A Combination Trial of Copaxone plus Estriol in RRMS

描述（由申请人提供）：这是我们的RO 1（NS 051591）的竞争性更新，该项目由国家多发性硬化症协会（RG 3915）共同资助，题为“RRMS中Copaxone+雌三醇的联合试验”。“这项申请正在寻求资金来完成目前形式的正在进行的试验，没有为任何新提出的结果措施或研究申请资金。 多发性硬化症（MS）复发是众所周知的显着减少在怀孕期间，雌三醇是一种主要的雌激素怀孕。使用MS的临床前模型，实验性自身免疫性脑脊髓炎（EAE），雌激素治疗，包括雌三醇，当以妊娠剂量给药时，显示出通过各种免疫机制抗炎，以及直接神经保护。接下来，在一项初步临床试验中，证明了6名RRMS受试者口服雌三醇治疗6个月导致连续脑MRI上钆增强病变的显著（80%）减少，引起免疫细胞产生细胞因子的有利转变，并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个月的治疗持续时间太短，无法评估治疗对复发的影响。 该提案将确定口服雌三醇（妊娠期主要雌激素）治疗与注射用克帕松联合使用时是否会降低RRMS受试者的复发率。本研究旨在确立原理验证、安全性，并为未来III期研究设定参数，并确立适当把握度计算的标准。将在一项多中心、双盲试验中比较克帕松注射液加雌三醇丸（每天8 mg）与克帕松注射液加安慰剂丸的联合治疗，每组65例受试者，治疗持续时间为2年，主要结局指标为复发率。次要结局将包括残疾指标（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标记物（增强病变、新发T2病变、萎缩）。还将遵循安全性措施（血液检查和妇科评价）。本研究的总体目标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.