A TSEC for Symptom Management in Menopausal Women With Multiple Sclerosis

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.

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.