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Effect of Pioglitazone Administered to Patients With Friedreich's Ataxia: Proof of Concept (ACTFRIE)

Primary Purpose

Friedreich's Ataxia

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
pioglitazone
Placebo
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Friedreich's Ataxia focused on measuring Friedreich's ataxia, Pioglitazone

Eligibility Criteria

7 Years - 24 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of FA with confirmed FRDA mutations
  • GAA repeat length of the shorter allele of frataxin gene > 300
  • Age ≤ 24 years
  • Ambulatory (assistance devices permitted) or able to stand up without support
  • Neurologically symptomatic
  • All subjects agree and commit to the use of 2 reliable methods of birth control for the duration of the study if sexually active
  • Willing (and parents if minor) to participate in all aspects of trial design and follow-up
  • No modification of the usual treatment 6 months before inclusion and agree to stay with the same treatment during the trial (idebenone with a stable dosage, cardiologic therapeutic)

Exclusion Criteria:

  • Composite heterozygote
  • Patients unable to stand up even with support
  • Pregnant women
  • Cardiac insufficiency NYHA III to IV and heart ejection fraction> 50%
  • Alkaline phosphatase, SGOT or SGPT greater than 1.5 X the upper limit of normal
  • Patients with diabetes
  • Modification of the concomitant medications taken by the patient within the 6 months before inclusion or during the trial
  • Clinically significant medical disease that, in the judgment of the investigators, would expose the patient to undue risk of harm or prevent the patient from completing the study.

Sites / Locations

  • Hôpital Robert Debré

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Pioglitazone

Control

Arm Description

pioglitazone

placebo

Outcomes

Primary Outcome Measures

evaluate the efficacy of Pioglitazone on the neurological function of FA patients. Success will be defined as a stabilisation or improvement on ICARS designed as no more than 2 points maximum increment on this scale in two year.

Secondary Outcome Measures

tolerance of Pioglitazone
efficacy of Pioglitazone on neurological function
efficacy of Pioglitazone on functional handicap and quality of life
effect of Pioglitazone on cardiac parameters

Full Information

First Posted
December 18, 2008
Last Updated
September 2, 2013
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT00811681
Brief Title
Effect of Pioglitazone Administered to Patients With Friedreich's Ataxia: Proof of Concept
Acronym
ACTFRIE
Official Title
Effect of Pioglitazone Administered to Patients With Friedreich's ATAXIA:Proof of Concept
Study Type
Interventional

