A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Trial to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Change in P100 latency on full-field visual evoked potential
研究概览
简要总结
The main purpose of this study is to assess clemastine as a remyelinating agent in patients with acute optic neuritis.The study will also evaluate the tolerability of clemastine, originally approved as first-generation antihistamine, in patients with optic neuritis. Study procedures will include assessments for evidence of remyelination in the anterior visual pathway and in the brain using electrophysiologic techniques and magnetic resonance imaging. If they are on one, patients in this study can remain on their standard disease modifying treatment during the course of the study. However, patients cannot participate in any other investigational new drug research study concurrently.
详细描述
Optic neuritis is an inflammatory, demyelinating disease of the optic nerve. It is most often characterized by visual loss or blurred vision along with dyschromatopsiaaccompanied by pain (especially with eye movement) and no demonstrable evidence of an alternate diagnosis such as ischemia or retinal disease. It can also be associated with a swollen optic disc (Optic Neuritis Study Group 1991, Hutchinson, W.M. 1976) and optic nerve enhancement on MRI (Kupersmith 2002).
Functional high-throughput screening for compounds that promote remyelination presents a major unmet need in the therapeutic arsenal for multiple sclerosis and other demyelinating conditions such as optic neuritis. Screening for myelin repair is problematic, as functional remyelination requires the presence of intact neuronal axons. Standard methods are not suited for high-throughput formats. We performed a detailed screen of over 1500 FDA approved small molecule drugs to identify agents that could be promising for remyelination. Engineered with conical dimensions, our micropillar technology permitted resolution of the extent and length of membrane wrapping from a single 2-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for the fluorescence detection of concentric wrapping observed as "rings" of myelin membrane. The platform was formatted in 96-well plates, amenable to semi-automated random acquisition and automated detection and quantification. Upon initiating a screen of 1500 bioactive molecules, we identified Clemastine as a compound that potentially enhances oligodendrocyte differentiation and remyelination. We then validated this and other drugs in preclinical assays as well as in animal models of primary myelination and remyelination after inflammatory and chemical demyelination. Together, our findings illustrate the proof of concept for a novel high-throughput screening platform for potential regenerative therapeutics in MS (Chan JR et al. 2014).
This study is intended to assess for clinical evidence of remyelination using Clemastine Fumarate in patients with acute inflammatory injury causing demyelination of the anterior visual pathway as a consequence of acute demyelinating optic neuritis. The study is designed to assess tolerability and clinical efficacy of Clemastine using outcomes intended to assess for (a) adverse events and (b) recovery of myelin. This study is complementary to an earlier study evaluating clemastine in chronic demyelinated optic neuropathy and serves as part of a proof of concept program intended to evaluate methods for conducting remyelination trials in MS.
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 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients diagnosed or suspected to have an acute demyelinating optic neuritis in at least one eye within 3 weeks from the onset of any visual symptom other than pain
- •Use of disease-modifying therapies is not a contraindication
- •Use of appropriate contraception during the period of trial (women)
- •Understand and sign the informed consent
排除标准
- •Other major ophthalmologic diseases / concomitant ophthalmologic disorders (e.g. diabetes, macular degeneration, glaucoma, severe myopia, etc)
- •Disc hemorrhages in the qualifying eye
- •No light perception in qualifying eye
- •Simultaneous bilateral optic neuritis
- •Cotton wool spots in the qualifying eye
- •Macular star in the qualifying eye
- •History of significant cardiac conduction block
- •History of cancer
- •Suicidal ideation or behavior in 6 months prior to baseline
- •Pregnancy, breastfeeding or planning to become pregnant
- •Involved with other study protocols simultaneously without prior approval
- •Concomitant use of any other putative remyelinating therapy as determined by the investigator
- •Serum creatinine > 1.5 mg/dL; aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase > 2 times the upper limit of normal
- •History of drug or alcohol abuse within the past year
- •Untreated B12 deficiency (as determined by B12 serological assessments and metabolites including methylmalonic acid (MMA) and homocysteine) or untreated hypothyroidism
- •Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal, or other major diseases that, in the PI's judgment, may affect the interpretation of study results or patient safety
- •History or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study.
- •Positive for NMO antibody discovered within the first 2 weeks after randomization.
研究组 & 干预措施
Clemastine
Participants will receive clemastine until 3 months and then will be off treatment until 9 month time point.
干预措施: Clemastine (Drug)
Placebo
Participants will receive placebo until 3 months and then will be off treatment until 9 month time point.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in P100 latency on full-field visual evoked potential
时间窗: baseline, 1 week, 1 month, 3 months, 9 months
To evaluate the efficacy of clemastine relative to placebo for reducing P100 latencies on full field transient pattern reversal visual evoked potentials. Measure will be reported as difference in P100 latency from baseline to 9 months.
Change in low contrast visual acuity
时间窗: baseline, 1 week, 1 month, 3 months, 9 months
The second primary outcome is to measure the effectiveness of clemastine relative to placebo at improving patient performance on ETDRS low contrast visual acuity chart testing (2.5% black on white) during the recovery from an acute optic neuritis. Measure will be reported as difference in ETDRS score from baseline to 9 months.
次要结局
- Change in retinal nerve fiber layer thickness on optical coherence tomography(baseline, 1 week, 1 month, 3 months, 9 months)
- Radiological outcomes assessed by magnetic resonance imaging(baseline, 9 month)
- Expanded Disability Status Scale score(baseline, 9 months)