Multiple Sclerosis, Relapsing-Remitting
Conditions
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.
Interventions
DRUGClemastine
4mg tablet twice daily
DRUGPlacebo
Placebo tablet twice daily
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Serum Creatinine Level | Baseline, 1 month, 3 month, 5 month | Blood sample will be collected at each visit to evaluate health status... |
| Serum Triglyceride Level | Baseline, 1 month, 3 month, 5 month | Blood sample will be collected at each visit to evaluate health status. |
| Vitamin B-12 Level | Baseline, 1 month, 3 month, 5 month | Blood sample will be collected at each visit to evaluate health status. |
| Human Chorionic Gonadotropin (hCG) Level in Female Patients of Childbearing Potential | Baseline, 1 month, 3 month, 5 month | Blood and urine sample will be collected to assess pregnancy status of all female participants of child bearing potential. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clemastine First, Then Placebo Participants first received Clemastine 4mg tablet twice daily for 3 months, then they received Placebo (matching Clemastine 4mg) for 2 months. | 25 |
| Placebo First, Then Clemastine Participants first received Placebo (matching Clemastine 4mg) tablet twice daily for 3 months, then they received Clemastine 4mg twice daily for 2 months. | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Total | Clemastine First, Then Placebo | Placebo First, Then Clemastine |
|---|---|---|---|
| 25-foot walk | 3.96 seconds STANDARD_DEVIATION 0.86 | 3.81 seconds STANDARD_DEVIATION 0.67 | 4.10 seconds STANDARD_DEVIATION 1.01 |
| 6-min walk | 1742.08 feet STANDARD_DEVIATION 271.66 | 1742.40 feet STANDARD_DEVIATION 288.14 | 1741.76 feet STANDARD_DEVIATION 260.08 |
| Age, Continuous | 40.1 years STANDARD_DEVIATION 10.2 | 40.2 years STANDARD_DEVIATION 10.8 | 40.0 years STANDARD_DEVIATION 10.1 |
| Disease duration | 5.1 years STANDARD_DEVIATION 5.2 | 5.7 years STANDARD_DEVIATION 6.5 | 4.4 years STANDARD_DEVIATION 3.6 |
| EDSS | 2.2 units on a scale STANDARD_DEVIATION 1.1 | 2.2 units on a scale STANDARD_DEVIATION 1 | 2.1 units on a scale STANDARD_DEVIATION 1.2 |
| FA white matter | 0.24 ratio STANDARD_DEVIATION 0.01 | 0.24 ratio STANDARD_DEVIATION 0.02 | 0.24 ratio STANDARD_DEVIATION 0.01 |
| History of optic neuritis | 28 Participants | 15 Participants | 13 Participants |
| LCLA | 22.8 Number of letters read correctly STANDARD_DEVIATION 9.6 | 24.0 Number of letters read correctly STANDARD_DEVIATION 8.4 | 21.6 Number of letters read correctly STANDARD_DEVIATION 10.7 |
| MAF | 19.13 units on a scale STANDARD_DEVIATION 11.62 | 17.82 units on a scale STANDARD_DEVIATION 12.39 | 20.43 units on a scale STANDARD_DEVIATION 10.88 |
| MTR 25 Brain | 0.39 ratio STANDARD_DEVIATION 0.04 | 0.39 ratio STANDARD_DEVIATION 0.05 | 0.38 ratio STANDARD_DEVIATION 0.03 |
| MTR 25 White matter | 0.54 ratio STANDARD_DEVIATION 0.02 | 0.54 ratio STANDARD_DEVIATION 0.02 | 0.54 ratio STANDARD_DEVIATION 0.02 |
| Myelin water fraction | 66.62 ratio STANDARD_DEVIATION 12.33 | 67.55 ratio STANDARD_DEVIATION 11.85 | 65.70 ratio STANDARD_DEVIATION 12.98 |
| OCT Macular volume | 3.03 mm^3 STANDARD_DEVIATION 0.13 | 3.05 mm^3 STANDARD_DEVIATION 0.14 | 3.01 mm^3 STANDARD_DEVIATION 0.11 |
| OCT Retinal Nerve Fiber Layer (RNFL) | 86.7 µm STANDARD_DEVIATION 10.4 | 90.2 µm STANDARD_DEVIATION 12 | 85.1 µm STANDARD_DEVIATION 7.9 |
| SDMT | 50.9 number of correct substitutions STANDARD_DEVIATION 10.6 | 51.8 number of correct substitutions STANDARD_DEVIATION 10.2 | 50.0 number of correct substitutions STANDARD_DEVIATION 11.1 |
| Sex: Female, Male Female | 32 Participants | 19 Participants | 13 Participants |
| Sex: Female, Male Male | 18 Participants | 6 Participants | 12 Participants |
| Time since optic neuritis | 4.3 years STANDARD_DEVIATION 4 | 3.7 years STANDARD_DEVIATION 3.4 | 4.9 years STANDARD_DEVIATION 4.6 |
| VEP P100 latency | 127.7 milliseconds STANDARD_DEVIATION 10.5 | 128.6 milliseconds STANDARD_DEVIATION 11.6 | 126.8 milliseconds STANDARD_DEVIATION 9.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 50 |
| other Total, other adverse events | 10 / 50 | 15 / 50 |
| serious Total, serious adverse events | 0 / 50 | 0 / 50 |
Outcome results
Primary
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.
