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Eligibility
for females ages 18 years to 62 years
Location
at San Francisco, California
Dates
study started
estimated completion:
Principal Investigator

Description

Summary

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.

Official Title

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

Details

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). In healthy women, after the abrupt decline in estradiol occurring with early oophorectomy, there is an increased risk for cognitive decline and dementia and gray matter (GM) loss in functionally important regions (e.g. hippocampus). Hormonal therapy (HT), when taken within a perimenopausal "window of opportunity" (5 years), may protect against neurodegeneration. 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. To date, there are no objective assessments of the impact of HT on MS disease course.
  • 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. Additionally, two recent randomized clinical trials of estrogenic compounds in MS [estriol (Voskuhl et al) and of ethinylestradiol 40 μg and desogestrel 125 μg (Pozzili et al 2015) found either a neutral or beneficial effect on inflammatory outcomes. Altogether, these findings suggest that CE+BZA may be a promising and safe agent in MS.

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.

Keywords

Menopause Multiple Sclerosis Hot flash Estrogen Women Estrogens

Eligibility

You can join if…

Open to females ages 18 years to 62 years

  • Women aged 40-62 years.
  • Perimenopausal: 6 months of amenorrhea
  • Women whom had a bi-lateral oöphorectomy
  • 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
  • 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)

You CAN'T join if...

  • BMI>30 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:

  • Left handed
  • Metal implants
  • Prior head trauma
  • Claustrophobia requiring anxiolytic or sedation, or other contraindication to MRI.

Location

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
University of California, San Francisco
ID
NCT02710214
Phase
Phase 2
Lead Scientist
Riley Bove
Study Type
Interventional
Last Updated
March 2016
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