Efficacy Study of Epoetin Alfa in Friedreich Ataxia

Friedreich Ataxia Clinical Trial

— FRIEMAX  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01493973
• Other study ID #: FA_BBK_8
• Status: Completed
• Phase: Phase 2
• First received: December 15, 2011
• Last updated: August 10, 2015
• Start date: January 2013
• Est. completion date: June 2015

Study information

• Verified date: August 2015
• Source: Federico II University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: June 2015
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Ataxia
• Cerebellar Ataxia
• Friedreich Ataxia

Intervention

Drug:
• Epoetin alfa
Epoetin alfa will be administered s.c. at 1200 IU/Kg every 12 weeks
• Placebo
Placebo

Locations

Country	Name	City	State
Italy	Università di Bari	Bari	BA
Italy	Dipartimento di Scienze Neurologiche	Napoli
Italy	Università la Sapienza, Neurologia C	Rome	RM

Sponsors (3)

Lead Sponsor	Collaborator
Federico II University	Associazione Italiana per la lotta alle Sindromi Atassiche (AISA), Friedreich's Ataxia Research Alliance

Country where clinical trial is conducted

Italy, 

References & Publications (5)

Acquaviva F, Castaldo I, Filla A, Giacchetti M, Marmolino D, Monticelli A, Pinelli M, Saccà 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. — View 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. — View 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. — View Citation

Saccà 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Secondary outcome variables at the CPET (anaerobic threshold, ventilatory efficiency, exercise duration, and power output).		24 and 48 weeks	No
Secondary	Frataxin levels in peripheral blood mononuclear cells (PBMCs).		all timepoints	No
Secondary	Echocardiography		24, and 48 weeks	No
Secondary	Vascular reactivity	Vascular reactivity will be measured by the Flow-Mediated Dilation technique (FMD)	24 and 48 weeks	No
Secondary	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	No
Secondary	Quality of life	Quality of life will be assessed with the EQ-5D, ADL, and IADL scales	24 and 48 weeks	Yes
Secondary	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	Yes

External Links

•   Associazione Italiana per la lotta alle Sindromi Atassiche
•   Clinical trials site
•   Friedreich Ataxia Research Alliance
•   University Federico II, Naples Italy