A TSEC for Symptom Management in Menopausal Women With Multiple Sclerosis

Study Overview
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Brief Summary
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Duavee is a hormone receptor modulator that has been approved for the treatment of menopausal symptoms in menopausal women. The goal of this 8-week randomized, double blind, placebo controlled pilot study, is to determine whether this medication alleviates menopausal symptoms in women with MS. The investigators will secondarily determine whether addressing menopausal symptoms ameliorates MS symptoms and, on MRIs, is not triggering worsening inflammation.

Detailed Description
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Menopause in MS. Multiple sclerosis (MS) affects 3 times more women than men, and before age 50 in about 90% cases, i.e. prior to menopause. There is broad evidence for hormonal regulation of MS in animal models and in clinical cohorts. Around menopause, many clinical patients report symptom worsening associated with hot flashes, sleep disturbance or mood changes. Additionally, individuals at MS may be at increased risk of developing osteoporosis. Longer-term, an age-related decline in gonadal steroids might represent one sex-specific influence on the known age-related increases in disability and conversion to progressive course, which is marked by accelerated brain volume loss and neurodegeneration. Recent data suggest that MS disease severity may worsen after menopause. Hormone therapy (HT). Despite the benefits of HT (menopausal symptoms, bone density), very few women (<30% of our cohort) are currently taking HT for menopausal symptoms; this is a result of risks such as (1) breast and endometrial cancer, and (2) stroke in older women in the Women's Health Initiative. Recent data on HT use in MS (Nurses Health Study) did not show any adverse effects on MS course, and women who used HT reported better physical function than women who did not (Bove et al, Neurology 2016). Study Drug: Duavee, a tissue selective estrogen complex (TSEC), combines conjugated estrogens (CE) with the selective estrogen receptor modulator (SERM) bazedoxifene (BZA). BZA offsets estrogenic stimulation of endometrial and breast tissue, and CE 0.45mg/BZA 20mg is approved for menopausal symptom (hot flash) relief and osteoporosis prevention, with a favorable tolerability and safety profile. In the current study, 24 women with MS and who are experiencing bothersome menopause symptoms will be enrolled and randomized to receive either 8 weeks of Duavee or 8 weeks of placebo. Visits will be: eligibility, baseline, and 2 month visit.

Official Title
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Effect of a Tissue Selective Estrogen Complex on Menopausal Symptoms in Women With MS: A Pilot Trial.

Conditions
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Menopause, Multiple Sclerosis

