AVONEX COMBINATION TRAIL (ACT)

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。摘要：初步数据表明，MTX联合干扰素- β 1a治疗多发性硬化症（MS）患者是安全且有益的。本研究是一项多中心、随机、盲法、平行组研究，比较了AVONEX与口服甲氨蝶呤（MTX）、静脉注射甲基强的松龙或两者联合治疗的复发-缓解型多发性硬化症（MS）患者，这些患者接受AVONEX单药治疗取得突破性进展。主要终点是对疾病复发率的影响。a .具体目的：在单纯使用AVONEX治疗取得突破性进展的复发-缓解型多发性硬化症患者中，对AVONEX与AVONEX +口服甲氨蝶呤、静脉注射甲基强的松龙或两者同时进行多中心、随机、盲法、平行组研究。初步数据表明甲氨喋呤联合干扰素- β 1a是安全有益的。这些数据证明MTX与干扰素- β -1a联合的进一步研究是合理的，但目前该联合的益处和安全性尚未得到证实。这需要像这样更明确的研究。假设：重组干扰素- (AVONEX) +口服甲氨蝶呤，静脉注射甲基强的松龙，或两者兼而有之，用于复发-缓解型多发性硬化症突破性疾病的患者，单独使用AVONEX治疗可降低疾病复发率。多发性硬化症（MS）是一种慢性神经系统疾病，病理特征为中枢神经系统（CNS）局灶性炎症、脱髓鞘、轴突损伤和变性。多发性硬化症有多种临床过程。(1)大约90%的患者有复发形式的疾病，最初表现为发作性神经系统症状和疾病活动的发作（复发），中间间隔有完全或部分临床缓解期（复发-缓解型MS， RR-MS）。RR期通常持续10-15年。大多数患者最终经历一段逐渐加重的残疾，伴有或不伴有叠加复发，即继发性进行性多发性硬化症（SP-MS）。预防残疾积累（从复发不完全恢复，发展到SP期，或在SP期进展）是MS治疗的最终目标。大约10-15%的患者从发病开始逐渐恶化，没有急性复发（原发性进行性MS）或随后的叠加复发（进行性复发MS）。在过去的10年里，免疫调节剂已经在美国、加拿大和欧洲用于治疗RR-MS。尽管这些药物已被证明对治疗RR-MS有效，但一些患者仍经历持续的疾病活动。目前还没有确定的策略来治疗在使用免疫调节剂作为单药治疗期间出现突破性疾病活动的RR-MS患者。潜在的选择包括转向替代单一疗法或联合疗法。虽然一些数据支持高剂量和更频繁的干扰素- β (IFN)治疗对MS炎症方面的标志物具有短期优势，但（2-5）报道的潜在优势很小。例如，在EVIDENCE中，与接受AVONEX治疗的受试者相比，接受Serono的IFN -1a （Rebif）治疗的受试者在治疗的最初24周内保持无复发的相对风险约为1.2。(4)相比之下，许多其他研究未能显示高剂量IFN在临床或MRI终点上的获益增加。（6-15）更重要的是，以高剂量开始治疗的长期优势尚未得到证实。例如，在EVIDENCE研究中，在治疗的前24周（保持无复发的相对风险约为1.2）中，Rebif优于AVONEX的明显优势在治疗的后24周（保持无复发的相对风险约为1.0）中消失了。（3,4）因此，对于已经使用AVONEX的突破性疾病患者来说，切换到另一种IFN制剂可能没有优势。相反，可能有几个潜在的缺点。首先，患者可能不能很好地耐受每周多次高剂量的干扰素。其次，与AVONEX治疗RR-MS第二年出现的全脑萎缩减缓相反（16,17），在其他IFN制剂的一些研究中，没有任何益处，反而提示脑萎缩加速（18,19）。最后，抗IFN中和抗体（NAb）的发生率在其他IFN制剂中大幅增加。所有IFN制剂都有可能刺激NAb的产生，通常在IFN治疗开始后9-15个月。在已发表的三种IFN产品的大规模试验中，AVONEX产生的NAb反应发生率最低，滴度为bb20（2-5%）。（3,12,20 -22）其他IFN的报道频率要高得多，Betaseron¿¿的27-38%（23,24）和Rebif¿¿的13-25%。（2,3,25）在与AVONEX¿¿直接比较其他IFN的研究中，AVONEX¿¿产生NAb的倾向降低得到了证实。（3,5,15,26 -31）免疫原性的差异可能是由于IFN制剂的理化性质不同造成的。给药途径和给药频率也可能起作用。例如，如果给予SC比给予IM，每周三次比每周一次，Rebif的免疫原性更大。（32）然而，对于给定的IFN？在给定的给药途径和给药计划下，对NAb的频率没有一致的剂量效应。（2,12,23） NAb的存在对IFN治疗患者的管理很重要，因为NAb阳性患者血清中IFN浓度较低或检测不到（33），并且体内对IFN的生物反应明显降低或消失。（26,29,31,34 -36） NAb降低或取消IFN对复发的治疗益处（2,23 - 25,37 -39）和MRI。（2,23,26,40）一种IFN治疗后产生的NAb与其他IFN交叉反应（27,28,32,41 -44）。一些研究表明，切换到免疫原性较低的IFN形式（即AVONEX）可能导致NAb的损失（26,45），但其他研究尚未证实这一观察结果。（43）因此，对一种IFN产生NAb的反应不仅取消了该药物的益处，而且也取消了在该患者中使用其他IFN制剂的能力。而不是将突破性疾病的患者从AVONEX单药治疗转向另一种IFN？对于NAb（-）患者来说，一个潜在的更好的方法可能是继续使用AVONEX并添加其他免疫调节剂（例如MTX或IVMP）。联合疗法在其他免疫介导的疾病，如类风湿关节炎中取得了成功。(46、47)

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. ABSTRACT: Preliminary data suggest that MTX in combination with interferon-beta 1a is safe and of benefit for patients with MS. This study is A multi-center, randomized, blinded, parallel-group study of AVONEX¿¿ compared with AVONEX¿¿ in combination with oral methotrexate (MTX), intravenous methylprednisolone, or both in subjects with relapsing-remitting multiple sclerosis (MS) who have breakthrough disease on AVONEX¿¿ monotherapy. The primary endpoint will be effect on disease relapse rate. A. SPECIFIC AIMS: To conduct a multi-center, randomized, blinded, parallel-group study of AVONEX¿¿ Vs. AVONEX¿¿ + oral methotrexate, intravenous methylprednisolone, or both in subjects with relapsing-remitting multiple sclerosis