Bazedoxifene Acetate as a Remyelinating Agent in Multiple Sclerosis

Multiple Sclerosis Clinical Trial

— ReWRAP  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04002934
• Other study ID #: ReWRAP
• Secondary ID: 13849518-24511
• Status: Recruiting
• Phase: Phase 2
• Start date: September 10, 2019
• Est. completion date: June 30, 2025

Study information

• Verified date: May 2024
• Source: University of California, San Francisco
• Contact: Stephanie Hsu
• Phone: 415-502-7209
• Email: stephanie.hsu[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 62
• Est. completion date: June 30, 2025
• Est. primary completion date: December 15, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 40 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Drug:
• Bazedoxifene Acetate
40 mg Bazedoxifene delivered orally in the form of 2x 20 mg blinded capsules

Locations

Country	Name	City	State
United States	Weill Institute for Neurosciences, University of California, San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Riley Bove, MD

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

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

External Links

•   Bove Lab
•   UCSF Health