title: Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Sanofi-Aventis, Paris, France.
authors.affiliation: The Institute of Cardiovascular Research, Vascular and Inflammatory Diseases Research Unit, Ninewells Hospital and Medical School, Dundee, UK. j.j.f.belch@dundee.ac.uk
authors.forename: Jill
authors.initials: J
authors.lastname: Belch
authors.forename: William R
authors.initials: WR
authors.lastname: Hiatt
authors.forename: Iris
authors.initials: I
authors.lastname: Baumgartner
authors.forename: I Vickie
authors.initials: IV
authors.lastname: Driver
authors.forename: Sigrid
authors.initials: S
authors.lastname: Nikol
authors.forename: Lars
authors.initials: L
authors.lastname: Norgren
authors.forename: Eric
authors.initials: E
authors.lastname: Van Belle
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000671:Amputation, Surgical; D016638:Critical Illness; D004311:Double-Blind Method; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000008:administration & dosage / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000401:mortality / Q000503:physiopathology / Q000601:surgery / Q000628:therapy*; D007866:Leg / Q000098:blood supply* / Q000601:surgery; D008297:Male; D008875:Middle Aged
chemical_list: D016220:Fibroblast Growth Factor 1