Efficacy Study of Epoetin Alfa in Friedreich Ataxia (FRIEMAX)

• Peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test (CPET) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  Patients will undergo a complete CPET as described in the methods section. CPET will be performed at baseline (Visit 2), at 24 weeks (Visit 5), and at 48 weeks (Visit 7).
  
  

• Secondary outcome variables at the CPET (anaerobic threshold, ventilatory efficiency, exercise duration, and power output). [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
  
• Frataxin levels in peripheral blood mononuclear cells (PBMCs). [ Time Frame: all timepoints ] [ Designated as safety issue: No ]
  
• Echocardiography [ Time Frame: 24, and 48 weeks ] [ Designated as safety issue: No ]
  
• Vascular reactivity [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
  Vascular reactivity will be measured by the Flow-Mediated Dilation technique (FMD)
  
  
• Neurological progression [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
  Neurological progression will be measured with the Scale for the Assessment and Rating of Ataxia (SARA), and with the 9 hole pegboard test (9-HPT)
  
  
• Quality of life [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: Yes ]
  Quality of life will be assessed with the EQ-5D, ADL, and IADL scales
  
  
• Safety and tolerability [ Time Frame: all visits ] [ Designated as safety issue: Yes ]
  Safety and tolerability will be assessed by recording all serious and non serious adverse events at all visits of the trial
  
  

Friedreich's ataxia (FA) is an autosomal recessive ataxia caused by a trinucleotide GAA expansion in the first intron of the FXN gene. The gene encodes for a 210aa mitochondrial protein called frataxin, whose mRNA and protein levels are severely reduced in FA. It has been suggested that frataxin is involved in iron-sulphur cluster and heme biogenesis, iron binding/storage, and chaperone activity. Clinically, the age of onset is generally around puberty and, as the disease progresses, there is increasing ataxia of the limbs, and eventually most patients are wheelchair bound by the twenties. Cardiomyopathy with myocardial hypertrophy occurs very often and is the predominant cause of death. Type II diabetes, scoliosis, foot deformities, optic atrophy, and deafness are other relatively frequent symptoms.

Erythropoietin (EPO) is a glycoprotein that acts as a main regulator for erythropoiesis. Evidence suggests that both EPO and its receptor are expressed in the nervous tissue, and neuroprotective effects have been shown in animal models of cerebral ischemic damage. EPO increases frataxin levels in cultured human lymphocytes from FRDA patients. However, frataxin protein increase is not preceded by mRNA increase, suggesting that a post-transcriptional mechanism is involved. To date, four phase II clinical trials have been published regarding the use of EPO in FRDA patients.