Bazedoxifene Acetate as a Remyelinating Agent in Multiple Sclerosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Randomized, Double-Blind, Parallel-Group, Placebo Controlled Delayed-Start Trial to Assess the Efficacy, Safety, and Tolerability of Bazedoxifene Acetate (BZA) as a Remyelinating Agent in Patients With Multiple Sclerosis

Conditions
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Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Bazedoxifene Acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 45-65 or 40+ post-menopausal. Documentation of a clinically definite diagnosis of relapsing-remitting MS Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study. Latency delay > 118 milliseconds on baseline full-field transient pattern reversal VEP in at least one eye (electrophysiological evidence of demyelination) RNFL > 70 microns on SD-OCT in the same eye meeting criteria for latency delay (sufficient axons) Stable immunomodulatory therapy - no switch or planned switch in > 6 months and no change in doses in 30 days prior to screening Use of contraceptive method with ≤1% failure rate during period of trial if premenopausal Understand and sign informed consent. EDSS 0-6.0 (inclusive) Exclusion Criteria: Multiple Sclerosis disease duration > 25 years Optic neuritis in prior 6 months Known optic neuritis in involved eye ≥ 10 years ago Major ophthalmologic disease/Concomitant ophthalmologic disorders (e.g. diabetes, macular degeneration, glaucoma, severe myopia, etc.). Myopia > -7 Diopters (severe myopia) Disc hemorrhages in qualifying eye No light perception in qualifying eye Simultaneous bilateral optic neuritis Cotton wool spots in qualifying eye Macular star in qualifying eye History of significant cardiac conduction block History of cancer (except non-melanoma skin cancer) Suicidal ideation or behavior in 6 months prior to baseline Pregnancy, breastfeeding, or planning to become pregnant Included with other study protocol simultaneously without prior approval Concomitant or prior use of any other putative remyelinating therapy as determined by investigator, including but not limited to Clemastine, Duavee, and Tamoxifen. Serum creatinine > 1.5mg/dL; AST, ALT, or alkaline phosphatase > 2 times the upper limit of normal History of drug or alcohol abuse within the past year Untreated 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, allergic, renal or other major diseases that in the PI's judgement 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. Patients whose lack of mobility exposes them to an increased risk of venous thromboembolism Patients with undiagnosed uterine bleeding Patients with unknown, suspected or past history of breast cancer Patients with known or suspected estrogen-dependent neoplasia Patients with active or a past history of venous thromboembolism Patients with active or a past history of arterial thromboembolism Patients with known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders Patients with hypersensitivity (angioedema, anaphylaxis) to estrogens, bazedoxifene, or any ingredients Patients with known hepatic impairment or disease

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

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: Parallel Assignment
Interventional Model Description: This is a randomized, placebo controlled, double-blind, delayed-start trial of BZA in 50 women with MS to be given as follows: Group A will receive 3 months of BZA + 3 months of BZA; Group B will receive 3 months of placebo + 3 months of BZA
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Group A is the early-start group and will receive a total of 6 months of BZA -- 3 months of BZA, followed by 3 months BZA | Drug: Bazedoxifene Acetate<br>* 40 mg Bazedoxifene delivered orally in the form of 2x 20 mg blinded capsules<br>* Other names: WAY-140424;|
| Experimental: Group B<br>Group B is the delayed-start group and will receive a total of 3 months of BZA -- 3 months of placebo, followed by 3 months of BZA | Drug: Bazedoxifene Acetate<br>* 40 mg Bazedoxifene delivered orally in the form of 2x 20 mg blinded capsules<br>* Other names: WAY-140424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P100 Latency on Full Field Visual Evoked Potential | The primary objective is to evaluate the efficacy of BZA relative to placebo for reducing P100 latencies on full field transient pattern reversal visual evoked potentials (VEPs). In response to a visual stimulus, cortically generated electrical potentials (VEPs) recorded over the scalp are used to measure the functional integrity of visual pathways. | 3 months | 
| P100 Latency on Full Field Visual Evoked Potential | Assess whether P100 latency delay at 6 months decreases to a greater extent in Group A (exposed to BZA for 3 months during both Stage 1 and Stage 2 -- 6 months total) when compared to Group B (exposed to placebo during Stage 1 and BZA for 3 months during Stage 2 -- 3 months total). | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MS, RRMS, Remyelination, Repair, Multiple Sclerosis, SERM, Estrogen, BZA, Bazedoxifene, Myelin Repair, Conbriza