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Efficacy Study of Epoetin Alfa in Friedreich Ataxia (FRIEMAX)

Primary Purpose

Friedreich Ataxia

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Epoetin alfa
Placebo
Sponsored by
Federico II University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Friedreich Ataxia focused on measuring Erythropoietin, EPO, Friedreich, Ataxia, Epoetin alfa, VO2 max, SARA, EQ-5D, frataxin

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Università di Bari
  • Università la Sapienza, Neurologia C
  • Dipartimento di Scienze Neurologiche

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Epoetin alfa

Placebo

Arm Description

Patients will be treated with Epoetin alfa 1200 IU/Kg s.c. every 12 weeks

Placebo 1200 IU/Kg s.c. every 12 weeks

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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

Full Information

First Posted
December 15, 2011
Last Updated
August 10, 2015
Sponsor
Federico II University
Collaborators
Friedreich's Ataxia Research Alliance, Associazione Italiana per la lotta alle Sindromi Atassiche (AISA)
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1. Study Identification

Unique Protocol Identification Number
NCT01493973
Brief Title
Efficacy Study of Epoetin Alfa in Friedreich Ataxia
Acronym
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.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2015
Overall Recruitment Status
Completed
Study Start Date
January 2013 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
June 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Federico II University
Collaborators
Friedreich's Ataxia Research Alliance, Associazione Italiana per la lotta alle Sindromi Atassiche (AISA)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Friedreich Ataxia
Keywords
Erythropoietin, EPO, Friedreich, Ataxia, Epoetin alfa, VO2 max, SARA, EQ-5D, frataxin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
56 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Epoetin alfa
Arm Type
Experimental
Arm Description
Patients will be treated with Epoetin alfa 1200 IU/Kg s.c. every 12 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo 1200 IU/Kg s.c. every 12 weeks
Intervention Type
Drug
Intervention Name(s)
Epoetin alfa
Other Intervention Name(s)
EPREX 40000 IU, EPREX 10000 IU
Intervention Description
Epoetin alfa will be administered s.c. at 1200 IU/Kg every 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test (CPET)
Description
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).
Time Frame
48 weeks
Secondary Outcome Measure Information:
Title
Secondary outcome variables at the CPET (anaerobic threshold, ventilatory efficiency, exercise duration, and power output).
Time Frame
24 and 48 weeks
Title
Frataxin levels in peripheral blood mononuclear cells (PBMCs).
Time Frame
all timepoints
Title
Echocardiography
Time Frame
24, and 48 weeks
Title
Vascular reactivity
Description
Vascular reactivity will be measured by the Flow-Mediated Dilation technique (FMD)
Time Frame
24 and 48 weeks
Title
Neurological progression
Description
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)
Time Frame
24 and 48 weeks
Title
Quality of life
Description
Quality of life will be assessed with the EQ-5D, ADL, and IADL scales
Time Frame
24 and 48 weeks
Title
Safety and tolerability
Description
Safety and tolerability will be assessed by recording all serious and non serious adverse events at all visits of the trial
Time Frame
all visits

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francesco Saccà, MD
Organizational Affiliation
University Federico II, Naples Italy
Official's Role
Study Director
Facility Information:
Facility Name
Università di Bari
City
Bari
State/Province
BA
ZIP/Postal Code
70124
Country
Italy
Facility Name
Università la Sapienza, Neurologia C
City
Rome
State/Province
RM
ZIP/Postal Code
00186
Country
Italy
Facility Name
Dipartimento di Scienze Neurologiche
City
Napoli
ZIP/Postal Code
80131
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
21506154
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.
Results Reference
background
PubMed Identifier
18581197
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.
Results Reference
background
PubMed Identifier
18759345
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.
Results Reference
background
PubMed Identifier
17702040
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.
Results Reference
background
PubMed Identifier
16269021
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.
Results Reference
background
Links:
URL
http://www.neurologia.unina.it
Description
Clinical trials site
URL
http://www.unina.it
Description
University Federico II, Naples Italy
URL
http://www.curefa.org
Description
Friedreich Ataxia Research Alliance
URL
http://www.atassia.it
Description
Associazione Italiana per la lotta alle Sindromi Atassiche

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Efficacy Study of Epoetin Alfa in Friedreich Ataxia

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