Effect of Pioglitazone Administered to Patients With Friedreich's Ataxia: Proof of Concept
Condition: Friedreich's Ataxia
MeSH terms: Ataxia; Cerebellar Ataxia; Friedreich Ataxia
Study type: Interventional
Phase: Phase 3

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).
    

Intervention name(s): pioglitazone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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; a placebo administered orally once a day after the first visit and for a total of 2 years.
Other intervention name(s): Control
Intervention MeSH terms: Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Friedreich's ataxia; Pioglitazone