- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02710214
A TSEC for Symptom Management in Menopausal Women With Multiple Sclerosis (MS-TSEC)
Effect of a Tissue Selective Estrogen Complex on Menopausal Symptoms in Women With MS: A Pilot Trial.
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
California
-
San Francisco, California, United States, 94158
- University of California, San Francisco
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Duavee
1 Tablet of 0.45mg conjugated estrogens/20 mg bazedoxifene daily for 8 weeks
|
Once-daily dosing of Duavee for 8 weeks.
Other Names:
|
Placebo Comparator: Placebo
Placebo pill daily for 8 weeks.
|
Once-daily dosing of placebo for 8 weeks
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Hot Flash Related Daily Interference Scale (HFRDIS) Score
Time Frame: Baseline and 8 weeks
|
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
Time Frame: Baseline and 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
Time Frame: Baseline and 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)
Time Frame: 8 weeks
|
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)
Time Frame: Baseline and 8 weeks
|
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)
Time Frame: Baseline and 8 weeks
|
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)
Time Frame: Baseline and 8 weeks
|
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)
Time Frame: Baseline and 8 weeks
|
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)
Time Frame: Baseline and 8 weeks
|
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
Time Frame: Baseline and 8 weeks
|
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
Time Frame: Baseline and 8 weeks
|
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
Time Frame: Baseline and 8 weeks
|
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
Time Frame: 8 weeks
|
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
Time Frame: 8 weeks
|
The number of missed doses will be assed at the end of study visit.
|
8 weeks
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Riley M Bove, MD, Assistant Professor of Clinical Neurology
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan;15(1):35-46. doi: 10.1016/S1474-4422(15)00322-1. Epub 2015 Nov 29.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Immune System Diseases
- Demyelinating Autoimmune Diseases, CNS
- Autoimmune Diseases of the Nervous System
- Demyelinating Diseases
- Autoimmune Diseases
- Multiple Sclerosis
- Sclerosis
- Physiological Effects of Drugs
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Estrogens
Other Study ID Numbers
- P0512236
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Multiple Sclerosis
-
University Hospital, Basel, SwitzerlandSwiss National Science FoundationRecruitingMultiple Sclerosis (MS) | Relapsing-remitting Multiple Sclerosis (RRMS) | Secondary-progressive Multiple Sclerosis (SPMS) | Primary Progressive Multiple Sclerosis (PPMS)Switzerland
-
University of California, Los AngelesUnknownRelapsing-remitting Multiple Sclerosis | Secondary-progressive Multiple Sclerosis | Primary-progressive Multiple SclerosisUnited States
-
BiogenCompletedMultiple Sclerosis | Relapsing-Remitting Multiple Sclerosis | Secondary Progressive Multiple Sclerosis | Multiple Sclerosis, Primary Progressive | Multiple Sclerosis, Remittent ProgressiveJapan
-
The Cleveland ClinicUniversity Hospitals Cleveland Medical CenterCompletedRelapsing-Remitting Multiple Sclerosis | Secondary Progressive Multiple Sclerosis | Progressive Relapsing Multiple SclerosisUnited States
-
Rigshospitalet, DenmarkOdense University Hospital; Aarhus University Hospital; Hvidovre University Hospital and other collaboratorsRecruitingRelapsing Remitting Multiple Sclerosis | Primary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisDenmark
-
University of California, San FranciscoUnited States Department of DefenseRecruitingMultiple Sclerosis, Chronic Progressive | Multiple Sclerosis, Relapsing-Remitting | Multiple Sclerosis (MS) | Multiple Sclerosis Relapse | Multiple Sclerosis, Primary Progressive | Multiple Sclerosis Brain Lesion | Multiple Sclerosis BenignUnited States
-
Icahn School of Medicine at Mount SinaiColumbia University; New York Stem Cell Foundation Research InstituteCompletedClinically Isolated Syndrome | Relapsing-Remitting Multiple Sclerosis | Primary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisUnited States
-
Brigham and Women's HospitalMassachusetts General HospitalRecruitingMultiple Sclerosis | Relapsing Multiple Sclerosis | Primary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisUnited States
-
University of MinnesotaMallinckrodtTerminatedPrimary Progressive Multiple Sclerosis | Secondary Progressive Multiple Sclerosis | Progressive Relapsing Multiple SclerosisUnited States
-
Queen Mary University of LondonTakeda Pharmaceuticals International, Inc.RecruitingRelapsing Remitting Multiple Sclerosis | Primary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisUnited Kingdom
Clinical Trials on Tissue Selective Estrogen Complex
-
Juan Gonzalo OlivieriRecruitingDental Caries | Dental MaterialsSpain
-
Faculty Sao Leopoldo Mandic CampinasCompleted
-
Pennington Biomedical Research CenterCompleted
-
Robert Bosch Gesellschaft für Medizinische Forschung...Completed
-
University Hospital, GhentUniversity Hospital, Antwerp; AZ Jan Palfijn Gent; Gedeon Richter Plc.; Our Lady...TerminatedPolycystic Ovary Syndrome | Ovulation Induction | Clomiphene | InositolBelgium
-
Vanderbilt-Ingram Cancer CenterNational Cancer Institute (NCI)TerminatedRecurrent Melanoma | Stage IV Melanoma | Stage IIIc MelanomaUnited States
-
University of Southern CaliforniaAstraZenecaTerminatedBreast CarcinomaUnited States
-
Eli Lilly and CompanyCompleted
-
Northwestern UniversityNational Cancer Institute (NCI)CompletedEndometrial CancerUnited States
-
Fundació Sant Joan de DéuCompleted