Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Neurofilament light chain in the cerebrospinal fluid (CSF)
研究概览
简要总结
This study aims to evaluate safety and efficacy of dimethyl fumarate treatment in patients with primary progressive multiple sclerosis (PPMS).
Half of the patients will receive dimethyl fumarate and the other half will receive placebo.
详细描述
Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and is presumed to be caused by T cell-mediated autoimmune processes. PPMS has no registered treatment options only symptomatic treatment exists. Progressive forms of MS are characterized clinically by gradual symptom development with or without superimposed relapses.
Fumarates have long been known to have disease-attenuating effects in psoriasis. They have been in routine use in dermatology in Germany for several decades. Dimethyl fumarate has the interesting property of combining immunological effects, at least partly mediated by interference with nuclear factor kappa B and other transcription factors, and also anti-oxidative and neuroprotective effects mediated by activation of the transcription factor Nuclear factor (erythroid-derived 2)-Related Factor 2 (NRF2). Dimethyl fumarate is currently approved for treatment of relapsing-remitting MS by the European medicines Agency in a dose of 240 mg twice per day.
Neurofilament light chain (NFL) is a treatment responsive biomarker of neuronal and axonal death when appearing in the cerebrospinal fluid (CSF) and it has been associated with long-term prognosis in MS. The concentration is often elevated in progressive MS patients. Treatment effect is measured by measuring changes in neurofilament light chain concentration over the course of 48 weeks of treatment with either active drug or placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 to 65 years
- •PPMS according to the McDonald (2010) and Lublin (2014) criteria
- •Disease duration at least one year
- •EDSS ≤ 6.5
- •Written informed consent to study participation
- •No other signs of significant disease judged by the investigator
- •Eligible for randomization to active treatment or placebo as assessed by CSF NFL levels above 380ng/L
- •Not eligible for randomization as assessed by CSF biomarker studies but accepts follow-up and open-label treatment per protocol
- •Patients not eligible for randomization due to low NFL concentrations in CSF at screening can be followed up after 48 weeks, and are eligible for open-label treatment if they fulfil one of the following clinical criteria of disease progression:
- •1 point increase in EDSS score from screening to week 48 if screening EDSS <6
- •0.5 point increase in EDSS score from screening to week 48 if screening EDSS>5.5
- •2 point increase in a physical functional system
- •Worsening in SDMT, 9HPT or T25FW >20% from screening to week 48
排除标准
- •Pregnancy or breast feeding
- •Lack of effective contraception for women of child-bearing potential
- •Relapse within 6 months of inclusion
- •Methylprednisolone treatment within 3 months of inclusion
- •Treatment with interferon-beta, glatiramer acetate, immunoglobulin G or other immunomodulatory treatment within 6 months of inclusion
- •Treatment with mitoxantrone, cyclophosphamide, azathioprine or other immunosuppressive treatment within 6 months of inclusion
- •Findings on the screening MRI judged to preclude participation by the treating physician
- •Other diseases associated with immunodeficiency
- •Other diseases judged to be relevant by the treating physician
- •Anticoagulant therapy other than platelet inhibitors
- •Active malignant disease in the previous 5 years
- •Renal insufficiency or blood creatinine > 150 μmol/l
- •Present or chronic infection with hepatitis B virus, hepatitis C virus, HIV (tested in the screening blood samples) or other infections found to be relevant by the treating physician.
- •Psychiatric disorders or other disorders impairing the patient's ability to participate in the trial
- •Contraindication to MRI
- •Known allergy or hypersensitivity to dimethyl fumarate
研究组 & 干预措施
Active drug
Dimethyl fumarate, 240mg twice daily for 48 weeks
干预措施: Dimethyl fumarate (Drug)
Placebo
Placebo Oral Capsules, 2 tablets twice daily for 48 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Neurofilament light chain in the cerebrospinal fluid (CSF)
时间窗: 0-48 weeks
CSF Neurofilament Light Chain (NFL) is measured twice over a course of 48 weeks. Patients will have a spinal tap performed at baseline and again at week 48.
次要结局
- Expanded Disability Status Scale (EDSS)(0-48 weeks)
- Timed 25-Foot Walk (T25FW)(0-48 weeks)
- Nine hole peg test (9HPT)(0-48 weeks)
- Symbol digit modalities test (SDMT)(0-48 weeks)
- CSF/Serum Immunoglobulin type G index(0-48 weeks)
- Cerebrospinal fluid-serum albumin quotient(0-48 weeks)
- soluble CD14 (sCD14)(0-48 weeks)
- soluble CD27 (sCD27)(0-48 weeks)
- BCMA(0-48 weeks)
- Chitinase 3-like-1(0-48 weeks)
- Myelin Basic protein (MBP)(0-48 weeks)
- Number of new or enlarged T2 lesions(0-48 weeks)
- Fractional anisotropy (FA) in Normal Appearing White Matter (NAWM)(0-48 weeks)
- Change in lesion volume(0-48 weeks)
- Change from screening in in magnetization transfer ratio (MTR) of T2 lesions(0-48 weeks)
- Thalamic volume(0-48 weeks)
- Percent brain volume change (PBVC)(0-48 weeks)
研究者
Jacob L Talbot
Principal Investigator
Rigshospitalet, Denmark