Effect of a Tissue Selective Estrogen Complex on Menopausal Symptoms in Women With MS: A Pilot Trial.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Hot Flash Related Daily Interference Scale (HFRDIS) Score
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 62 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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.
研究组 & 干预措施
Duavee
1 Tablet of 0.45mg conjugated estrogens/20 mg bazedoxifene daily for 8 weeks
干预措施: Tissue Selective Estrogen Complex (Drug)
Placebo
Placebo pill daily for 8 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Hot Flash Related Daily Interference Scale (HFRDIS) Score
时间窗: 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.
Change in Number of Participants Who Experienced a Reduction in Hot Flashes Per 24 Hours From Baseline to 8 Weeks
时间窗: 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.
Change in Average Hot Flashes Per Day From Baseline to 8 Weeks
时间窗: 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.
Number of Participants Reporting Side Effects on the Treatment Satisfaction Questionnaire for Medication (TSQM)
时间窗: 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.
Change in the Expanded Disability Status Scale (EDSS)
时间窗: 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.
次要结局
- Change in the MS Quality of Life 54 (MSQOL-54)(Baseline and 8 weeks)
- Change in the Bladder Control Scale (BLCS)(Baseline and 8 weeks)
- Change in the Multiple Sclerosis Rating Scale (MSRS)(Baseline and 8 weeks)
- Change in the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ)(Baseline and 8 weeks)
- Change in Letter Number Sequencing (LNS) Performance(Baseline and 8 weeks)
- Number of Participants With New or Enhancing Lesions on MRI(8 weeks)
- Number of Missed Doses(8 weeks)
- Change in the Symbol Digit Modalities Test (SDMT) Raw Score(Baseline and 8 weeks)
- Change in SDMT Z-score(Baseline and 8 weeks)