Efficacy Study of Epoetin Alfa in Friedreich Ataxia

Study Overview
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Brief Summary
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Friedreich's ataxia (FRDA) is a rare genetic disorder characterised by severe neurological disability and cardiomyopathy. Friedreich's ataxia is the consequence of frataxin deficiency. Although several drugs have been proposed, there is no available treatment. Four trials recently demonstrated that erythropoietin can increase the intracellular levels of frataxin. The present project is aimed at testing a long term therapeutic approach using erythropoietin, which is an already available and commercialised drug. The study will test the effect of erythropoietin on exercise capacity, which is reduced in patients with FRDA. Additional objectives of the study will be the drug's safety and tolerability, and its effect on frataxin, blood vessel reactivity, heart functional indexes, and disease progression.

Detailed Description
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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.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Clinical Trial to Test the Efficacy of Epoetin Alfa on Physical Performance of Friedreich Ataxia Patients.

Conditions
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Friedreich Ataxia

Intervention / Treatment
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* Drug: Epoetin alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Molecular diagnosis of Friedreich Ataxia Age ≥12 years Body weight ≥30, ≤90 Kg SARA score ≤30 Patient able to read and sign the informed consent Patients able to perform a cardiopulmonary test Exclusion Criteria: Treatment with Erythropoietin in the previous 12 months Treatment with Idebenone Contraindications to CPET: cardiac valve disease, ischemic cardiomyopathy, atrial fibrillation, asthma, chronic obstructive pulmonary disease, other arrhythmias judged as not compatible with exercise. Any Cardiac and/or Hepatic and/or Renal disease judged as clinically relevant by the investigator Any clinically relevant ECG abnormalities that may interfere with the study Any abnormal and clinically relevant laboratory exams at screening visit that may interfere with the trial Anemia with Hemoglobin <10 g/dL Positive history for venous and/or arterial thrombosis Drug-resistant arterial hypertension Positive history for drug-resistant epilepsy Patients in treatment with not allowed study drugs (starting from 3 months prior to screening) Any acute/chronic disease that might interfere with the clinical trial, as judged by the investigator Hypersensitivity to Epoetin alfa or any other component of the study drug Patients not able to comply to the study For female patients (Sexually not active, hysterectomized, sterilized, menopause patients are excluded from the following criteria): pregnancy and/or breastfeeding and/or inadequate contraception.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epoetin alfa<br>Patients will be treated with Epoetin alfa 1200 IU/Kg s.c. every 12 weeks | Drug: Epoetin alfa<br>* Epoetin alfa will be administered s.c. at 1200 IU/Kg every 12 weeks<br>* Other names: EPREX 10000 IU;|
| Placebo Comparator: Placebo<br>Placebo 1200 IU/Kg s.c. every 12 weeks | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test (CPET) | 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). | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary outcome variables at the CPET (anaerobic threshold, ventilatory efficiency, exercise duration, and power output). |  | 24 and 48 weeks | 
| Frataxin levels in peripheral blood mononuclear cells (PBMCs). |  | all timepoints | 
| Echocardiography |  | 24, and 48 weeks | 
| Vascular reactivity | Vascular reactivity will be measured by the Flow-Mediated Dilation technique (FMD) | 24 and 48 weeks | 
| Neurological progression | 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) | 24 and 48 weeks | 
| Quality of life | Quality of life will be assessed with the EQ-5D, ADL, and IADL scales | 24 and 48 weeks | 
| Safety and tolerability | Safety and tolerability will be assessed by recording all serious and non serious adverse events at all visits of the trial | all visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Erythropoietin, EPO, Friedreich, Ataxia, Epoetin alfa, VO2 max, SARA, EQ-5D, frataxin