The primary goal of this study is to assess the efficacy of bazedoxifene (BZA) as remyelinating agent in patients with relapsing-remitting multiple sclerosis (RRMS). The investigators will utilize electrophysiologic techniques and magnetic resonance imaging to quantify the effect of treatment in 50 women over the course of 6 months. Participants may remain on their standard disease modifying treatment during the course of the trial but may not concurrently participate in any other investigational new drug research study.
Multiple Sclerosis (MS) is a chronic neurologic disorder characterized by the loss of myelin, which results in disruption of nerve signal, damage to axons, and, ultimately, neurodegeneration. In order to treat MS, new methods for promoting repair (remyelination) are sorely needed. There is a strong preclinical (including EAE) and epidemiologic rationale for investigating the remyelinating potential of estrogenic compounds, including evidence of endogenous (puberty, postpartum periods) and exogenous hormonal influences on MS risk and course. MS affects 3 times more women than men, and disease course in women appears overall less aggressive (on MRI, fewer T2-hyperintense demyelinated lesions develop into axonal destruction visualized as hypointense T1 "black holes"). Bazedoxifene (BZA), a third-generation SERM with extensive safety data in humans, was identified in a novel high-throughput screen (BIMA screen) for compounds capable of promoting remyelination. Subsequent analysis validated BZA's remyelinating effect in vitro and in vivo following demyelinating insult. Given strong pre-clinical support for BZA's remyelinating potential, and the clinical success of other compounds identified using the BIMA screen (Green et al., 2017), the investigators will investigate the use of BZA as a remyelinating therapy in patients with MS.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
40 mg Bazedoxifene delivered orally in the form of 2x 20 mg blinded capsules
Weill Institute for Neurosciences, University of California, San Francisco
San Francisco, California, United States
Myelin Water Fraction (MWF) on MRI
The primary objective is to evaluate the efficacy of BZA relative to placebo for increasing MWF on MRI within normal appearing white matter of the corpus callosum, between baseline and 90 days in a double-blinded trial (1st 90 days in the early start group versus 1st 90 days of the delayed start group).
Time frame: 3 months
Changes in BICAMS scores
The first key secondary objective is changes in BICAMS scores over 3 months.
Time frame: 3 months
Changes in MSFC scores
The second key secondary objective is changes in MSFC scores over 3 months.
Time frame: 3 months
Changes in BICAMS scores
The third key secondary objective is changes in BICAMS scores over 6 months.
Time frame: 6 months
Changes in MSFC scores
The fourth key secondary objective is changes in MSFC scores over 6 months.
Time frame: 6 months
Myelin Water Fraction (MWF) on MRI
The fifth key secondary objective is to assess whether MWF at 180 days increases to a greater extent in the early start group (exposed to BZA for 90 days during both Stage 1 and Stage 2) when compared to the delayed start group (exposed to placebo during Stage 1 and BZA for only 90 days during Stage 2).
Time frame: 6 months
Visual Evoked Potential (VEP) P100 Latency
The sixth key secondary objective is changes in visual evoked potential (VEP) P100 latency.
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Time frame: 3 months
Visual Evoked Potential (VEP) P100 Latency
The seventh key secondary objective is changes in visual evoked potential (VEP) P100 latency.
Time frame: 6 months
Novel Digital Measures of Cognition
The eighth key secondary objective is to assess novel digital measures of cognition (processing speed from EVO Monitor).
Time frame: 6 months
FitBit Activity
The ninth key secondary objective is to assess daily activity by average daily step count as well as sleep activity by various sleep metrics recorded through FitBit.
Time frame: 6 months
Serum Neurofilament Light Chain (NFL) levels
The tenth key secondary objective is to assess NFL levels.
Time frame: 6 months
Expanded Disability Status Scale (EDSS)
The last key secondary objective is an assessment of exploratory outcomes, including EDSS.
Time frame: 6 months
Bladder Control Scale (BLCS)
The last key secondary objective is an assessment of exploratory outcomes, including the BLCS, a patient-reported outcome.
Time frame: 6 months
Bowel Control Scale (BWCS)
The last key secondary objective is an assessment of exploratory outcomes, including the BWCS, a patient-reported outcome.
Time frame: 6 months
Pittsburgh Sleep Quality Index (PSQI)
The last key secondary objective is an assessment of exploratory outcomes, including the PSQI, a patient-reported outcome.
Time frame: 6 months
12-Item Multiple Sclerosis Walking Scale (MSWS-12)
The last key secondary objective is an assessment of exploratory outcomes, including the MSWS-12, a patient-reported outcome.
Time frame: 6 months
Center for Epidemiological Studies Depression Scale (CESD)
The last key secondary objective is an assessment of exploratory outcomes, including the CESD, a patient-reported outcome.
Time frame: 6 months
Modified Fatigue Impact Score (MFIS)
The last key secondary objective is an assessment of exploratory outcomes, including the MFIS, a patient-reported outcome.
Time frame: 6 months
36-Item Short Form Survey (SF36)
The last key secondary objective is an assessment of exploratory outcomes, including the SF36, a patient-reported outcome. , Visual Function Questionnaire (VFQ25); other MRI metrics, including total volume of T2 lesions, number of new/enlarging T2 lesions, atrophy in corpus callosum, thalamus, prefrontal cortex, and other exploratory structures; Timed Up and Go test; and FitBit measures of variability in step count.
Time frame: 6 months
Visual Function Questionnaire (VFQ25)
The last key secondary objective is an assessment of exploratory outcomes, including the VFQ25, a patient-reported outcome.
Time frame: 6 months
Total T2 Lesion Volume
The last key secondary objective is an assessment of exploratory outcomes, including total volume of T2 lesions.
Time frame: 6 months
Number of New/Enlarging T2 Lesions
The last key secondary objective is an assessment of exploratory outcomes, including the number of new/enlarging T2 lesions.
Time frame: 6 months
Levels of Brain Atrophy
The last key secondary objective is an assessment of exploratory outcomes, including levels of atrophy in the corpus callosum, thalamus, prefrontal cortex, and other exploratory structures.
Time frame: 6 months
Timed Up and Go (TUG) test
The last key secondary objective is an assessment of exploratory outcomes, including the TUG test.
Time frame: 6 months