Assessment of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis

Study Overview
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Brief Summary
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The main purpose of this study is to assess clemastine as a remyelinating agent in patients with relapsing forms of multiple sclerosis. The study will also evaluate the tolerability of clemastine, originally approved as first-generation antihistamine, in patients with multiple sclerosis. 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. The study will also assess the robustness and stability of this clinical effect in patients taking clemastine for up to 3 months. 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.

Official Title
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A Phase II Randomized, Double-Blind, Parallel-Group, Placebo Controlled Crossover Trial to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Clemastine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsing remitting Multiple Sclerosis by 2010 Revised McDonald Criteria Age 18-60. Latency delay > 125 milliseconds on baseline full-field transient pattern reversal visual evoked potential (VEP) in at least one eye (electrophysiological evidence of demyelination) Retinal nerve fiber layer (RNFL) > 70 microns on Spectralis Domain Optical Coherence Topography (SD-OCT) in the same eye meeting criteria for latency delay (sufficient axons) No optic neuritis in prior 6 months Stable immunomodulatory therapy - no switch or planned switch in > 6 months and no change in doses in 30 days prior to screening Use of appropriate contraception during period of trial (females of child bearing potential) Understand and sign informed consent. Expanded disability status scale (EDSS) 0-6.0 (inclusive) Exclusion Criteria: Major ophthalmologic disease / Concomitant ophthalmologic disorders (e.g. diabetes, macular degeneration, glaucoma, severe myopia , etc). Myopia > -7 Diopters (Severe myopia) History of significant cardiac conduction block History of cancer Known optic neuritis in involved eye > 5 years ago OR disease duration > 15 years Suicidal ideation or behaviour in 6 months prior to screening Pregnancy, breastfeeding, or planning to become pregnant. Involved with other study protocol simultaneously without prior approval. 9. Concomitant use of Dalfampridine (4AP or diamino4AP) or any other formulation of 4AP or diamino4AP. Concomitant use of any other putative remyelinating therapy as determined by investigator. Treatment with corticosteroids within 30 days prior to screening Prior treatment with total lymphoid irradiation, T cell or T cell receptor vaccination Prior treatment with alemtuzumab, mitoxantrone, or cyclophosphamide Serum creatinine > 1.5 mg/dL; aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 2 times the upper limit of normal History of drug or alcohol abuse within the past year Untreated vitamin 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, psychiatric allergic, renal or other major diseases that in the PI's judgment may affect interpretation of study results or patient safety. History of or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 3 months Clemastine, 2 months Placebo<br>4mg clemastine twice daily for first 3 months -- crossover -- equivalent quantity/frequency of placebo for last 2 months | Drug: Clemastine<br>* 4mg tablet twice daily<br>* Other names: Tavist -1;Drug: Placebo<br>* Placebo tablet twice daily<br>|
| Active Comparator: 3 months Placebo , 2 months Clemastine<br>Placebo for first 3 months -- crossover -- 4mg clemastine twice daily for last 2 months. | Drug: Clemastine<br>* 4mg tablet twice daily<br>* Other names: Tavist -1;Drug: Placebo<br>* Placebo tablet twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full Field Visual Evoked Potential (VEP) | The primary objective is to evaluate the efficacy of Clemastine relative to placebo for reducing P100 latencies on full field transient pattern reversal visual evoked potentials.Visual evoked potentials (VEP) are used primarily to measure the functional integrity of the visual pathways from the retina to the visual cortex of the brain. VEP latencies were collected at Baseline, Month 1, Month 3, and Month 5. | Treatment start to treatment end, up to 3 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of Clemastine in Multiple Sclerosis (MS) Patients | Will demonstrate the tolerability of Clemastine in this population. This will include special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis.This will be assessed by administering a fatigue questionnaire called the Multidimensional Assessment of Fatigue (MAF) at all four visits throughout the study. MAF scale range is 0-50. Lower scores indicate lower levels of fatigue and higher scores indicate higher levels of fatigue. | Treatment start to treatment end, up to 3 months. | 
| Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | To evaluate the efficacy of Clemastine relative to placebo in increasing magnetization transfer ratios derived from magnetic resonance imaging (MRI) of the brain during the period of exposure to active treatment. To evaluate the efficacy of Clemastine relative to placebo at reducing radial diffusivity derived from diffusion tensor imaging as assessed by magnetic resonance imaging (MRI) during the period of exposure to active medication. | Treatment start to treatment end, up to 3 months. | 
| Expanded Disability Status Scale (EDSS) Score | To evaluate the efficacy of Clemastine relative to placebo in reducing the EDSS score at 90 days compared to placebo (Group A) & at 150 days compared to day 90 (Group B). EDSS is an ordinal scale for assessing neurological impairment of MS based on a neurological examination. It consists of scores in each of seven functional systems (FS) & an ambulation score that are then combined to determine the EDSS [ranging from 0 (normal) to 10 (death due to MS)]. The FSs are the Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, & Cerebral functions. FSs & EDSS steps assessed in a standardized manner. EDSS is a widely used &accepted instrument to evaluate disability status at a given time & longitudinally, to assess disability progression in clinical studies in MS. | Start of treatment to end of treatment, up to 3 months |