Intervention / Treatment
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* Drug: Tissue Selective Estrogen Complex
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 40-62 years. Perimenopausal: 6 months of amenorrhea; women who had a bi-lateral oophorectomy; women without a uterus and who still have one or both ovaries, with FSH level > 20 mIU/mL and estradiol ≤ 50 pg/mL; women with a uterus who have skipped 2 or more menstrual cycles with an amenorrhea interval; women who are using the Mirena IUD or who have had an endometrial ablation and who still have one or both ovaries, with FSH level > 20 mIU/mL and estradiol ≤ 50 pg/mL Bothersome MS symptoms: Mean of two or more hot flashes/night sweats per 24 hrs; Hot flashes/night sweats rated as bothersome ('moderately' to 'a lot') and/or severe ('moderate' to 'severe') on 4 or more 12 hour (day/night) blocks of times In general good health (determined by medical history, blood pressure, and heart rate) No history of endometrial, ovarian, or breast cancer; No abnormal mammogram in the last 2 years; Absence of any current severe or unstable medical illness MS considerations: If using psychotropic medications: no change in the past 3 months If on DMT, no change in past 6 months Normal vitamin D levels (20-50 ng/mL) Exclusion Criteria: BMI >35 kg/m2 as higher BMI may affect PK/PD Use of hormone therapy or hormonal contraceptives 2 months prior to enrollment Use of any prescribed therapy that is taken specifically for hot flashes in the past 1 month. Use of any over-the-counter or herbal therapies that are taken specifically for hot flashes in the past 2 weeks. Use of selective estrogen receptor modulators (SERMs) or aromatase inhibitors during the 2 months before enrollment. Known hypersensitivity or contraindications to estrogen. Drug or alcohol abuse in the past 1 year Depression: moderate or severe (HAD score > 8) Other psychiatric disease meeting DSM-IV criteria Lifetime diagnosis of psychosis or bipolar disorder. Pregnancy, intending pregnancy, or breast feeding History of any of the following, as determined by clinician review of the potential participant's medical history: Pre-breast cancer or high-risk breast cancer condition; Abnormal bleeding suggestive of endometrial pre-cancer; Endometrial hyperplasia; Asthma, diabetes mellitus, epilepsy, and migraine disorders that are not stable or under medical management; Active or past history of venous or arterial thromboembolism History of gallstones IF gallbladder intact Known or suspected estrogen-dependent neoplasia History of coronary artery disease Hypersensitivity (angioedema, anaphylaxis) to estrogens, bazedoxifene, or any ingredients Known hepatic impairment or disease Thyroid dysfunction on thyroid medications Known hypoparathyroidism Blood test results indicating: Liver function tests: AST >2.5 times upper limit of normal; ALT >2.5 times upper limit of normal; total bilirubin 1.5 times upper limit of normal; Kidney test: creatinine >1.5 mg/dL; Blood count: hematocrit <30%; Hemoglobin <8 g/dL. Current participation in another drug trial or intervention study. Inability or unwillingness to complete the study procedures. MS considerations: Clinical relapse within the last three months (to ensure disease stability) Steroid treatment in prior 1 month Evidence of other structural brain disease (e.g. prior stroke) MRI considerations: Metal implants Prior head trauma Claustrophobia requiring anxiolytic or sedation, or other contraindication to MRI.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 62 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duavee<br>1 Tablet of 0.45mg conjugated estrogens/20 mg bazedoxifene daily for 8 weeks | Drug: Tissue Selective Estrogen Complex<br>* Once-daily dosing of Duavee for 8 weeks.<br>* Other names: TSEC;|
| Placebo Comparator: Placebo<br>Placebo pill daily for 8 weeks. | Drug: Placebo<br>* Once-daily dosing of placebo for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hot Flash Related Daily Interference Scale (HFRDIS) Score | The interference of vasomotor symptoms (VMS) with daily life will be assessed using the HFRDIS. Scores range from 0 to 100; higher scores indicate greater interference of hot flashes with daily life. | Baseline and 8 weeks | 
| Change in Number of Participants Who Experienced a Reduction in Hot Flashes Per 24 Hours From Baseline to 8 Weeks | The number of daily vasomotor symptoms (VMS) will be collected in the form of hot flashes per 24 hours. The average hot flashes per day will be determined at 2 week intervals (baseline, 2 weeks, 4 weeks, and 8 weeks). The number of women experiencing reduction in hot flashes at week 8 compared to baseline will be counted; when baseline data is unavailable 1-2 week on study data will be used. | Baseline and 8 weeks | 
| Change in Average Hot Flashes Per Day From Baseline to 8 Weeks | The number of daily vasomotor symptoms (VMS) will be collected in the form of hot flashes per 24 hours. The average hot flashes per day will be determined at 2 week intervals (baseline, 2 weeks, 4 weeks, and 8 weeks). The average reduction in hot flashes per day over the course of the trial will be determined from the difference between 8 week and baseline frequency (by randomization group, treatment or placebo). When baseline data is not available, the 2 weeks on study data will be used as 'baseline'. Differences <0 indicate reduction in hot flash frequency over the course of the trial. | Baseline and 8 weeks | 
| Number of Participants Reporting Side Effects on the Treatment Satisfaction Questionnaire for Medication (TSQM) | The primary measure will be the percentage of subjects reporting side effects (yes or no) on the Satisfaction Questionnaire for Medication (TSQM). The TSQM is used to assess patients' satisfaction with medication, providing scores on four scales - side effects, effectiveness, convenience and global satisfaction. | 8 weeks | 
| Change in the Expanded Disability Status Scale (EDSS) | EDSS total score is a metric used for quantifying disability in MS and monitoring changes in the level of disability over time. The EDSS will be assessed by a the trial neurologist at baseline and end of study (8 weeks). The score range is 0 to 10; higher scores indicate greater disability. All analyses were performed according to the intention-to-treat principle (primary) then the per-protocol principle. | Baseline and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the MS Quality of Life 54 (MSQOL-54) | MS Quality of Life 54 (MSQOL-54) composite scores provide a patient reported quality of life score assessing physical QOL and mental QOL. A sub-scale of this assessment also assesses energy QOL. These will be measured at baseline and end of study (8 weeks). These scores fall within the range of 0 to 100; higher scores indicate better QOL within that domain or sub-scale. | Baseline and 8 weeks | 
| Change in the Bladder Control Scale (BLCS) | Bladder function will be assessed using the BLCS. Patient reported scores will be collected at baseline and at the end of study (8 weeks); scores fall within the range of 0 to 12. Higher scores indicate worse bladder function. | Baseline and 8 weeks | 
| Change in the Multiple Sclerosis Rating Scale (MSRS) | Patient reported disability will be measured by the MSRS at baseline and end of study (8 weeks). Scores range of 0 to 32; higher scores indicate worse patient reported disability. | Baseline and 8 weeks | 
| Change in the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) | Cognitive function will be assessed by the MSNQ at baseline and end of study (8 weeks). Scores range 0 to 60 (scores >27 indicate cognitive impairment). | Baseline and 8 weeks | 
| Change in the Symbol Digit Modalities Test (SDMT) Raw Score | SDMT is a screening instrument commonly used in clinical and research settings to assess cognitive dysfunction in MS. The SDMT will be administered at baseline and end of study (8 weeks). The final raw score is the correct number responses completed in 90 seconds and scores range between 0 and 110; higher scores indicate better performance. | Baseline and 8 weeks | 
| Change in SDMT Z-score | Regression-based norms for the SDMT were used to convert participants' raw scores at baseline and end of study (8 weeks) to demographically adjusted Z-scores, correcting for the effects of age, gender, and education. Scores are normalized so that 0 represents the mean, scores above 0 fall above the mean and are associated with greater performance on the SDMT. Scores below 0 fall below the mean and are associated with poorer performance on the SDMT. | Baseline and 8 weeks | 
| Change in Letter Number Sequencing (LNS) Performance | The LNS is administered to asses working memory and processing speed at baseline and end of study (8 weeks). The score range is 0 to 21; higher scores indicate better performance on this test. | Baseline and 8 weeks | 
| Number of Participants With New or Enhancing Lesions on MRI | To verify that CE+BZA does not yield any marked changes in inflammatory activity, a randomized subset of 12 participants will undergo MRI at baseline and end of study (8 weeks) to evaluate for new T2 lesions and new gadolinium enhancing lesions. | 8 weeks | 
| Number of Missed Doses | The number of missed doses will be assed at the end of study visit. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Women, Hot flash, Estrogen