Friedreich Ataxia
Conditions
Keywords
Erythropoietin, EPO, Friedreich, Ataxia, Epoetin alfa, VO2 max, SARA, EQ-5D, frataxin
Brief summary
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
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.
Interventions
DRUGEpoetin alfa
Epoetin alfa will be administered s.c. at 1200 IU/Kg every 12 weeks
DRUGPlacebo
Placebo
Sponsors
Friedreich's Ataxia Research Alliance
Associazione Italiana per la lotta alle Sindromi Atassiche (AISA)
Federico II University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test (CPET) | 48 weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| Frataxin levels in peripheral blood mononuclear cells (PBMCs). | all timepoints | — |
| Echocardiography | 24, and 48 weeks | — |
| Vascular reactivity | 24 and 48 weeks | Vascular reactivity will be measured by the Flow-Mediated Dilation technique (FMD) |
| Secondary outcome variables at the CPET (anaerobic threshold, ventilatory efficiency, exercise duration, and power output). | 24 and 48 weeks | — |
| Quality of life | 24 and 48 weeks | Quality of life will be assessed with the EQ-5D, ADL, and IADL scales |
| Safety and tolerability | all visits | Safety and tolerability will be assessed by recording all serious and non serious adverse events at all visits of the trial |
| Neurological progression | 24 and 48 weeks | 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) |
Countries
Italy
Outcome results
None listed