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Proteinuria in a placebo-controlled study of basic fibroblast growth factor for intermittent claudication

Mayo Clinic and Foundation, Cardiovascular Division, Rochester, MN, USA, cooper.leslie{at}mayo.edu

William R Hiatt

University of Colorado Health Sciences Center, Section of Vascular Medicine and the Colorado Prevention Center, Denver, CO, USA (WRH, Novartis Foundation Professor of Cardiovascular Research)

Mark A Creager

Brigham and Women’s Hospital, Cardiovascular Division, Boston, MA, USA

Judith G Regensteiner

University of Colorado Health Sciences Center, Section of Vascular Medicine and the Colorado Prevention Center, Denver, CO, USA (WRH, Novartis Foundation Professor of Cardiovascular Research)

Ward Casscells

University of Texas at Houston, Cardiovascular Division, Houston, TX, USA

Jeffrey M Isner

Saint Elizabeth’s Hospital, Cardiovascular Division, Boston, MA, USA

John P Cooke

Stanford University Medical Center, Cardiovascular Division, Stanford, CA, USA

Alan T Hirsch

Vascular Medicine Program, University of Minnesota Vascular Diseases Center, University of Minnesota Medical School, Minneapolis, MN, USA

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 µg/kg for 6 sequential weeks (total dose 12 µg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.

Key Words: angiogenesis • claudication • growth substances • trials

Vascular Medicine, Vol. 6, No. 4, 235-239 (2001)
DOI: 10.1177/1358836X0100600406


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