Clinical trial NCT04002934: Bazedoxifene Acetate as a Remyelinating Agent in Multiple Sclerosis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Keywords: MS
RRMS
Remyelination
Repair
Multiple Sclerosis
SERM
Estrogen
BZA
Bazedoxifene
Myelin Repair
Conbriza
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2019-07-01
Enrollment: 63
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Myelin Water Fraction (MWF) on MRI
timeFrame: 3 months
Secondary outcomes:
measure: Changes in BICAMS scores
timeFrame: 3 months
measure: Changes in MSFC scores
timeFrame: 3 months
measure: Changes in BICAMS scores
timeFrame: 6 months
measure: Changes in MSFC scores
timeFrame: 6 months
measure: Myelin Water Fraction (MWF) on MRI
timeFrame: 6 months
measure: Visual Evoked Potential (VEP) P100 Latency
timeFrame: 3 months
measure: Visual Evoked Potential (VEP) P100 Latency
timeFrame: 6 months
measure: Novel Digital Measures of Cognition
timeFrame: 6 months
measure: FitBit Activity
timeFrame: 6 months
measure: Serum Neurofilament Light Chain (NFL) levels
timeFrame: 6 months
measure: Expanded Disability Status Scale (EDSS)
timeFrame: 6 months
measure: Bladder Control Scale (BLCS)
timeFrame: 6 months
measure: Bowel Control Scale (BWCS)
timeFrame: 6 months
measure: Pittsburgh Sleep Quality Index (PSQI)
timeFrame: 6 months
measure: 12-Item Multiple Sclerosis Walking Scale (MSWS-12)
timeFrame: 6 months
measure: Center for Epidemiological Studies Depression Scale (CESD)
timeFrame: 6 months
measure: Modified Fatigue Impact Score (MFIS)
timeFrame: 6 months
measure: 36-Item Short Form Survey (SF36)
timeFrame: 6 months
measure: Visual Function Questionnaire (VFQ25)
timeFrame: 6 months
measure: Total T2 Lesion Volume
timeFrame: 6 months
measure: Number of New/Enlarging T2 Lesions
timeFrame: 6 months
measure: Levels of Brain Atrophy
timeFrame: 6 months
measure: Timed Up and Go (TUG) test
timeFrame: 6 months
Other outcomes:
measure: Tolerability and Safety of BZA - Patient Hot Flash Diary
timeFrame: 6 months
measure: Tolerability and Safety of BZA - Treatment Satisfaction Questionnaire for Medication (TSQM)
timeFrame: 6 months
measure: Tolerability and Safety of BZA - Patient Reports of Spasms
timeFrame: 6 months
measure: Tolerability and Safety of BZA - Safety Monitoring Labs
timeFrame: 6 months
measure: Tolerability and Safety of BZA - Records of Adverse Events
timeFrame: 6 months
measure: Tolerability and Safety of BZA - Monitoring MS Relapses
timeFrame: 6 months
Locations:
city: San Francisco
country: United States
facility: Weill Institute for Neurosciences, University of California, San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Riley M Bove, MD MMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.