AVONEX COMBINATION TRIAL (ACT)

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。大约90%的多发性硬化症(MS)患者有复发-缓解型(RR-MS)。这些患者最初表现为间歇性的神经症状/疾病活动，随着临床完全或部分缓解期的改变。该病的RR期通常持续10至15年，大多数患者最终会经历随后逐渐增加的残疾。防止残疾积累是多发性硬化的最终治疗方法。在过去的10年里，免疫调节剂已成为治疗RR-MS的有效药物。尽管这些药物被证明对治疗RR-MS有效，但一些患者仍有疾病活动。目前还没有确定的策略来治疗在作为单一疗法的免疫调节剂治疗期间具有突破性疾病活动性的RR-MS患者。潜在的选择包括转向替代单一疗法或联合疗法。到目前为止的研究已经表明，在这些突破性的发作中，使用更高剂量和更频繁的剂量的干扰素似乎没有太大的优势，如果有的话，在控制疾病活动方面。此外，在较高剂量下开始治疗的长期优势尚未得到证实。研究还表明，对于已经服用Avonex的突破性疾病患者来说，改用另一种β干扰素制剂可能没有优势，如倍他舒隆或Rebif。所有干扰素制剂都有可能刺激中和抗体(NAB)的产生，通常是在干扰素治疗开始后9至15个月。一种干扰素与另一种干扰素发生交叉反应产生NAB。在大型临床试验中，Avonex的NAB反应率最低。NAB的存在在接受干扰素治疗的患者的治疗中非常重要，因为NAB阳性患者的血清干扰素浓度较低或无法检测，并且对干扰素的体内生物反应显著降低或消失(即复发和磁共振成像-MRI)。对于NAB阴性患者，一个潜在的更好的方法是继续使用Avonex并添加其他免疫调节剂，如甲氨蝶呤(MTX)或静脉注射甲基强的松龙(IVMP)，而不是将单一使用Avonex的突破性疾病患者转换为另一种干扰素制剂。本研究是一项随机、安慰剂对照、2x2析因设计、联合治疗的研究，观察24个月。将受试者随机分为1或4个治疗组：第1组：Avonex每周+安慰剂每周；第2组：Avonex每周+MTX每周；第3组：Avonex每周+安慰剂+IVMP每2个月连续3天；第4组：Avonex每周+MTX每周+IVMP每2个月连续3天。复发率将通过临床评估进行评估，疾病活动将通过核磁共振进行监测。

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. Approximately 90% of patients with multiple sclerosis (MS) have a relapsing-remitting form of the disease (RR-MS). These patients present initially with episodic neurological symptoms/disease activity altering with periods of total or partial clinical remission. The RR phase of the disease typically lasts for 10 to 15 years, with most patients eventually experiencing a subsequent period of gradually increasing disability. Prevention of disability accumulation is the ultimate goad therapy in MS. Over the past 10 years, immunomodulatory agents have become available for the treatment of RR-MS. Although these drugs are proven to be effective for the treatment of RR-MS, some patients continue to have disease activity. There are no established strategies for treating patients with RR-MS who have breakthrough disease activity during treatment with an immunomodualtory agent as monotherapy. Potential options include switching to alternative monotherapy or combination therapy. Research to date has shown that using higher doses and more frequent dosing of interferon-beta (IFN¿¿) does not appear to give much advantage, if any, in controlling disease activity in these breakthrough episodes. Also, the long-term advantage of initiating treatment at higher doses is unproven. Research has also shown that for patients who have breakthrough disease that are already on Avonex, that there may be no advantage to switching to another interferon beta preparation such as Betaseron or Rebif. All IFN¿¿ preparations have the potential to stimulate the production of neutralizing antibodies (NAb), typically 9 to 15 months after IFN¿¿ therapy is started. NAb generated in response to treatment with one IFN¿¿ cross react with other IFN¿¿s. In large clinical trials, Avonex had the lowest incidence of NAb response. The presence of Nab is important in the management of patients treated with IFN¿¿, because Nab-positive patients have low or undectable serum concentrations of IFN¿¿ and markedly reduced or absent in vivo biologic response to IFN¿¿ (ie - relapses and magnetic resonance imaging - MRI). Rather than switching patients with breakthrough disease on Avonex monotherapy to another IFN¿¿ preparation, a potentially better approach for NAb negative patients may be continuation of Avonex and adding other immunomodulatory agents such as methotrexate (MTX) or intravenous methylprednisolone (IVMP). This study is a randomized, placebo-controlled, 2x2 factorial design, combination therapy study with 24 months of observation. Subjects will be randomized to 1 or 4 treatment groups: Group 1: Avonex weekly and placebo weekly; Group 2: Avonex weekly and MTX weekly; Group 3: Avonex weekly and placebo weekly and IVMP for 3 consecutive days every 2 months; Group 4: Avonex weekly and MTX weekly and IVMP for 3 consecutive days every 2 months. Relapse rates will be assessed by clinical evaluations and disease activity will be monitored by MRI.