Suitability of Nitisinone in Alkaptonuria (SONIA1)

• Research type

  Research Study

• Full title

  An international, multicentre, randomised, open-label, no-treatment controlled, parallel group, dose-response study to investigate the effect of once daily nitisinone on 24-hour urinary homogentisic acid excretion in patients with alkaptonuria after 4-weeks treatment.

• IRAS ID

  121963

• Contact name

  Lakshminarayan Ranganath

• Eudract number

  2012-005340-24

• Research summary

  Alkaptonuria (AKU) is a serious, autosomal recessive, multisystem disorder. The rarity of the disease makes it an ultra-orphan indication. Morbidity in Alkaptonuria is caused by increased levels of homogentisic acid. The absence of homogentisate 1,2-dioxygenase (HGD) results in patients being unable to fully metabolize the amino acid tyrosine, resulting in high plasma levels of HGA. Nitisinone has been shown to reduce plasma HGA levels and urinary excretion in patients with AKU, but as yet the most appropriate dose has not been established. It is hypothesized that if HGA levels are reduced to, and maintained at, normal, or near normal levels in AKU patients before the onset of overt ochronosis, this might prevent the development of the debilitating clinical features of the disease. It is therefore necessary to determine the dose of Nitisinone required to achieve target HGA levels, with an acceptable safety profile. Due to its effect on the tyrosine metabolic pathway, Nitisinone also prevents the accumulation of the toxic intermediates Maleylacetoacetate (MAA) and Fumarylacetoacetate (FAA) in HT-1 patients. Plasma HGA levels and urinary excretion of HGA are closely correlated, but plasma HGA is an unreliable marker for HGA load, due to high inter- and intra-patient variability and due to lack of sufficiently sensitive assays to determine the very low levels which result from treatment with Nitisinone. Therefore, this study will investigate the effect of different doses of once daily nitisinone on 24-hour urinary homogentisic acid excretion (u-HGA24) in patients with Alkaptonuria after 4-weeks treatment.

• REC name

  North West - Liverpool Central Research Ethics Committee

• REC reference

  13/NW/0024

• Date of REC Opinion

  24 Jan 2013

• REC opinion

  Further Information Favourable Opinion