PHASE III STUDY OF DOSE REGIMEN IN INITIAL NEUROLOGICAL WILSON'S DISEASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们过去的研究已经导致了FDA批准锌用于威尔森氏病维持治疗的发展。锌现在可以取代青霉胺和曲恩汀，这两种毒性更大。当威尔逊氏病患者首次出现急性铜毒性疾病时，锌的作用太慢。这些患者可能因脑损伤或肝损伤而急性发病。对于出现脑（神经）发育的患者，我们正在开发一种安全、快速、有效的新药——四硫钼酸盐（TM）。然而，在当前给药方案下，约12%的患者出现缺铜症状（贫血、白细胞减少），12%的患者出现转氨酶轻度升高。通过减少TM的剂量，这两种轻微的副作用都很容易逆转。我们开发了这种双盲方案来测试一种新的剂量方案，该方案比标准方案在更长的时间内提供更低剂量的TM，希望在保持治疗效果的同时消除这些副作用。我们将纳入所有患者（包括儿童），包括男性和女性，所有种族。他们将被随机分配标准TM方案或改良TM剂量方案。所有患者也将接受锌治疗。患者将在密歇根大学医院综合临床研究中心接受约6周的治疗，然后在家中接受另外10周的药物治疗。每两周在家抽血进行持续评估。治疗16周后，患者将返回UM进行随访。接受传统TM剂量的患者在TM治疗8周后继续进行锌维持治疗。在第16周之前，他们将服用含锌的中药安慰剂。新TM方案的患者将在TM治疗16周后过渡到锌维持治疗。如果本研究表明新的TM给药方案对于这类患者是一种较好的治疗方案，那么它将降低过度治疗和转氨酶升高的发生率，同时保留患者的神经功能。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our past research has led to the development of an FDA approval of zinc for maintenance therapy of Wilson's disease. Zinc can now replace penicillamine and trientine, which have much more toxicity. Zinc is too slow acting for treating Wilson's disease patients when they first present with acute copper toxicity illness. These patients may be acutely ill from brain damage or liver damage. For the patients presenting with brain (neurologic) development, we are well along on developing a new drug, tetrathiomolybdate (TM), which is safe, fast-acting, and effective. However, approximately 12% of patients develop symptoms of copper deficiency (anemia, leukopenia), and 12% of patients develop mild elevations in transaminase enzymes under the current dose regimen. Both of these minor side effects are readily reversible by reducing the TM dose. We have developed this double-blind protocol to test a new dose regimen, which gives a lower dose of TM over a longer period of time than the standard regimen, in the hope of eliminating these side effects while preserving the efficacy of the treatment. We will include all patients (including children), both males and females, all ethnic groups in this study. They will be randomly assigned either the standard TM regimen or the modified TM dose regimen. All patients will receive zinc as well. Patients will be in the General Clinical Research Center of University of Michigan Hospital for about 6 weeks, then receive the drugs at home for another 10 weeks. Blood will be drawn every two weeks at home for continuing evaluation. After 16 weeks of therapy, patients will return to UM for a follow-up visit. Patients receiving the traditional TM dose will be kept on zinc maintenance therapy after 8 weeks of TM. They will receive a TM-placebo with the zinc until week 16. Patients on the new TM regimen will be transitioned to zinc maintenance therapy after 16 weeks of TM treatment. If this study shows the new TM dose regimen to be a superior treatment for this kind of patient, it will decrease the incidence of overtreatment and transaminase enzyme elevations, while preserving the neurologic function of patients.