2. Study Status

Record Verification Date
August 2013
Overall Recruitment Status
Completed
Study Start Date
December 2008 (undefined)
Primary Completion Date
March 2013 (Actual)
Study Completion Date
March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Friedreich's ataxia (FA) is a rare progressive neurological disorder affecting approximately 1/30, 000 individuals. No treatment is presently available to counteract the neurodegeneration of this extremely severe disease. Pioglitazone, a well known PPAR gamma (peroxysome proliferators-activated receptor gamma) ligand induces the expression of many enzymes involved in the mitochondrial metabolism, including the superoxide dismutases. This agent may be therapeutic by counteracting the disabled recruitment of antioxidant enzymes in FA patients. This potential neuroprotective agent crosses the brain blood barrier in human. Primary objective: To explore the effects of Pioglitazone on neurological function in FA patients. We expect neurological benefits taking into account the natural course of the disease. Population: Subjects for this study will be limited to patients not older than 25 years Methodology: Prospective, randomized double-blind trial of Pioglitazone versus placebo in FA patients. Patients will be treated two years and will undergo clinical exams and testing during three days each six months at the clinical investigation centre.
Detailed Description
State of the art Friedreich's ataxia (FA) is a rare progressive neurological disorder affecting approximately 1/30, 000 individuals. No treatment is presently available to counteract the neurodegeneration of this extremely severe disease. The cardinal feature is a progressive gait and limb ataxia. Other commonly associated clinical signs include: dysarthria, sensory loss, distal weakness, pyramidal signs, absent reflexes, nystagmus and cardiomyopathy. Pes caves, scoliosis, diabetes and decline of vision or audition are also found in many patients. The disease often reveals before adulthood and leads to a progressive loss of autonomy about ten years after disease onset. FA is recessively inherited with a GAA trinucleotide repeat expansion in the first intron of a gene encoding frataxin a mitochondrial protein. Decreased frataxin leads to a mitochondrial iron-sulfur protein deficiency and hampered signalling pathways for superoxide dismutases, key enzymes of early antioxidant defences of the cells. As a result, cultured patient cells are particularly sensitive to oxidative insult. One aspect of the pathogenesis in vivo might be explained by this phenomenon. Pioglitazone, a well known PPAR gamma (peroxysome proliferators-activated receptor gamma) ligand induces the expression of many enzymes involved in the mitochondrial metabolism, including the superoxide dismutases. This agent may be therapeutic by counteracting the disabled recruitment of antioxidant enzymes in FA patients. This potential neuroprotective agent crosses the brain blood barrier in human. A clinical study has shown that a daily treatment with Pioglitazone during three years induced apparent clinical improvement without adverse events in multiple sclerosis patients. Pioglitazone has been shown to possibly act on neurodegeneration in humans and animals models thus it appears a promising agent to be tested in Friedreich ataxia. This agent also didn't show any peculiar toxicity in cultured human cells with low frataxin compared with control. All these facts lead us to propose a clinical trial with Pioglitazone in patients with FA. . Primary objective: To explore the effects of Pioglitazone on neurological function in FA patients. We expect neurological benefits taking into account the natural course of the disease. Population: Subjects for this study will be limited to patients not older than 25 years Methodology: Prospective, randomized double-blind trial of Pioglitazone versus placebo in FA patients. Patients will be treated two years and will undergo clinical exams and testing during three days each six months at the clinical investigation centre. Patients number justification: 20 patients in each group will be enrolled in the study with considerations to inclusion possibilities and the Bayes statistical analysis methodology. Evaluation of prior distribution of success probability per arm will be based on previous literature data and experts consensus. Primary endpoint : change in neurological testing as performed using the International Cooperative Ataxia Rating Scale (ICARS) settled down by the World Federation of Neurology. Success will be defined as a stabilisation or improvement on ICARS designed as no more than 2 points maximum increment on this scale in two years. Secondary endpoints include measurements of the following: Neurological score by the Friedreich's Ataxia Rating Scale (FARS), gait record and analysis of its components, posture study, kinetic study of the upper limbs, speech, oculomotor and auditory disorders, functional handicap using the Disability Status Scale (DSS), quality of life by SF-36 score; Cardiac involvement (electrocardiography, 24 hours holter, echocardiography with tissue doppler) and drug tolerance. Benefits expected with this clinical trial: Expected results will be reduced symptoms or stabilization of the natural evolution of this threat full progressive disease with bad prognosis in patients treated with Pioglitazone. Furthermore, study results will possibly contribute in the validation and standardization of new clinical evaluation tools used in the follow-up of Friedreich ataxia patients. Specific monitoring was initiated in all patients included in the study taking into account a potential risk of bladder cancer. All patients included in the protocol ACTFRIE, will be asked to participate in the study of tolerance. They will receive pioglitazone at a dose of 45 mg per day, until the data on the effectiveness or otherwise of this treatment, its side effects in patients with Friedreich's ataxia are known by the results of ACTFRIE testing (approximately April 2014).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Friedreich's Ataxia
Keywords
Friedreich's ataxia, Pioglitazone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pioglitazone
Arm Type
Experimental
Arm Description
pioglitazone
Arm Title
Control
Arm Type
Placebo Comparator
Arm Description
placebo
Intervention Type
Drug
Intervention Name(s)
pioglitazone
Intervention Description
administered orally once a day after the first visit and for a total of 2 years. Initially, Pioglitazone will be started at 15mg /day. Dosage will then increase by 15mg /d/ week up to the maximal dose of 45mg /day
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Control
Intervention Description
a placebo administered orally once a day after the first visit and for a total of 2 years.
Primary Outcome Measure Information:
Title
evaluate the efficacy of Pioglitazone on the neurological function of FA patients. Success will be defined as a stabilisation or improvement on ICARS designed as no more than 2 points maximum increment on this scale in two year.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
tolerance of Pioglitazone
Time Frame
2 years
Title
efficacy of Pioglitazone on neurological function
Time Frame
2 years
Title
efficacy of Pioglitazone on functional handicap and quality of life
Time Frame
2 years
Title
effect of Pioglitazone on cardiac parameters
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
24 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of FA with confirmed FRDA mutations GAA repeat length of the shorter allele of frataxin gene > 300 Age ≤ 24 years Ambulatory (assistance devices permitted) or able to stand up without support Neurologically symptomatic All subjects agree and commit to the use of 2 reliable methods of birth control for the duration of the study if sexually active Willing (and parents if minor) to participate in all aspects of trial design and follow-up No modification of the usual treatment 6 months before inclusion and agree to stay with the same treatment during the trial (idebenone with a stable dosage, cardiologic therapeutic) Exclusion Criteria: Composite heterozygote Patients unable to stand up even with support Pregnant women Cardiac insufficiency NYHA III to IV and heart ejection fraction> 50% Alkaline phosphatase, SGOT or SGPT greater than 1.5 X the upper limit of normal Patients with diabetes Modification of the concomitant medications taken by the patient within the 6 months before inclusion or during the trial Clinically significant medical disease that, in the judgment of the investigators, would expose the patient to undue risk of harm or prevent the patient from completing the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Isabelle Husson
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Robert Debré
City
Paris
ZIP/Postal Code
75019
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
31495483
Citation
Simon AL, Meyblum J, Roche B, Vidal C, Mazda K, Husson I, Ilharreborde B. Scoliosis in Patients With Friedreich Ataxia: Results of a Consecutive Prospective Series. Spine Deform. 2019 Sep;7(5):812-821. doi: 10.1016/j.jspd.2019.02.005.
Results Reference
derived

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Effect of Pioglitazone Administered to Patients With Friedreich's Ataxia: Proof of Concept

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