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）的竞争性续期，由国家多发性硬化症协会（RG 3915）共同资助，题为“Copaxone加雌三醇在RRMS中的联合试验”。该申请正在寻求资金以完成其目前形式的正在进行的试验，没有为任何新提出的结果测量或研究要求资金。众所周知，多发性硬化症（MS）的复发在怀孕期间明显减少，雌三醇是怀孕期间的主要雌激素。使用MS临床前模型，实验性自身免疫性脑脊髓炎（EAE），雌激素治疗，包括雌三醇，在妊娠剂量时被证明通过各种免疫机制具有抗炎作用，以及直接的神经保护作用。接下来，在一项试点临床试验中，研究表明，6名RRMS患者口服雌三醇治疗6个月后，在一系列脑mri上钆增强病变显著减少（80%），导致免疫细胞产生细胞因子的有利转变，降低免疫细胞迁移标志物基质金属蛋白酶-9 （MMP-9）的水平。6个月的治疗时间太短，无法评估治疗对复发的影响。该建议将确定口服雌三醇（妊娠期主要雌激素）与可注射的科帕松联合使用时，是否能减少RRMS患者的复发。本研究旨在为未来的第三期研究建立原理验证、安全性和参数设置，并为适当的功率计算建立标准。在一项多中心、双盲试验中，将Copaxone注射加雌三醇丸（每天8mg）联合治疗与Copaxone注射加安慰剂丸进行比较，每组65名受试者。治疗时间为2年，主要观察指标为复发率。次要结果将包括残疾测量（MSFC， EDSS， 7-24 MS生活质量，改良疲劳影响量表和贝克抑郁量表）和MRI标记（增强病变，新T2病变，萎缩）。还将采取安全措施（血液检查和妇科评估）。这项研究的总体目标是开发一种安全的口服治疗方法雌三醇，用于RRMS。

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.