Elsevier

The Lancet

Volume 377, Issue 9781, 4–10 June 2011, Pages 1929-1937
The Lancet

Articles
Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia

https://doi.org/10.1016/S0140-6736(11)60394-2Get rights and content

Summary

Background

Patients with critical limb ischaemia have a high rate of amputation and mortality. We tested the hypothesis that non-viral 1 fibroblast growth factor (NV1FGF) would improve amputation-free survival.

Methods

In this phase 3 trial (EFC6145/TAMARIS), 525 patients with critical limb ischaemia unsuitable for revascularisation were enrolled from 171 sites in 30 countries. All had ischaemic ulcer in legs or minor skin gangrene and met haemodynamic criteria (ankle pressure <70 mm Hg or a toe pressure <50 mm Hg, or both, or a transcutaneous oxygen pressure <30 mm Hg on the treated leg). Patients were randomly assigned to either NV1FGF at 0·2 mg/mL or matching placebo (visually identical) in a 1:1 ratio. Randomisation was done with a central interactive voice response system by block size 4 and was stratified by diabetes status and country. Investigators, patients, and study teams were masked to treatment. Patients received eight intramuscular injections of their assigned treatment in the index leg on days 1, 15, 29, and 43. The primary endpoint was time to major amputation or death at 1 year analysed by intention to treat with a log-rank test using a multivariate Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00566657.

Findings

259 patients were assigned to NV1FGF and 266 to placebo. All 525 patients were analysed. The mean age was 70 years (range 50–92), 365 (70%) were men, 280 (53%) had diabetes, and 248 (47%) had a history of coronary artery disease. The primary endpoint or components of the primary did not differ between treatment groups, with major amputation or death in 86 patients (33%) in the placebo group, and 96 (36%) in the active group (hazard ratio 1·11, 95% CI 0·83–1·49; p=0·48). No significant safety issues were recorded.

Interpretation

TAMARIS provided no evidence that NV1FGF is effective in reduction of amputation or death in patients with critical limb ischaemia. Thus, this group of patients remains a major therapeutic challenge for the clinician.

Funding

Sanofi-Aventis, Paris, France.

Introduction

Peripheral artery disease1, 2 affects up to 20 million individuals in North America and Europe, with 2–5% developing the most severe form of the disease, critical limb ischaemia. This disorder is most often caused by atherosclerosis, but has a worse natural history than that of patients presenting with stable coronary or cerebrovascular disease. Although outcome is poorly documented, studies have supported the contention that prognosis is poor.3, 4, 5, 6 For example, 46% of patients unsuitable for revascularisation will have major amputation within 12 months,3 with the substantial morbidity that this procedure entails. 2 years after a below-knee amputation, no more than 40% of the amputees will have reached full mobility, 15% will have had contralateral amputation and 15% an above-knee amputation, and 30% will have died.4 Results from studies5, 6 have shown that the quality of life of a patient with critical limb disease equates to cancer patients with terminal disease.

In 1991, the European Working Group on Critical Limb Ischaemia concluded that no medical treatment had been shown to alter this natural history,7 and little progress has been reported since then. Despite the success of limb salvage with leg bypass, this procedure remains associated with a substantial morbidity and mortality,8 with the need for subsequent surgery and hospitalisation for wound complications as high as 50%. Furthermore, in a substantial proportion of patients, poor general health, or lack of a suitable vein for revascularisation precludes open surgery, and the multifocal distribution and extent of the arterial occlusive disease might also make both open surgical or endovascular revascularisation impossible. At present, no effective alternatives to either percutaneous or surgical revascularisation in patients with critical limb ischaemia exist.9, 10 Techniques to improve the perfusion of the ischaemic leg by less invasive means are needed. Substantial research has focused on development of therapeutic angiogenesis. In a meta-analysis11 of trials that included gene and cell-based therapies in peripheral artery disease, the investigators concluded that these therapies had the potential for clinical benefit.

Fibroblast growth factor type 1 (FGF1) modulates and enhances new blood-vessel formation12 and activates migration, proliferation, and differentiation of endothelial cells, which result in sprouting of capillaries from pre-existing vessels. Non-viral 1 (NV1) FGF (riferminogene pecaplasmid), a naked DNA plasmid that includes the gene encoding for human FGF1, given intramuscularly into the calf and thigh leads to expression of human FGF1 protein. Results from studies in human beings of intramuscular administrations of NV1FGF showed expression of FGF1, and those from studies in animals12, 13, 14 showed restoration of a functional vascular network near the site of administration.

In an open label phase 1 trial of 51 patients,15 one intramuscular administration of NV1FGF in patients with critical limb ischaemia significantly improved symptoms (pain, ulcer size) and haemodynamic variables in the treated limb.15 In the phase 2 TALISMAN trial,16 administration of NV1FGF (4 mg every 2 weeks) showed a similar improvement in ulcer healing (the primary endpoint) to that of placebo, but a 62·9% reduction of the risk of major amputation (p=0·015) and a 56% reduction of the risk of major amputation or death (p=0·009) at 12 months as compared with placebo.

The main objective of this study was to show the clinical benefit of NV1FGF in delay of the time to major amputation or death in patients with clinical limb ischaemia with non-healing ischaemic skin lesions, in whom revascularisation was not possible.

Section snippets

Patients

This TAMARIS study is a multinational, double-blind, placebo-controlled phase 3 randomised gene therapy trial (EFC6145), in critical limb ischaemia. Trial recruitment was from Dec 1, 2007, to July 31, 2009 in 171 hospitals in 30 countries. For enrolment, patients had to have critical limb ischaemia with ischaemic lesions (Fontaine stage IV), and the diagnosis confirmed by at least one haemodynamic measurement (ankle pressure <70 mm Hg or toe pressure <50 mm Hg, or transcutaneous oxygen pressure

Results

880 patients were screened during a period of 2–8 weeks to check the stability of the skin lesions and to screen for cancer and 525 were randomly assigned (figure 2). Most of these patients were at least 65 years old (364, 69%), men (365, 70%), white (481, 92%), were former or present smokers (321, 61%), and about 92 (18%) were obese (defined as a body-mass index >30 kg/m2). Key baseline patient characteristics were well balanced (table 1).18

Other manifestations of atherosclerosis were very

Discussion

The primary endpoint (fewer deaths or first major amputation of the treated leg whichever came first) was not achieved, nor were the secondary endpoints. This result contrasts with the phase 2 TALISMAN study in which significant benefit was recorded in the secondary endpoint (major amputation) and in the combined endpoint (major amputation or death, whichever came first).

Examination of the populations studied in the two trials showed no clear evidence of any baseline differences that could have

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