A Combination Trial of Copaxone plus Estriol in RRMS

Copaxone 加雌三醇治疗 RRMS 的联合试验

• 批准号: 8462004
• 负责人: RHONDA R VOSKUHL
• 金额: $ 28.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462004
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Atrophic; Beck depression inventory; Blood Tests; Brain; Cells; Clinical Trials; Copaxone; Development; Disease; Dose; Double-Blind Method; Enhancing Lesion; Estriol; Estrogens; Evaluation; Experimental Autoimmune Encephalomyelitis; Fatigue; Funding; Future; Goals; Gynecologic; Immune; In Vitro; Injectable; Injection of therapeutic agent; Legal patent; Lesion; Magnetic Resonance Imaging; Measures; Mediating; Metalloproteases; Modeling; Multiple Sclerosis; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Oral; Outcome Measure; Outcome Study; Placebos; Pre-Clinical Model; Pregnancy; Production; Quality of life; Relapse; Relapsing-Remitting Multiple Sclerosis; Safety; Sample Size; Societies; Testing; Translating; arm; base; cell motility; cytokine; disability; in vivo Model; phase 3 study; pill; primary outcome; protective effect; public health relevance; secondary outcome; treatment duration; treatment effect

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.

描述（由申请人提供）：这是我们的 RO1 (NS 051591) 的竞争性更新，由国家多发性硬化症协会 (RG 3915) 共同资助，题为“RRMS 中 Copaxone 加雌三醇的组合试验”。该申请正在寻求资金来完成当前形式的正在进行的试验，并且不需要为任何新提出的结果测量或研究提供资金。 众所周知，多发性硬化症 (MS) 复发在怀孕期间会显着减少，而雌三醇是怀孕期间的主要雌激素。使用多发性硬化症、实验性自身免疫性脑脊髓炎 (EAE) 的临床前模型，雌激素治疗（包括雌三醇）在妊娠剂量下给药时被证明既可以通过多种免疫机制抗炎，也可以直接保护神经。接下来，在一项试点临床试验中，结果表明，用口服雌三醇治疗 6 名 RRMS 受试者六个月，可显着（80%）减少连续脑 MRI 上的钆增强病变，导致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记物基质金属蛋白酶-9 (MMP-9) 的水平。六个月的治疗时间太短，无法评估治疗对复发的效果。 该提案将确定口服雌三醇（妊娠的主要雌激素）与注射用 Copaxone 联合使用时是否会减少 RRMS 受试者的复发率。本研究旨在建立原理验证、安全性并为未来的 III 期研究设置参数，并建立适当功率计算的标准。 Copaxone 注射液加雌三醇药丸（每天 8 毫克）的联合治疗将在一项多中心、双盲试验中与 Copaxone 注射液加安慰剂药丸的联合治疗进行比较，每组有 65 名受试者。治疗持续时间为两年，主要结果指标为复发率。次要结果将包括残疾指标（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（增强病变、新 T2 病变、萎缩）。还将遵循安全措施（血液测试和妇科评估）。这项研究的总体目标是开发一种安全的口服治疗 RRMS 的雌三醇。

项目成果

Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis.

• DOI: 10.1016/j.jneuroim.2016.09.017
• 发表时间: 2017-03-15
• 期刊: Journal of neuroimmunology
• 影响因子: 3.3
• 作者: Itoh N;Kim R;Peng M;DiFilippo E;Johnsonbaugh H;MacKenzie-Graham A;Voskuhl RR
• 通讯作者: Voskuhl RR

It is time to conduct phase 3 clinical trials of sex hormones in MS - Yes.

是时候对多发性硬化症进行性激素三期临床试验了 - 是的。

• DOI: 10.1177/1352458518768764
• 发表时间: 2018
• 期刊: Multiple sclerosis (Houndmills, Basingstoke, England)
• 作者: Voskuhl,Rhonda