Clinical trial NCT02710214: A TSEC for Symptom Management in Menopausal Women With Multiple Sclerosis
Official title: Effect of a Tissue Selective Estrogen Complex on Menopausal Symptoms in Women With MS: A Pilot Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Menopause
Multiple Sclerosis
Keywords: Hot flash
Estrogen
Women
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Multiple Sclerosis Society
First posted: 2016-03-16
Enrollment: 24
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Hot Flash Related Daily Interference Scale (HFRDIS) Score
timeFrame: Baseline and 8 weeks
measure: Change in Number of Participants Who Experienced a Reduction in Hot Flashes Per 24 Hours From Baseline to 8 Weeks
timeFrame: Baseline and 8 weeks
measure: Change in Average Hot Flashes Per Day From Baseline to 8 Weeks
timeFrame: Baseline and 8 weeks
measure: Number of Participants Reporting Side Effects on the Treatment Satisfaction Questionnaire for Medication (TSQM)
timeFrame: 8 weeks
measure: Change in the Expanded Disability Status Scale (EDSS)
timeFrame: Baseline and 8 weeks
Secondary outcomes:
measure: Change in the MS Quality of Life 54 (MSQOL-54)
timeFrame: Baseline and 8 weeks
measure: Change in the Bladder Control Scale (BLCS)
timeFrame: Baseline and 8 weeks
measure: Change in the Multiple Sclerosis Rating Scale (MSRS)
timeFrame: Baseline and 8 weeks
measure: Change in the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ)
timeFrame: Baseline and 8 weeks
measure: Change in the Symbol Digit Modalities Test (SDMT) Raw Score
timeFrame: Baseline and 8 weeks
measure: Change in SDMT Z-score
timeFrame: Baseline and 8 weeks
measure: Change in Letter Number Sequencing (LNS) Performance
timeFrame: Baseline and 8 weeks
measure: Number of Participants With New or Enhancing Lesions on MRI
timeFrame: 8 weeks
measure: Number of Missed Doses
timeFrame: 8 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
Study officials:
affiliation: Assistant Professor of Clinical Neurology
name: Riley M Bove, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bove R, Healy BC, Musallam A, Glanz BI, De Jager PL, Chitnis T. Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort. Mult Scler. 2016 Jun;22(7):935-43. doi: 10.1177/1352458515606211. Epub 2015 Oct 7.
citation: Bove R, Chitnis T, Houtchens M. Menopause in multiple sclerosis: therapeutic considerations. J Neurol. 2014 Jul;261(7):1257-68. doi: 10.1007/s00415-013-7131-8. Epub 2013 Oct 8.
citation: Bove R, Healy BC, Secor E, Vaughan T, Katic B, Chitnis T, Wicks P, De Jager PL. Patients report worse MS symptoms after menopause: findings from an online cohort. Mult Scler Relat Disord. 2015 Jan;4(1):18-24. doi: 10.1016/j.msard.2014.11.009. Epub 2014 Dec 9.
citation: Bebo BF Jr, Dehghani B, Foster S, Kurniawan A, Lopez FJ, Sherman LS. Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis. Glia. 2009 May;57(7):777-90. doi: 10.1002/glia.20805.
citation: Boccardi M, Ghidoni R, Govoni S, Testa C, Benussi L, Bonetti M, Binetti G, Frisoni GB. Effects of hormone therapy on brain morphology of healthy postmenopausal women: a Voxel-based morphometry study. Menopause. 2006 Jul-Aug;13(4):584-91. doi: 10.1097/01.gme.0000196811.88505.10.
citation: Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA, De Jager PL. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology. 2014 Jan 21;82(3):222-9. doi: 10.1212/WNL.0000000000000033. Epub 2013 Dec 11.
citation: North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012 Mar;19(3):257-71. doi: 10.1097/gme.0b013e31824b970a.
citation: Pozzilli C, De Giglio L, Barletta VT, Marinelli F, Angelis FD, Gallo V, Pagano VA, Marini S, Piattella MC, Tomassini V, Pantano P. Oral contraceptives combined with interferon beta in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2015 Jun 18;2(4):e120. doi: 10.1212/NXI.0000000000000120. eCollection 2015 Aug.
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