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

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.