Efficacy and safety of nicotinamide in patients with Friedreich´s ataxia (NICOFA)

Friedreichs ataxia (FRDA) is a rare incurable and devastating disease. The clinical presentation includes poor balance, impaired coordination, difficult articulation of speech and swallowing, distal weakness, deep sensory loss, visual and hearing impairment, but also heart failure, diabetes mellitus, scoliosis and foot deformities. Onset of disease is normally around puberty. Patients become progressively more dependent on carers and frequently die prematurely of heart disease. There is no cure or treatment that can slow down the disease which frequently results in severe disability by early adulthood. Friedreichs ataxia is an autosomal-recessive inherited disorder due to a gene mutation resulting in expansion of a repeating DNA sequence (GAA) which partially switches off the Frataxin gene. The deficiency of Frataxin causes the disease. This proposal builds on a small first study in Friedreichs ataxia patients in ten patients showing that daily high doses of nicotinamide restored the amount of Frataxin up to normal levels. This multinational study called NICOFA will investigate whether nicotinamide is an effective treatment for Friedreichs ataxia. Patients with Friedreichs ataxia will be given medication in form of tablets, either nicotinamide or placebo (ratio 2 nicotinamide: 1 placebo), and at a dose shown to be well tolerated and safe. The study will be performed double-blinded. Patients will be monitored at intervals of four to six months for two years to determine safety of the treatment and the rate of disease progression. For this purpose they will be physically examined to assess disturbances of balance, coordination and speech. This will be done using a standardized and established scoring system (the scale for assessment and rating of ataxia - SARA) which has been specifically developed and validated for ataxias. A high SARA score corresponds to a high degree of disability. We know from our previous work, studying the natural history of Friedreichs ataxia that this SARA score correlates well with the daily activities of patients and quality of life is a good measure of disease progression. Therefore, it will be used as a primary outcome measure to determine whether nicotinamide prevents or slows deterioration. Furthermore, quality of life and cognitive measures as well as functional motor assessments will be obtained. Magnetic resonance imaging will allow us to examine brain structure and function over time, with and without treatment, providing information about brain alterations in Friedreichs ataxia. An ultrasound examination of the heart and an electrocardiogram will give objective data regarding cardiac function. Statistical analysis of these measures will determine the treatment effect of nicotinamide during the two- year clinical trial in order to develop a medical treatment for this devastating neurodegenerative disease. (440 words)