AVONEX COMBINATION TRIAL (ACT)

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 大约90%的多发性硬化症（MS）患者患有复发-缓解型疾病（RR-MS）。 这些患者最初表现为发作性神经系统症状/疾病活动，随着完全或部分临床缓解期的变化而变化。 该疾病的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期。 在过去的10年里，免疫调节剂已成为治疗RR-MS的最终目标，预防残疾积累。虽然这些药物被证明是有效的治疗RR-MS，一些患者继续有疾病活动。对于在免疫调节剂单药治疗期间出现突破性疾病活动的RR-MS患者，尚无既定的治疗策略。 潜在的选择包括转换为替代单药治疗或联合治疗。 迄今为止的研究表明，在这些突破性事件中，使用更高剂量和更频繁的干扰素β（IFN？）给药似乎并没有在控制疾病活动方面产生多大优势。 此外，以较高剂量开始治疗的长期优势尚未得到证实。 研究还表明，对于已经使用Avonex的突破性疾病患者，改用另一种干扰素β制剂（如Betaseron或Rebif）可能没有优势。 所有IFN？制剂有可能刺激中和抗体（NAb）的产生，通常在IFN治疗开始后9至15个月。 一种干扰素处理后产生的NAb与其他干扰素交叉反应。 在大型临床试验中，Avonex的NAb反应发生率最低。Nab的存在对于IFN？治疗患者的管理非常重要，因为Nab阳性患者的IFN？血清浓度较低或不可检测，并且对IFN？的体内生物学应答显著降低或缺失（即复发和磁共振成像- MRI）。 对于NAb阴性患者，可能更好的方法是继续Avonex并添加其他免疫调节剂，如甲氨蝶呤（MTX）或静脉内甲泼尼龙（IVMP），而不是将Avonex单药治疗的突破性疾病患者转换为另一种IFN？制剂。 本研究是一项随机、安慰剂对照、2x2析因设计、联合治疗研究，观察期为24个月。 受试者将被随机分配至1个或4个治疗组：第1组：Avonex每周一次和安慰剂每周一次;第2组：Avonex每周一次和MTX每周一次;第3组：Avonex每周一次和安慰剂每周一次，IVMP每2个月连续3天;第4组：Avonex每周一次和MTX每周一次，IVMP每2个月连续3天。 将通过临床评价评估复发率，并通过MRI监测疾病活动。

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.