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Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (the TRAFFIC study): A Randomized Trial - TRAFFIC
Description:
This was a phase II multicenter, randomized, double-blind, placebo-controlled trial designed to compare the effects of intra-arterial infusions of recombinant fibroblast growth factor-2 (rFGF-2) with placebo on exercise capacity in patients with moderate to severe lower extremity claudication.
Hypothesis:
Intra-arterial infusion of rFGF-2 will be associated with improved treadmill performance in patients with intermittent lower extremity claudication.
Study Design
Study Design:
Patients Screened: 377
Patients Enrolled: 190
Mean Follow Up: 180 days
Mean Patient Age: Mean age 67 years
Female: 25
Patient Populations:
Patients were older than 40 years, had moderate to severe claudication limiting exercise, had evidence of infra-inguinal obstructive atherosclerosis (≥70% stenosis) with patent femoral inflow, and had a resting ankle-brachial index of <0.8. To be included in the study, patients also had to have two reproducible (within 20%) Gardner treadmill examinations with peak walking time between 1 and 12 minutes.
Exclusions:
History of malignancy within 10 years, suspicion of malignancy, renal insufficiency or proteinuria, retinopathy, inflammatory or progressive fibrotic disorders, or women of childbearing potential
Primary Endpoints:
Peak walking time change from baseline to 90 days measured with a standardized Gardner treadmill protocol
Secondary Endpoints:
Peak walking time change from baseline to 180 days; claudication onset time; ankle-brachial index change from baseline to 90 and 180 days; and quality of life change from baseline to 30, 90, and 180 days
Drug/Procedures Used:
All patients underwent radiocontrast angiography of the lower extremities. Patients were randomized in a 1:1:1 fashion to single-dose, double-dose, or placebo groups.
The single-dose study drug group received rFGF-2 30 µg/kg divided evenly into each common femoral artery on day 1 and placebo on day 30. Patients randomized to the double-dose group received rFGF-2 30 µg/kg divided evenly into each common femoral artery on day 1 and day 30. Patients randomized to the placebo group received bilateral intra-arterial placebo on day 1 and day 30. All patients received a bolus of heparin (40 U/kg) 10-20 minutes before study drug or placebo.
Arterial access was usually performed via one femoral artery puncture with iliac crossover to the contralateral femoral artery. Exercise performance was measured with a standardized Gardner treadmill protocol at baseline, 90 days, and 180 days. Ankle-brachial index and quality of life (validated questionnaires) were measured at baseline, 90 days, and 180 days.
Concomitant Medications:
Aspirin (73%), other antiplatelet drugs (21%), warfarin (19%), statins (64%), beta-blockers (41%), angiotensin-converting enzyme inhibitors (49%), cilostazol (9%), and pentoxifylline (15%)
Principal Findings:
A total of 190 patients were randomized and underwent angiography. The baseline characteristics were well-balanced among the three groups, with the exception that current smokers were more common in the placebo group. Baseline angiography revealed that 86% of patients had femoropopliteal disease and 48% had multiple levels of obstruction.
At 90 days, 92% of patients underwent follow-up exercise treadmill testing. Compared with baseline, patients in the placebo group increased peak walking time by 0.6 minutes (14%) and patients in the single-dose group by 1.77 minutes (34%, p=0.026). Patients in the double-dose group increased peak walking time by 1.54 minutes (20%, p=0.45 compared with placebo). Change in peak walking time did not differ significantly among the three groups at 180 days. The change in resting ankle-brachial index from baseline was significantly greater in both study groups compared with placebo at 90 days (p=0.037 for single-dose and p=0.047 for double-dose), but this difference was not statistically significant at 180 days.
Quality of life scores did not differ significantly among the three groups at 90 days or 180 days. Prespecified subgroup analysis revealed a significant association of study drug and change in peak walking time compared with placebo among nonsmokers (p=0.045).
Adverse reactions were uncommon, but transient acute hypotension and proteinuria were more common in the groups receiving the study drug versus placebo (7% vs. 3% and 10% vs. 3%, respectively).
Interpretation:
In this randomized, double-blind, placebo-controlled trial, infusion of a single dose of intra-arterial rFGF-2 was associated with an increased improvement in peak walking time and ankle-brachial index at 90 days among patients with moderate to severe lower extremity claudication. Repeat infusion of rFGF-2 at 30 days was not associated with a significant change in peak walking times, and clinical outcomes did not differ signficantly from placebo in either group at 180 days after the initial infusion. One caveat to this study is that few patients were on other approved medical treatments for claudication such as cilostazol and pentoxifylline.
References:
Lederman RJ, Mendelsohn FO, Anderson RD, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002;359:2053-8.
Keywords: Intermittent Claudication, Follow-Up Studies, Atherosclerosis, Ankle Brachial Index, Fibroblast Growth Factor 2, Infusions, Intra-Arterial, Heparin, Hypotension, Femoral Artery, Pentoxifylline, Proteinuria, Constriction, Pathologic, Tetrazoles, Peripheral Vascular Diseases, Walking, Quality of Life, Surveys and Questionnaires, Exercise Test
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