Suitability of Nitisinone in Alkaptonuria(SONIA2)
Research type
Research Study
Full title
An international, multicenter, randomized, evaluator-blinded, no-treatment controlled, parallel-group study to assess the efficacy and safety of once daily nitisinone in patients with alkaptonuria after 12 months of treatment, followed by an additional 36-month treatment period.
IRAS ID
136411
Contact name
Lakshminarayan Ranganath
Contact email
Sponsor organisation
University of Liverpool
Eudract number
2013-001633-41
Research summary
Alkaptonuria (AKU) is a serious, autosomal recessive, multisystem disorder.The rarity of the disease makes it an ultra-orphan indication.
Morbidity in AKU is caused by increased levels of homogentisic acid (2,5-dihydroxyphenylacetic acid, HGA) due to a deficient enzyme, homogentisate 1,2-dioxygenase (HGD).
Nitisinone has been shown to reduce p-HGA levels and urinary excretion of HGA in patients with AKU. However, prior to the SONIA 1 study, the clinical studies had been small and had not systematically investigated the dose-response relationship between nitisinone and HGA levels. 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.
However, it is not feasible to demonstrate this in a controlled clinical trial due to the time it takes for ochronosis to develop. Therefore, a practical approach to the development of nitisinone for the treatment of AKU is to make use of HGA as a surrogate marker as far as possible, whilst still attempting to generate robust data on clinical endpoints.
The main limitation of the biochemical surrogate marker HGA is that there is currently no clinical data to support the assumption that the control of HGA levels will prevent or arrest ochronosis. From a regulatory point of view therefore, HGA may be considered as a non-qualified surrogate, even though the rationale for a link is strong and supported by non-clinical data. For this reason, the clinical relevance of a reduction in HGA needs to be supported and the SONIA 2 study is designed to obtain clinical data using a number of clinical parameters such as the AKU Severity Score Index (AKUSSI).REC name
North West - Liverpool Central Research Ethics Committee
REC reference
13/NW/0567
Date of REC Opinion
17 Sep 2013
REC opinion
Further Information Favourable Opinion