尼替西农治疗尿黑酸尿症 1 型（SONIA 1）的适用性：一项国际、多中心、随机、开放标签、无治疗对照、平行分组、剂量反应研究，旨在探究尼替西农每日一次给药对治疗 4 周后尿黑酸尿症患者 24 小时尿同型胱氨酸排泄量的影响。
Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.
机构信息
Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK.
出版信息
Ann Rheum Dis. 2016 Feb;75(2):362-7. doi: 10.1136/annrheumdis-2014-206033. Epub 2014 Dec 4.
BACKGROUND
Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied.
METHODS
Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone.
FINDINGS
A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy.
CONCLUSIONS
In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range.
TRIAL REGISTRATION NUMBER
EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.
背景
尿黑酸尿症（AKU）是一种严重的遗传性疾病，其特征为早发性脊柱关节病。目前正在研究 Homogentisate 降低疗法用于 AKU。尼替西农可降低 AKU 中的 Homogentisic 酸（HGA），但以前并未研究过其剂量反应关系。
方法
尿黑酸尿症中的尼替西农适用性研究 1（SONIA 1）是一项国际性、多中心、随机、开放标签、无治疗对照、平行组、剂量反应研究。主要目的是研究每日 1 次不同剂量尼替西农治疗 4 周后对 AKU 患者 24 小时尿 HGA 排泄（u-HGA24）的影响。40 例患者随机分为 5 组，每组 8 例，分别接受无治疗或 1mg、2mg、4mg 和 8mg 尼替西农。
结果
尼替西农与 HGA 的尿排泄之间存在明显的剂量反应关系。在 4 周时，未治疗或接受 1mg、2mg、4mg 和 8mg 尼替西农治疗的患者的调整后几何均数 u-HGA24 分别为 31.53mmol、3.26mmol、1.44mmol、0.57mmol 和 0.15mmol。对于最有效的 8mg 每日剂量，与基线相比，u-HGA24 的平均降低幅度为 98.8%。所有剂量下酪氨酸水平均升高，但与 HGA 相比，剂量反应关系不太明确。尽管出现酪氨酸血症，但在接受尼替西农治疗的 4 周内没有安全性问题，也没有报告严重不良事件。
结论
在这项 AKU 患者研究中，尼替西农治疗以剂量依赖性方式降低尿 HGA 排泄至低水平，且在研究剂量范围内具有良好的耐受性。
临床试验注册号
EudraCT 编号：2012-005340-24。在 ClinicalTrials.gov 注册：NCT01828463。
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