Time frame: Treatment start to treatment end, up to 3 months.
Population: The data for 7 eyes did not meet criteria for inclusion in analysis (i.e., absent or unidentifiable waveforms.).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clemastine | Full Field Visual Evoked Potential (VEP) | VEP at baseline | 124.8 ms | Standard Deviation 11.5 |
| Clemastine | Full Field Visual Evoked Potential (VEP) | VEP change from baseline | -2.86 ms | Standard Deviation 6.85 |
| Placebo | Full Field Visual Evoked Potential (VEP) | VEP at baseline | 126.4 ms | Standard Deviation 10.9 |
| Placebo | Full Field Visual Evoked Potential (VEP) | VEP change from baseline | -1.50 ms | Standard Deviation 3.86 |
Secondary
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.
Time frame: Start of treatment to end of treatment, up to 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clemastine | Expanded Disability Status Scale (EDSS) Score | EDSS at baseline | 2.06 score on a scale | Standard Deviation 1.21 |
| Clemastine | Expanded Disability Status Scale (EDSS) Score | EDSS change from baseline | -0.09 score on a scale | Standard Deviation 0.87 |
| Placebo | Expanded Disability Status Scale (EDSS) Score | EDSS at baseline | 2.14 score on a scale | Standard Deviation 1.15 |
| Placebo | Expanded Disability Status Scale (EDSS) Score | EDSS change from baseline | -0.03 score on a scale | Standard Deviation 0.69 |
Secondary
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.
Time frame: Treatment start to treatment end, up to 3 months.
Population: MRI done at baseline, month 3, month 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clemastine | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR 25: full brain at baseline | 0,380 Ratio | Standard Deviation 0.04 |
| Clemastine | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR: white matter at baseline | 0.533 Ratio | Standard Deviation 0.018 |
| Clemastine | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MWF 50 at baseline | 66.38 Ratio | Standard Deviation 13.06 |
| Clemastine | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR 25: full brain change from baseline | -0.008 Ratio | Standard Deviation 0.016 |
| Clemastine | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR: white matter change from baseline | -0.004 Ratio | Standard Deviation 0.021 |
| Clemastine | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MWF 50 change from baseline | 0.23 Ratio | Standard Deviation 13.2 |
| Placebo | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR: white matter change from baseline | -0.004 Ratio | Standard Deviation 0.018 |
| Placebo | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR 25: full brain at baseline | 0.379 Ratio | Standard Deviation 0.041 |
| Placebo | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR 25: full brain change from baseline | -0.009 Ratio | Standard Deviation 0.018 |
| Placebo | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MTR: white matter at baseline | 0.533 Ratio | Standard Deviation 0.021 |
| Placebo | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MWF 50 change from baseline | -0.55 Ratio | Standard Deviation 10.78 |
| Placebo | Myelin Water Fraction (MWF) and Magnetization Transfer Ratios (MTR) | MWF 50 at baseline | 66.12 Ratio | Standard Deviation 12.69 |
Secondary
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.
Time frame: Treatment start to treatment end, up to 3 months.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clemastine | Tolerability of Clemastine in Multiple Sclerosis (MS) Patients | MAF at baseline | 21.0 score on a scale | Standard Deviation 10.9 |
| Clemastine | Tolerability of Clemastine in Multiple Sclerosis (MS) Patients | MAF change from baseline | 1.9 score on a scale | Standard Deviation 6.8 |
| Placebo | Tolerability of Clemastine in Multiple Sclerosis (MS) Patients | MAF at baseline | 18.8 score on a scale | Standard Deviation 12.2 |
| Placebo | Tolerability of Clemastine in Multiple Sclerosis (MS) Patients | MAF change from baseline | -0.4 score on a scale | Standard Deviation 6.9 |
Other Pre-specified
Human Chorionic Gonadotropin (hCG) Level in Female Patients of Childbearing Potential
Blood and urine sample will be collected to assess pregnancy status of all female participants of child bearing potential.
Time frame: Baseline, 1 month, 3 month, 5 month
Other Pre-specified
Serum Creatinine Level
Blood sample will be collected at each visit to evaluate health status...
Time frame: Baseline, 1 month, 3 month, 5 month
Other Pre-specified
Serum Triglyceride Level
Blood sample will be collected at each visit to evaluate health status.
Time frame: Baseline, 1 month, 3 month, 5 month
Other Pre-specified
Vitamin B-12 Level
Blood sample will be collected at each visit to evaluate health status.
Time frame: Baseline, 1 month, 3 month, 5 month