Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
MS, RRMS, Remyelination, Repair, Multiple Sclerosis, SERM, Estrogen, BZA, Bazedoxifene, Myelin Repair, Conbriza
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.
Interventions
40 mg Bazedoxifene delivered orally in the form of 2x 20 mg blinded capsules
Sponsors
Riley Bove, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myelin Water Fraction (MWF) on MRI | 3 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Expanded Disability Status Scale (EDSS) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including EDSS. |
| 36-Item Short Form Survey (SF36) | 6 months | 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. |
| Visual Function Questionnaire (VFQ25) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the VFQ25, a patient-reported outcome. |
| Total T2 Lesion Volume | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including total volume of T2 lesions. |
| Number of New/Enlarging T2 Lesions | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the number of new/enlarging T2 lesions. |
| Levels of Brain Atrophy | 6 months | 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. |
| Timed Up and Go (TUG) test | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the TUG test. |
| Changes in BICAMS scores | 3 months | The first key secondary objective is changes in BICAMS scores over 3 months. |
| Changes in MSFC scores | 3 months | The second key secondary objective is changes in MSFC scores over 3 months. |
| Myelin Water Fraction (MWF) on MRI | 6 months | 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). |
| Visual Evoked Potential (VEP) P100 Latency | 3 months | The sixth key secondary objective is changes in visual evoked potential (VEP) P100 latency. |
| Novel Digital Measures of Cognition | 6 months | The eighth key secondary objective is to assess novel digital measures of cognition (processing speed from EVO Monitor). |
| FitBit Activity | 6 months | 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. |
| Serum Neurofilament Light Chain (NFL) levels | 6 months | The tenth key secondary objective is to assess NFL levels. |
| Bladder Control Scale (BLCS) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the BLCS, a patient-reported outcome. |
| Bowel Control Scale (BWCS) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the BWCS, a patient-reported outcome. |
| Pittsburgh Sleep Quality Index (PSQI) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the PSQI, a patient-reported outcome. |
| 12-Item Multiple Sclerosis Walking Scale (MSWS-12) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the MSWS-12, a patient-reported outcome. |
| Center for Epidemiological Studies Depression Scale (CESD) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the CESD, a patient-reported outcome. |
| Modified Fatigue Impact Score (MFIS) | 6 months | The last key secondary objective is an assessment of exploratory outcomes, including the MFIS, a patient-reported outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tolerability and Safety of BZA - Patient Reports of Spasms | 6 months | 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. |
| Tolerability and Safety of BZA - Safety Monitoring Labs | 6 months | 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. |
| Tolerability and Safety of BZA - Records of Adverse Events | 6 months | 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. |
| Tolerability and Safety of BZA - Monitoring MS Relapses | 6 months | 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. |
| Tolerability and Safety of BZA - Treatment Satisfaction Questionnaire for Medication (TSQM) | 6 months | 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). |
| Tolerability and Safety of BZA - Patient Hot Flash Diary | 6 months | 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. |
Countries
United States
Outcome results
None listed