AVONEX COMBINATION TRAIL (ACT)

AVONEX 组合路线（ACT）

• 批准号: 7376145
• 负责人: HEIDI J CRAYTON
• 金额: $ 1.6万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376145
• 关键词: AVONEX; COMBINATION; TRAIL; ACT

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)

该主题是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是针对该中心的，这不是调查人员的机构。摘要：初步数据表明，MTX与Interferon-Beta 1a结合使用是安全的，对MS患者的好处是有益的。这项研究是对Avonex€的多中心，随机，盲目的，平行组研究的研究，与Avonex€与口服方法二羟基甲酸（MTX），静脉甲基甲基甲醇酮或在患有复发性多发性硬化（MS）的受试者中相比，这是对Avonepoipe有突破性疾病的受试者。主要终点将影响疾病的救济率。 A.具体目的：进行多中心，随机，盲目的，平行组研究的Avonex€vs。 avonex¿初步数据表明，MTX与Interferon-Beta 1a结合使用是安全且有益的。这些数据证明了MTX与Inteferon-Beta-1a结合的进一步研究是合理的，但是此时，这种组合具有未经证实的好处和安全性。这需要这样的更明确的研究。假设：重组干扰素 - （Avonex¿感染，脱髓鞘，轴突损伤和变性。 MS遵循多种临床课程。（1）大约90％的患者具有这种疾病的相对形式，最初出现了疾病活动的发作性神经系统症状和疾病活动的回合（复发），该疾病（复发）由总或部分临床缓解的周期（复发缓解MS，RR-MS）分开。 RR阶段通常持续10 - 15年。大多数患者最终经历了随后逐渐增加残疾的时期，有或没有叠加的继电器，继发性MS（SP-MS）。最终，预防残疾积累（从浮雕，进化到SP阶段的进化或在SP阶段进展的不完全恢复）最终是MS治疗的目标。大约10-15％的患者在没有急性继电器（主要进行性MS）或随后的叠加继电器（渐进率降低的MS）的情况下，从疾病的发作中担心。在过去的10年中，美国，加拿大和欧洲已获得免疫调节剂，用于治疗RR-MS。尽管这些药物被证明可有效治疗RR-MS，但一些患者经历了持续的疾病活动。目前，尚无针对治疗RR-MS患者的既定策略，这些患者在以免疫调节剂为单一疗法治疗期间具有突破性的疾病活动。潜在的选择包括切换到替代性单一疗法或联合疗法。尽管某些数据支持MS的炎症方面标志物的短期优势，该标志是通过更高剂量和更频繁的给药启动干扰素β（IFN）治疗，但（2-5）报告的潜在优势的幅度很小。例如，在证据中，与用Avonex€（4）相比，用Serono的IFN -1A（Rebif ??）治疗的受试者治疗的受试者的相对风险约为1.2，相比之下（4）相反，许多其他研究未能显示出高度剂量的持续率更高的持续性或MRI Ensiat的优势（6-1 1-15）。在较高剂量下未经证实。例如，在证据研究中，在治疗的头24周中，在avonex上的明显优势（在治疗的第二个24周中，相对无继电器约1.2）的相对风险丢失了（相对无接力的相对风险，即保持大约1.0的无效的相对风险）。相反，可能有几种潜在的缺点。首先，患者的IFN剂量每周几次给予较高的剂量。第二，与在Avonex的第二年看到的整个大脑萎缩相比，RR-MS的处理（16，17）没有好处，而是在与其他IFNs。（18，19）的一些研究中提出了加速脑萎缩的建议（18，19），最后，抗IFN中性抗体（NAB）的事件与其他IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFNIFNIFNIFNIFNIFNIF。所有IFN制剂都有可能刺激NAB的产生，通常是在开始IFN治疗后9-15个月。在已发表的三种IFN产品的大规模试验中，Avonex€产生了最低的NAB响应事件，滴度> 20（2-5％）。（3，12，20-22）其他IFN S的报告频率较高，Betaseron的27-38％的Betaseron€27-38％的betaseron€（23，24）和13-25％的aveif（22.25）（22.22）（22.22）（22.22）为了生成NAB，已在直接比较其他IFNS与Avonex€（3、5、15、26-31）的研究中证实了差异免疫原性，这可能是由于IFN制剂物理性质的差异而导致的。给药途径和给药频率也可能起作用。例如，如果给出SC与IM，而每周三次，则Rebif？的免疫原性更大。（32）对于给定的IFN？通过给定的途径和给药时间表进行给药，对NAB的频率没有一致的剂量影响。（2，12，23）NAB的存在在接受IFN治疗的患者的治疗中至关重要，因为NAB阳性患者的IFN较低或不可检测的IFN（33）（33）（33）（33）（33），并且在Vivo Biologic Response中均可降低31 n-ifn。或废除IFN在继电器（2、23-25、37-39）和MRI中的治疗益处（2、23、26、40）NAB，响应于使用一个IFN交叉的治疗而产生的IFNs。（27、28、28、282、41-44）的治疗，一些研究表明，该研究较少提高到较小的IFNIM型损失（ifn ifn的损失）（i.26）。 45）但是其他研究尚未证实这一观察结果。（43），响应于一个IFN的NAB的产生不仅会使该药物的益处，而且还可以在该患者中使用其他IFN制剂。与其将AVONEX上的突破性疾病的患者转换为另一个IFN的患者？准备工作，可能是NAB（ - ）患者的一种更好的方法，可能是延续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（例如类风湿关节炎）中已经成功。（46，47）