A Combination Trial of Copaxone plus Estriol in RRMS

描述(由申请人提供)：这是我们的RO1(NS 051591)的竞争性续签，该项目由国家多发性硬化症学会(RG3915)共同资助，题为“Copaxone加雌三醇在RRMS中的联合试验”。这项申请正在寻求资金，以完成目前的形式进行的试验，没有为任何新提出的结果措施或研究申请资金。已知多发性硬化症(MS)的复发在怀孕期间显著减少，而雌三醇是怀孕的主要雌激素。在实验性自身免疫性脑脊髓炎(EAE)的临床前模型中，孕期剂量的雌激素治疗，包括雌三醇，被证明既可以通过各种免疫机制抗炎，也可以直接保护神经。接下来，在一项试点临床试验中，研究表明，口服雌三醇治疗6个月的RRMS患者，在一系列脑磁共振成像中，Gd增强病变显著减少(80%)，导致免疫细胞产生有利的细胞因子转移，并降低免疫细胞迁移标记基质金属蛋白酶-9(MMP-9)的水平。六个月的疗程太短，无法评估复发的治疗效果。这项建议将确定口服雌三醇(妊娠的主要雌激素)与注射用科帕松联合使用是否能减少RRMS受试者的复发。这项研究旨在为未来的第三阶段研究建立原则证明、安全性和设置参数，并建立适当的功率计算标准。在一项多中心的双盲试验中，将比较科帕松注射和雌三醇丸(每天8毫克)和科帕松注射加安慰剂的联合治疗，两组各有65名受试者。疗程为两年，主要疗效指标为复发率。次要结果将包括残疾测量(MSFC、EDSS、7-24毫秒生活质量、修订的疲劳影响量表和贝克抑郁问卷)和MRI标记物(强化病变、新的T2病变、萎缩)。还将遵循安全措施(验血和妇科评估)。这项研究的总体目标将是开发一种安全的口服治疗RRMS的雌三醇。

DESCRIPTION (provided by applicant): This is a competitive renewal for our RO1 (NS 051591), which is co-funded by the National Multiple Sclerosis Society (RG 3915), entitled "A Combination Trial of Copaxone Plus Estriol in RRMS." This application is seeking funds to complete the ongoing trial its current form, with no funding requested for any newly proposed outcome measures or studies. Multiple sclerosis (MS) relapses are known to be significantly decreased during pregnancy, and estriol is a major estrogen of pregnancy. Using the preclinical model of MS, experimental autoimmune encephalomyelitis (EAE), estrogen treatments, including estriol, when administered at pregnancy doses were shown to be both anti-inflammatory through a variety of immune mechanisms, as well as directly neuroprotective. Next, in a pilot clinical trial, it was demonstrated that treatment of 6 RRMS subjects with oral estriol for six months resulted in a significant (80%) reduction in gadolinium enhancing lesions on serial brain MRIs, caused a favorable shift in cytokine production by immune cells and decreased levels of the immune cell migration marker matrix metalloprotease-9 (MMP-9). Treatment duration of six months was too short to assess treatment effects on relapses. This proposal will establish whether treatment with oral estriol, the major estrogen of pregnancy, induces a decrease in relapses in RRMS subjects when used in combination with injectable Copaxone. This study intends to establish proof-of-principle, safety and set the parameters for a future phase III study and to establish the criteria for appropriate power calculation. Combination treatment with Copaxone injection plus estriol pill (8 mg per day) will be compared to Copaxone injection plus placebo pill in a multicenter, double blinded trial, with 65 subjects in each arm. The duration of treatment will be two years and the primary outcome measure will be relapse rate. Secondary outcomes will include disability measures (MSFC, EDSS, 7-24 MS Quality of Life, Modified Fatigue Impact Scale and Beck Depression Inventory) and MRI markers (enhancing lesions, new T2 lesions, atrophy). Safety measures (blood tests and gynecologic evaluations) will also be followed. The overall goal of this study will be the development of a safe, oral treatment, estriol, for RRMS.