Assessment of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis

Phase 2

Completed

Conditions: Multiple Sclerosis, Relapsing-Remitting

Interventions: Drug: Clemastine
Drug: Placebo

Registration Number: NCT02040298

Lead Sponsor: University of California, San Francisco

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
3 months Clemastine, 2 months Placebo	Clemastine	4mg clemastine twice daily for first 3 months -- crossover -- equivalent quantity/frequency of placebo for last 2 months
3 months Clemastine, 2 months Placebo	Placebo	4mg clemastine twice daily for first 3 months -- crossover -- equivalent quantity/frequency of placebo for last 2 months
3 months Placebo , 2 months Clemastine	Clemastine	Placebo for first 3 months -- crossover -- 4mg clemastine twice daily for last 2 months.
3 months Placebo , 2 months Clemastine	Placebo	Placebo for first 3 months -- crossover -- 4mg clemastine twice daily for last 2 months.

Primary Outcome Measures

Name	Time	Method
Full Field Visual Evoked Potential (VEP)	Treatment start to treatment end, up to 3 months.	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.

Secondary Outcome Measures

Name	Time	Method
Tolerability of Clemastine in Multiple Sclerosis (MS) Patients	Treatment start to treatment end, up to 3 months.	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.
Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR)	Treatment start to treatment end, up to 3 months.	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.
Expanded Disability Status Scale (EDSS) Score	Start of treatment to end of treatment, up to 3 months	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.