1b. When stratified by type of virus (adenovirus or enterovirus ± parvovirus, and parvovirus only), there was no difference between the two groups.

NYHA improvement was significantly better in the IFNB-1b group compared with placebo at 12 weeks (p = 0.013), but not at 24 weeks (p = 0.073) of follow-up. At the end of 24 weeks, there was a significant improvement in the quality of life, as assessed by the Minnesota Living with Heart Failure (MLHF) scale (p = 0.032). The effects on other endpoints such as echocardiographic and hemodynamic parameters, 6-minute walk test, inflammatory state on biopsy, and serological markers for disease, response, and virus did not achieve statistical significance. The composite clinical endpoint of patient global assessment at 24 weeks was significantly lower in the IFNB-1b arm compared with placebo (p < 0.039).

No significant safety concerns were noted with the 2 doses of IFNB-1b. The incidence of serious adverse events at 24 weeks was roughly similar between the three groups (2.3% vs. 7.0% vs. 2.3%).

Interpretation:

The results of the BICC trial indicate that IFNB-1b is associated with a nearly twofold increase in viral load reduction or elimination compared with placebo in patients with CVC from adenovirus, enterovirus, or parvovirus.

Although this is a phase II clinical trial, several questions remain. It is unclear what the optimal timing of initiation of IFNB-1b treatment should be in these patients. Also, the use of this medication requires routine endomyocardial biopsy, which brings into question the relative safety (especially when applied more broadly) and cost-effectiveness of this strategy. Results of the phase III trial are awaited.

References:

Presented by Dr. Heinz Peter Schultheiss at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Keywords: Odds Ratio, Inflammation, Enterovirus, Follow-Up Studies, Genome, Viral, Viral Load, Multiple Sclerosis, Interferon-beta, Parvovirus, Quality of Life, Heart Failure, Stroke Volume, Cardiomyopathy, Dilated, Polymerase Chain Reaction


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