who have breakthrough disease on AVONEX¿¿ therapy alone. Preliminary data suggest that MTX in combination with interferon-beta 1a is safe and of benefit. These data justify further study of MTX in combination with inteferon-beta-1a, but at this time the combination is of unproven benefit and safety. That requires a more definitive study such as this. Hypothesis: Recombinant interferon- (AVONEX¿¿) + oral methotrexate, intravenous methylprednisolone, or both in subjects with relapsing-remitting multiple sclerosis who have breakthrough disease on AVONEX¿¿ therapy alone will reduce the relapse rate of the disease B. BACKGROUND AND SIGNIFICANCE: Multiple sclerosis (MS) is a chronic neurologic disease, characterized pathologically by focal areas of central nervous system (CNS) inflammation, demyelination, axonal injury, and degeneration. MS follows a variety of clinical courses.(1) Approximately 90% of patients have a relapsing form of the disease, presenting initially with episodic neurological symptoms and bouts of disease activity (relapses) separated by periods of total or partial clinical remission (relapsing-remitting MS, RR-MS). The RR phase typically lasts for 10-15 years. Most patients eventually experience a subsequent period of gradually increasing disability, with or without superimposed relapses, secondary progressive MS (SP-MS). Prevention of disability accumulation (either from incomplete recovery from relapses, evolution to the SP phase, or progression during the SP phase) ultimately is the goal of therapy in MS. Approximately 10-15% of patients have gradual worsening from the onset of the disease without acute relapses (primary progressive MS) or with subsequent superimposed relapses (progressive-relapsing MS). Over the past 10 years, immunomodulatory agents have become available in the United States (US), Canada, and Europe for the treatment of RR-MS. Although these drugs are proven to be effective for the treatment of RR-MS, some patients experience continued disease activity. Currently there is no established strategy for treating patients with RR-MS who have breakthrough disease activity during treatment with an immunomodulatory agent as monotherapy. Potential options include switching to alternative monotherapy or combination therapy. While some data support a short-term advantage on markers of inflammatory aspects of MS of initiating interferon-beta (IFN ) therapy with higher doses and more frequent dosing,(2-5) the reported magnitude of the potential advantage is small. For example, in EVIDENCE, the relative risk of remaining relapse-free during the initial 24 weeks of therapy was approximately 1.2 for subjects treated with Serono's IFN -1a (Rebif¿¿) as compared to subjects treated with AVONEX¿¿.(4) In contrast, a number of other studies failed to show increased benefit of higher-dose IFN on either clinical or MRI endpoints.