Clinical trial NCT02040298: Assessment of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis, Relapsing-Remitting
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2014-01-20
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Full Field Visual Evoked Potential (VEP)
timeFrame: Treatment start to treatment end, up to 3 months.
Secondary outcomes:
measure: Tolerability of Clemastine in Multiple Sclerosis (MS) Patients
timeFrame: Treatment start to treatment end, up to 3 months.
measure: Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR)
timeFrame: Treatment start to treatment end, up to 3 months.
measure: Expanded Disability Status Scale (EDSS) Score
timeFrame: Start of treatment to end of treatment, up to 3 months
Other outcomes:
measure: Serum Creatinine Level
timeFrame: Baseline, 1 month, 3 month, 5 month
measure: Serum Triglyceride Level
timeFrame: Baseline, 1 month, 3 month, 5 month
measure: Vitamin B-12 Level
timeFrame: Baseline, 1 month, 3 month, 5 month
measure: Human Chorionic Gonadotropin (hCG) Level in Female Patients of Childbearing Potential
timeFrame: Baseline, 1 month, 3 month, 5 month
Locations:
city: San Francisco
country: United States
facility: UCSF Multiple Sclerosis Center
state: California
Study officials:
affiliation: University of California, San Francisco
name: Ari J. Green, MD, MCR
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fischer JS, LaRocca NG, Miller DM, Ritvo PG, Andrews H, Paty D. Recent developments in the assessment of quality of life in multiple sclerosis (MS). Mult Scler. 1999 Aug;5(4):251-9. doi: 10.1177/135245859900500410.
citation: Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Budingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. Epub 2017 Oct 10.
citation: Abdelhak A, Cordano C, Boscardin WJ, Caverzasi E, Kuhle J, Chan B, Gelfand JM, Yiu HH, Oertel FC, Beaudry-Richard A, Condor Montes S, Oksenberg JR, Lario Lago A, Boxer A, Rojas-Martinez JC, Elahi FM, Chan JR, Green AJ. Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 Jun 16:jnnp-2022-329221. doi: 10.1136/jnnp-2022-329221. Online ahead of print.