Bazedoxifene Acetate as a Remyelinating Agent in Multiple Sclerosis (ReWRAP)

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Bazedoxifene Acetate

Detailed Description

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
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • Weill Institute for Neurosciences, University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Expanded Inclusion Criteria:

1. Relapsing remitting Multiple Sclerosis by 2017 Revised McDonald Criteria
2. Women aged 45-65 or 40+ post-menopausal.
3. Stable immunomodulatory therapy - no switch or planned switch in < 6 months and no change in doses in 30 days prior to screening
4. Use of contraceptive method with ≤1% failure rate during period of trial if premenopausal
5. Understand and sign informed consent.
6. EDSS 0-6.0 (inclusive)

Chronic Optic Neuropathy Subgroup Inclusion Criteria (including broader inclusion criteria):

1. Expanded inclusion criteria
2. Latency delay > 118 milliseconds on baseline full-field transient pattern reversal VEP in at least one eye (electrophysiological evidence of demyelination)

Expanded Exclusion Criteria:

1. Multiple Sclerosis disease duration > 25 years
2. History of significant cardiac conduction block
3. Patients with a known, suspected or past history of breast, gynecological, or gastrointestinal cancer
4. Suicidal ideation or behavior in 6 months prior to baseline
5. Pregnancy, breastfeeding, or planning to become pregnant
6. Included with other study protocol simultaneously without prior approval
7. Concomitant or prior use of any other putative remyelinating therapy as determined by investigator, including but not limited to Clemastine, Duavee, and Tamoxifen.
8. Serum creatinine > 1.5mg/dL; AST, ALT, or alkaline phosphatase > 2 times the upper limit of normal
9. History of drug or alcohol abuse within the past year
10. Untreated B12 deficiency (as determined by B12 serological assessments and metabolites including methylmalonic acid [MMA] and homocysteine) or untreated hypothyroidism
11. 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.
12. 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.
13. Patients whose lack of mobility exposes them to an increased risk of venous thromboembolism
14. Patients with undiagnosed uterine bleeding
15. Patients with unknown, suspected or past history of breast cancer
16. Patients with known or suspected estrogen-dependent neoplasia
17. Patients with active or a past history of venous thromboembolism
18. Patients with active or a past history of arterial thromboembolism
19. Patients with known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders
20. Patients with hypersensitivity (angioedema, anaphylaxis) to estrogens, bazedoxifene, or any ingredients
21. Patients with known hepatic impairment or disease

Chronic Optic Neuropathy Subgroup Exclusion Criteria:

1. Expanded exclusion criteria
2. Optic neuritis in prior 6 months
3. Known optic neuritis in involved eye ≥ 15 years ago
4. Major ophthalmologic disease/Concomitant ophthalmologic disorders (e.g. diabetes, macular degeneration, glaucoma, severe myopia, etc.).
5. Myopia > -7 Diopters (severe myopia)
6. Disc hemorrhages in qualifying eye
7. No light perception in qualifying eye
8. Simultaneous bilateral optic neuritis
9. Cotton wool spots in qualifying eye
10. Macular star in qualifying eye

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A; 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; 40 mg Bazedoxifene delivered orally in the form of 2x 20 mg blinded capsules; Other Names: Viviant; Bazedoxifene; Conbriza; TSE-424; WAY 140424; WAY-140424
Experimental: Group B; 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; 40 mg Bazedoxifene delivered orally in the form of 2x 20 mg blinded capsules; Other Names: Viviant; Bazedoxifene; Conbriza; TSE-424; WAY 140424; WAY-140424

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in BICAMS scores	The first key secondary objective is changes in BICAMS scores over 3 months.	3 months
Changes in MSFC scores	The second key secondary objective is changes in MSFC scores over 3 months.	3 months
Changes in BICAMS scores	The third key secondary objective is changes in BICAMS scores over 6 months.	6 months
Changes in MSFC scores	The fourth key secondary objective is changes in MSFC scores over 6 months.	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).	6 months
Visual Evoked Potential (VEP) P100 Latency	The sixth key secondary objective is changes in visual evoked potential (VEP) P100 latency.	3 months
Visual Evoked Potential (VEP) P100 Latency	The seventh key secondary objective is changes in visual evoked potential (VEP) P100 latency.	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).	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.	6 months
Serum Neurofilament Light Chain (NFL) levels	The tenth key secondary objective is to assess NFL levels.	6 months
Expanded Disability Status Scale (EDSS)	The last key secondary objective is an assessment of exploratory outcomes, including EDSS.	6 months
Bladder Control Scale (BLCS)	The last key secondary objective is an assessment of exploratory outcomes, including the BLCS, a patient-reported outcome.	6 months
Bowel Control Scale (BWCS)	The last key secondary objective is an assessment of exploratory outcomes, including the BWCS, a patient-reported outcome.	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.	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.	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.	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.	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.	6 months
Visual Function Questionnaire (VFQ25)	The last key secondary objective is an assessment of exploratory outcomes, including the VFQ25, a patient-reported outcome.	6 months
Total T2 Lesion Volume	The last key secondary objective is an assessment of exploratory outcomes, including total volume of T2 lesions.	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.	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.	6 months
Timed Up and Go (TUG) test	The last key secondary objective is an assessment of exploratory outcomes, including the TUG test.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability and Safety of BZA - Patient Hot Flash Diary	The tertiary objectives are to demonstrate the tolerability and document the safety of BZA in this population of patients. Tolerability and safety of BZA will be assessed by patient hot flash diaries.	6 months
Tolerability and Safety of BZA - Treatment Satisfaction Questionnaire for Medication (TSQM)	The tertiary objectives are to demonstrate the tolerability and document the safety of BZA in this population of patients. Tolerability and safety of BZA will be assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM).	6 months
Tolerability and Safety of BZA - Patient Reports of Spasms	The tertiary objectives are to demonstrate the tolerability and document the safety of BZA in this population of patients. Tolerability and safety of BZA will be assessed by patient reports of spasms.	6 months
Tolerability and Safety of BZA - Safety Monitoring Labs	The tertiary objectives are to demonstrate the tolerability and document the safety of BZA in this population of patients. Tolerability and safety of BZA will be assessed by safety monitoring labs.	6 months
Tolerability and Safety of BZA - Records of Adverse Events	The tertiary objectives are to demonstrate the tolerability and document the safety of BZA in this population of patients. Tolerability and safety of BZA will be assessed by records of adverse events.	6 months
Tolerability and Safety of BZA - Monitoring MS Relapses	The tertiary objectives are to demonstrate the tolerability and document the safety of BZA in this population of patients. Tolerability and safety of BZA will be assessed by monitoring MS relapses throughout the study.	6 months

Collaborators and Investigators

• Sponsor: Riley Bove, MD
• Investigators: Principal Investigator: Riley M Bove, MD MMSc, University of California, San Francisco

Publications and helpful links

General Publications

• 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.

Helpful Links

• Bove Lab
• UCSF Health

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2019
• Primary Completion (Actual): May 13, 2025
• Study Completion (Actual): May 20, 2025

Study Registration Dates

• First Submitted: June 25, 2019
• First Submitted That Met QC Criteria: June 26, 2019
• First Posted (Actual): July 1, 2019

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: June 4, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; RRMS; MS; Repair; Estrogen; SERM; Remyelination; BZA; Bazedoxifene; Myelin Repair; Conbriza
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Bone Density Conservation Agents; Hormone Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Bazedoxifene
• Other Study ID Numbers: ReWRAP; 138495 (Other Identifier: FDA -- Investigational New Drug Number); 18-24511 (Other Identifier: UCSF IRB No.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No