Clinical trial NCT01493973: Efficacy Study of Epoetin Alfa in Friedreich Ataxia
Official title: A Double-blind, Randomized, Placebo-controlled, Clinical Trial to Test the Efficacy of Epoetin Alfa on Physical Performance of Friedreich Ataxia Patients.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Friedreich Ataxia
Keywords: Erythropoietin
EPO
Friedreich
Ataxia
Epoetin alfa
VO2 max
SARA
EQ-5D
frataxin
Lead sponsor: Federico II University
Sponsor class: OTHER
Collaborators: name: Friedreich's Ataxia Research Alliance
name: Associazione Italiana per la lotta alle Sindromi Atassiche (AISA)
First posted: 2011-12-16
Enrollment: 56
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test (CPET)
timeFrame: 48 weeks
Secondary outcomes:
measure: Secondary outcome variables at the CPET (anaerobic threshold, ventilatory efficiency, exercise duration, and power output).
timeFrame: 24 and 48 weeks
measure: Frataxin levels in peripheral blood mononuclear cells (PBMCs).
timeFrame: all timepoints
measure: Echocardiography
timeFrame: 24, and 48 weeks
measure: Vascular reactivity
timeFrame: 24 and 48 weeks
measure: Neurological progression
timeFrame: 24 and 48 weeks
measure: Quality of life
timeFrame: 24 and 48 weeks
measure: Safety and tolerability
timeFrame: all visits
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Università di Bari
state: BA
city: Rome
country: Italy
facility: Università la Sapienza, Neurologia C
state: RM
city: Napoli
country: Italy
facility: Dipartimento di Scienze Neurologiche
Study officials:
affiliation: University Federico II, Naples Italy
name: Francesco Saccà, MD
role: STUDY_DIRECTOR
References:
citation: Sacca F, Piro R, De Michele G, Acquaviva F, Antenora A, Carlomagno G, Cocozza S, Denaro A, Guacci A, Marsili A, Perrotta G, Puorro G, Cittadini A, Filla A. Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit. Mov Disord. 2011 Mar;26(4):739-42. doi: 10.1002/mds.23435. Epub 2010 Nov 10.
citation: Acquaviva F, Castaldo I, Filla A, Giacchetti M, Marmolino D, Monticelli A, Pinelli M, Sacca F, Cocozza S. Recombinant human erythropoietin increases frataxin protein expression without increasing mRNA expression. Cerebellum. 2008;7(3):360-5. doi: 10.1007/s12311-008-0036-x.
citation: Boesch S, Sturm B, Hering S, Scheiber-Mojdehkar B, Steinkellner H, Goldenberg H, Poewe W. Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: a clinical pilot trial. Mov Disord. 2008 Oct 15;23(13):1940-4. doi: 10.1002/mds.22294.
citation: Boesch S, Sturm B, Hering S, Goldenberg H, Poewe W, Scheiber-Mojdehkar B. Friedreich's ataxia: clinical pilot trial with recombinant human erythropoietin. Ann Neurol. 2007 Nov;62(5):521-4. doi: 10.1002/ana.21177.
citation: Sturm B, Stupphann D, Kaun C, Boesch S, Schranzhofer M, Wojta J, Goldenberg H, Scheiber-Mojdehkar B. Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur J Clin Invest. 2005 Nov;35(11):711-7. doi: 10.1111/j.1365-2362.2005.01568.x.