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

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ClinicalTrials.gov Identifier: NCT04002934
Recruitment Status : Recruiting
First Posted : July 1, 2019
Last Update Posted : November 1, 2019
Sponsor:
Information provided by (Responsible Party):
Riley Bove, MD, University of California, San Francisco

Brief 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.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Multiple Sclerosis, Relapsing-Remitting Drug: Bazedoxifene Acetate Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : September 10, 2019
Estimated Primary Completion Date : February 15, 2021
Estimated Study Completion Date : August 31, 2021

Resource links provided by the National Library of Medicine


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:
  • Bazedoxifene
  • Conbriza
  • Viviant
  • 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:
  • Bazedoxifene
  • Conbriza
  • Viviant
  • TSE-424
  • WAY 140424
  • WAY-140424




Primary Outcome Measures :
  1. P100 Latency on Full Field Visual Evoked Potential [ Time Frame: 3 months ]
    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.

  2. P100 Latency on Full Field Visual Evoked Potential [ Time Frame: 6 months ]
    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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Women aged 45-65 or 40+ post-menopausal.
  2. Documentation of a clinically definite diagnosis of relapsing-remitting MS
  3. 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.
  4. Latency delay > 118 milliseconds on baseline full-field transient pattern reversal VEP in at least one eye (electrophysiological evidence of demyelination)
  5. RNFL > 70 microns on SD-OCT in the same eye meeting criteria for latency delay (sufficient axons)
  6. Stable immunomodulatory therapy - no switch or planned switch in > 6 months and no change in doses in 30 days prior to screening
  7. Use of contraceptive method with ≤1% failure rate during period of trial if premenopausal
  8. Understand and sign informed consent.
  9. EDSS 0-6.0 (inclusive)

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04002934


Contacts
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Contact: Annika Anderson 415-353-8903 annika.anderson@ucsf.edu
Contact: William Rowles 415-502-7209 william.rowles@ucsf.edu

Locations
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United States, California
Weill Institute for Neurosciences, University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Annika Anderson    415-353-8903    annika.anderson@ucsf.edu   
Contact: William Rowles    415-502-7209    william.rowles@ucsf.edu   
Principal Investigator: Riley Bove, MD         
Sponsors and Collaborators
Riley Bove, MD
Investigators
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Principal Investigator: Riley M Bove, MD MMSc University of California, San Francisco
Additional Information:
Publications:
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Responsible Party: Riley Bove, MD, Assistant Professor of Neurology, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04002934    
Other Study ID Numbers: ReWRAP
138495 ( Other Identifier: FDA -- Investigational New Drug Number )
18-24511 ( Other Identifier: UCSF IRB No. )
First Posted: July 1, 2019    Key Record Dates
Last Update Posted: November 1, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Riley Bove, MD, University of California, San Francisco:
MS
RRMS
Remyelination
Repair
Multiple Sclerosis
SERM
Estrogen
BZA
Bazedoxifene
Myelin Repair
Conbriza
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Bazedoxifene
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Bone Density Conservation Agents