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AGENT - AGENT
Description:
The goal of the Angiogenic Gene Therapy (AGENT) trial was to assess the safety and efficacy of angiogenesis therapy with a human fibroblast growth factor gene among patients with chronic stable angina, and to select safe and effective doses of the gene for future studies.
Hypothesis:
Angiogenesis therapy with a replication-defective adenovirus containing a human fibroblast growth factor (FGF) gene (Ad5-FGF4) would provide significant anti-ischemic effects without major adverse effects.
Study Design
Study Design:
Patients Enrolled: 79
Mean Follow Up: 12 weeks
Mean Patient Age: 30-75 years
Female: 10
Mean Ejection Fraction: >40%
Patient Populations:
Patients 30 to 75 years old with chronic stable angina, Canadian Cardiovascular Society angina class II or III, stable for >2 months, who were able to exercise for at least three minutes on an ETT using the modified Balke protocol, were enrolled. Patients were required to show 1 mm of ST-segment change (horizontal or downsloping) and stop exercise for angina severity of 3 on a scale of 1-4 during screening ETT, with exercise time that differed by <25% on="" two="" consecutive="" baseline="" tests="" on="" separate="" days.="" patients="" with="" one-,="" two-,="" or="" three-vessel="" coronary="" artery="" disease="" were="" included,="" provided="" that="" at="" least="" one="" proximal="" major="" vessel="" had="">/70%>
Exclusions:
Cardiovascular exclusion criteria: left main stenosis >50%, coronary aorto-ostial stenosis that would prevent catheter placement, ejection fraction <40%, patent="" bypass="" grafts,="" cabg="" surgery="" within="" one="" year,="" angioplasty="" within="" six="" months,="" transmyocardial="" revascularization,="" unstable="" angina,="" new="" york="" heart="" association="" congestive="" heart="" failure="" class="" iii="" or="" iv,="" left="" bundle="" branch="" block,="" paced="" rhythm,="" mobitz="" 2="" second-degree="" or="" greater="" heart="" block,="" documented="" life-threatening="" ventricular="" arrhythmia,="" atrial="" fibrillation,="" and="" patients="" who="" required="" immediate="" revascularization="" at="" the="" time="" of="" coronary="" angiography.="">
Other exclusion criteria: childbearing potential (for women), diabetic retinopathy, suspicion of malignancy, history of malignancy within 10 years except basal cell carcinoma, creatinine clearance <45 ml/min="" by="" cockcroft-gault="" formula,="" proteinuria="">2+, human immunodeficiency virus positivity, immunosuppressive therapy, abnormal liver function, or hepatitis B or C.
Primary Endpoints:
Change in exercise capacity, as measured by an exercise treadmill test (ETT) using the modified Balke protocol performed at four and 12 weeks after administration of the Ad5-FGF4, and safety, as measured by the incidence of serious adverse events defined as unstable angina, hepatotoxicity, and malignancy.
Secondary Endpoints:
Fever
Drug/Procedures Used:
Eligible patients were randomized to receive placebo or one of six ascending doses of Ad5-FGF4 delivered via one-time intracoronary infusions (3.3 x 108 to 1011 viral particles).
Principal Findings:
There was not a significant increase in exercise time at four and 12 weeks between the pooled treatment group and the placebo group. When the patients who had a baseline exercise time of >10 minutes were excluded, however, there was a significant difference in the increase in exercise time in the placebo group versus the pooled treatment group at four weeks (12% vs. 27%, p=0.01) and 12 weeks (22% vs. 30%, p=0.047).
Additionally, individuals in the pooled treatment group who had low initial neutralizing titers to adenovirus (<1:100) runat="server" xmlns:1="http://www.sitecore.net/xhtml"><0.05). there="" was="" also="" no="" significant="" difference="" between="" the="" two="" groups="" in="" incidence="" of="" serious="" events="" during="" follow-up="" period.="">
Interpretation:
Among patients with chronic stable angina, angiogenesis therapy with Ad5-FGF4 is safe, and in patients with a baseline exercise time <10 minutes,="" was="" associated="" with="" a="" significant="" increase="" in="" exercise="" time="" when="" compared="" to="" placebo.="" however,="" there="" was="" no="" difference="" in="" exercise="" time="" in="" the="" analysis="" of="" all="" patients,="" including="" those="" with="" baseline="" exercise="" time="">10 minutes.
References:
Grines CL, Watkins MW, Helmer G, et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002;105:1291-7.
Keywords: Coronary Artery Disease, DNA, Antisense, Genetic Therapy, Angina, Stable, Fibroblast Growth Factors, Virion
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