NV1FGF Gene Therapy on Amputation-Free Survival in Critical Limb Ischemia - TAMARIS

Description:

The goal of the trial was to evaluate treatment with NV1FGF gene therapy compared with placebo among patients with critical limb ischemia.

NV1FGF is a nonviral recombinant DNA plasmid, containing a gene encoding FGF1, which promotes proliferation of vascular cells.

Hypothesis:

Local delivery of NV1FGF gene therapy will improve amputation-free survival.

Study Design

  • Blinded
  • Randomized
  • Placebo Controlled
  • Parallel

Patient Populations:

  • Patients at least 50 years of age with lower extremity ischemic ulcer or gangrene
  • Unsuitable for revascularization
  • Ankle pressure <70 mm Hg, or toe pressure <50 mm Hg, or a transcutaneous oxygen pressure ≤30 mm Hg in the treated leg
  • Inflow to the femoral artery confirmed by imaging
  • Negative cancer screen

    Number of enrollees: 525
    Duration of follow-up: 12 months
    Mean patient age: 71 years
    Percentage female: 31%

Exclusions:

  • Major amputation of the treated leg
  • Infected gangrene
  • Nonischemic ulcer
  • Cardiovascular event in the last 3 months
  • Proliferative retinopathy

Primary Endpoints:

  • Composite of death or major amputation at 12 months

Secondary Endpoints:

  • All amputations
  • Death
  • Ulcer healing
  • Pain relief
  • Functional status

Drug/Procedures Used:

Patients with critical limb ischemia unsuitable for revascularization were randomized to eight intramuscular injections of NV1FGF gene therapy (n = 259) versus intramuscular injections of placebo (n = 266). Injections occurred on days 1, 15, 29, and 43.

Principal Findings:

Overall, 525 patients were randomized. In the gene therapy group, the mean age was 71 years, 31% were women, 52% had diabetes, 59% were current or former smokers, 23% had prior myocardial infarction, 15% had prior stroke, and 20% had prior congestive heart failure.

Death or major amputation at 12 months occurred in 37% in the gene therapy group versus 33% in the placebo group (p = 0.48). Death occurred in 18% versus 15% (p = 0.53), and major amputation occurred in 26% versus 21% (p = 0.31), respectively. Serious adverse events occurred in 61% versus 59%, malignant neoplasm occurred in 2.6% versus 1.6% (p = 0.55), and retinal disorder occurred in 4.1% versus 5.8% (p = 0.42), respectively.

Interpretation:

Among patients with critical limb ischemia, there was no benefit (or important safety signals) at 12 months from intramuscular gene therapy compared with placebo. Treatment of patients with advanced lower extremity vascular disease remains challenging.

References:

Presented by Dr. William Hiatt at the American Heart Association Scientific Sessions, Chicago, IL, November 16, 2010.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Myocardial Infarction, Stroke, Neoplasms, Follow-Up Studies, Gangrene, Femoral Artery, Leg Ulcer, Fibroblast Growth Factor 1, DNA, Recombinant, Genetic Therapy, Plasmids, Heart Failure, Injections, Intramuscular, Oxygen, Diabetes Mellitus


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