(6-15) More importantly, the long-term advantage of initiating treatment at higher doses is unproven. For example, in the EVIDENCE study, the apparent advantage Rebif¿¿ over AVONEX¿¿ seen during the first 24 weeks of therapy (relative risk of remaining relapse-free of approximately 1.2) was lost during the second 24 weeks of therapy (relative risk of remaining relapse-free of approximately 1.0).(3, 4) Thus, for patients with breakthrough disease already on AVONEX¿¿ there may be no advantage to switching to another IFN preparation. Rather, there may be several potential disadvantages. First, IFN s given at higher doses several times per week may not be as well tolerated by patients. Second, in contrast to the slowing of whole brain atrophy seen in the second year of AVONEX¿¿ treatment of RR-MS,(16, 17) there was no benefit but rather a suggestion of accelerated brain atrophy in some studies with the other IFN s.(18, 19) Finally, the incidence of anti-IFN neutralizing antibodies (NAb) is substantially increased with the other IFN preparations. All of the IFN preparations have the potential to stimulate the production of NAb, typically 9-15 months after IFN therapy is started. In the published large-scale trials of the three IFN products, AVONEX¿¿ generated the lowest incidence of NAb responses with titer >20 (2-5%).(3, 12, 20-22) The reported frequencies for the other IFN s were substantially higher, 27-38% for Betaseron¿¿(23, 24) and 13-25% for Rebif¿¿.(2, 3, 25) The decreased propensity of AVONEX¿¿ to generate NAb has been corroborated in studies directly comparing other IFN s with AVONEX¿¿.(3, 5, 15, 26-31) The differential immunogenicity probably results from differences in physicochemical properties of the IFN preparations. Route of administration and dosing frequency also may play a role. For example, the immunogenicity of Rebif¿¿ is greater if it is given SC vs. IM and three times per week vs. once per week.(32) However, for a given IFN? administered by a given route and dosing schedule, there has been no consistent dose effect on the frequency of NAb.(2, 12, 23) The presence of NAb is of importance in the management of patients treated with IFN , because NAb-positive patients have low or undetectable serum concentrations of IFN (33) and markedly reduced or abolished in vivo biologic response to IFN .(26, 29, 31, 34-36) NAb reduce or abolish the therapeutic benefit of IFN on relapses(2, 23-25, 37-39) and MRI.(2, 23, 26, 40) NAb generated in response to treatment with one IFN cross react with other IFN s.(27, 28, 32, 41-44) Some studies have suggested that switching to a less immunogenic form of IFN (i.e., AVONEX¿¿) may lead to loss of NAb,(26, 45) but other studies have not confirmed this observation.(43) Thus, the generation of NAb in response to one IFN not only abrogates the benefit of that agent but also the ability to use other IFN preparations in that patient. Rather than switching patients with breakthrough disease on AVONEX¿¿ monotherapy to another IFN? preparation, a potentially better approach for NAb(-) patients may be continuation of AVONEX¿¿ and addition of other immunomodulatory agents (e.g., MTX or IVMP). Combination therapy has been successful in other immune-mediated diseases, e.g., rheumatoid arthritis.(46, 47)