THERAPY OF WILSONS DISEASE W/ TETRATHIOMOLYBDATE COMPARISON W/ TRIENTINE

四硫代钼酸盐治疗威尔逊病与曲恩汀的比较

• 批准号: 6263713
• 负责人: GEORGE J BREWER
• 金额: $ 0.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6263713
• 关键词: chelating agents; chelation therapy; clinical research; clinical trials; copper; drug adverse effect; drug screening /evaluation; hepatolenticular degeneration; human subject; human therapy evaluation; liver disorder chemotherapy; longitudinal human study; metal complex; orphan disease /drug; outcomes research

The maintenance therapy of Wilson's disease is now well covered with the recent FDA approval of zinc acetate. However, the initial therapy of patients presenting with neurologic disease is problematic. Zinc is rather slow-acting and the disease of the acutely ill patient may progress prior to zinc controlling copper toxicity. The copper chelator that has been used the longest for Wilson's disease, penicillamine, is extremely dangerous for these patients. We've shown that half of penicillamine treated patients deteriorate neurologically, with many failing to recover, probably due to redistribution of copper into the brain. The copper chelator, trientine, has seen limited use, but seems to have fewer side effects than penicillamine. Initial worsening has not yet been reported, although it is a theoretical risk with trientine.We have introduced a new orphan drug (tetrathiomolybdate, or TM) for the initial treatment of these patients. TM has ideal properties of fast action, and doesn't cause initial worsening. Supported by grants from the Orphan Products Office, we have carried out an open study of an initial 8 weeks of therapy in 51 patients. We have shown excellent initial preservation of neurological function, and excellent recovery at 1 and 2 years. Side effects have been minimal and have occurred primarily at high doses. Here we propose a 3 year, phase II/III double blind, two site, study comparing TM to trientine for initial therapy of neurologically presenting patients. We project a trial of 90 patients, 45 in each arm, but power calculations show that we can get very useful data with 60 patients. The major questions to be answered are: Is there a difference in the rate of initial neurological deterioration? Is there a difference in degree of neuological recovery at years 1 and 2? Are there differences in the incidence of serious side effects? At the completion of the study, we will not only have answered the questions relating to TM vs. trientine, but we will have characterized the efficacy and toxicity of trientine, a drug already on the market, in the initial treatment setting.

现在，Wilson病的维持疗法已被FDA近期乙酸锌的批准所覆盖。 但是，出现神经系统疾病的患者的初始治疗是有问题的。 锌的作用相当缓慢，并且在控制铜毒性之前，患者的疾病可能会进展。 用于威尔逊氏病最长的铜螯合剂，青霉素对这些患者极为危险。 我们已经表明，一半的青霉素治疗患者在神经方面恶化，许多人未能恢复，可能是由于铜重新分布到大脑中。 铜螯合剂Trientine的使用有限，但似乎比青霉素更少。 尽管这是Trientine的理论风险，但尚未报告最初的恶化。我们引入了一种新的孤儿药（Tetrathiomolybdate或TM），用于初步治疗这些患者。 TM具有快速动作的理想特性，并且不会导致初始恶化。 在孤儿产品办公室的赠款的支持下，我们对51名患者进行了8周的治疗开放研究。 我们已经显示出对神经功能的极好的初始保存，并在1和2年时表现出了出色的恢复。 副作用很小，主要发生在高剂量下。 在这里，我们提出了3年，II/III期双盲，两个地点，将TM与Trientine进行了研究，以初步治疗神经学出现的患者。 我们预测了90名患者的试验，每个手臂中有45例，但功率计算表明，我们可以与60名患者获得非常有用的数据。 要回答的主要问题是：初始神经系统恶化的速度是否有差异？ 在第1和2年度，神经恢复程度有差异吗？ 严重副作用的发生率是否有差异？ 研究完成后，我们不仅会回答与TM与Trientine有关的问题，而且我们将在最初的治疗环境中表征Trientine的功效和毒性。