Copenhagen Menopause Study (COMPASS): A Randomized Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 192
- 试验地点
- 1
- 主要终点
- Change in bone remodeling from baseline to week 8.
研究概览
简要总结
During menopause, estrogen levels drop while the level of another hormone - LH (luteinizing hormone) substantially increases. This hormonal shift is linked to bone Loss and other complications. Estrogen therapy can help, but some women avoid it due to the increased risk of blood clots and cancer. This project will investigate whether blocking LH could offer a safe alternative to alleviate symptoms and complications of menopause since it is known from previous research that high LH levels contribute to both bone deterioration and metabolic issues. The goal is to explore new treatment options that can improve health and quality of life for women both during and after menopause. This randomized clinical trial is a single center, sponsor-investigator-initiated single-blinded 8 weeks clinical trial with four parallel groups comparing the effect of an gonadotropin releasing hormone(GnRH)-analog with placebo, and with two additional arms given estrogen or testosterone on change on bone health in postmenopausal women with moderate-to-severe symptoms.
详细描述
The hormonal changes occurring in perimenopause and menopause exert multiple effects on several organs and the accompanied symptoms can be very distressing and impair quality of life. Vasomotor symptoms (VMS) defined as hot flashes and sweating are the most frequent and bothersome symptoms of menopause and are experienced by up to 80% of women. Additionally, in the Western world, 66% of postmenopausal women are obese and 54% have osteoporosis. Along with obesity comes a wide variety of health issues such as type 2 diabetes, metabolic syndrome, and atherosclerosis, which can lead to cardiovascular disease. Osteoporosis is a huge economic cost for society, it impairs quality of life and vertebral and hip fractures are associated with increased mortality. Postmenopausal symptoms and complications take a large toll on both the physical and mental well-being of women and are a huge cost to society. Menopausal Hormonal Therapy (MHT) with estrogen and gestagen is used by many women as it alleviates symptoms and reduces the risk of osteoporosis and cardiovascular disease. However, due to the increased risk of breast cancer and venous thromboembolism, some women refuse MHT and there is an ongoing search for new treatments. The newly approved Veoza® (Fezolinetant) is also approved and on the marked, but only targets VMS and not menopausal complications, but can be a treatment option, if the woman can or will not have MHT.
Menopause is characterized by low circulating estrogen, but also by very high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and these hormonal changes are linked with increased bone resorption and weight gain. Despite the high LH in menopause, LH pulses occur simultaneously with hot flashes also in postmenopausal women, and LH may be involved in the events. In a clinical study 10 postmenopausal women with severe VMS were given a GnRH antagonist cetrorelix 250 μg two times a day in 6 weeks. They found a significant decrease in VMS symptoms. Postmenopausal women experience a decline in core temperature, which we suggest is due to LH actions on brown and white fat cells leading to less heat generation, beta-oxidation, and more storing of fat. Furthermore, LH appears to be a rapid and potent inducer of renal calcium excretion, which induces a secondary and persistent increase in parathyroid hormone (PTH) that mobilizes calcium from the skeleton. The LH-induced calcium excretion occurs several hours before the subsequent changes in sex steroids, particularly estrogen, which indicates a direct effect of LH that can lead to increased bone resorption and eventually osteoporosis. This may be of great importance during the perimenopause/early phase of menopause, where the decrease in bone mineral density and increase in visceral adiposity is high concurrent with serum LH increasing dramatically, while serum estrogen is still not greatly reduced. The investigators propose to investigate if lowering LH using a gonadotropin releasing hormone (GnRH) analog against placebo can improve bone markers and secondarily reduce the frequency and severity of VMS in postmenopausal women with a direct comparison to estrogen - the gold standard treatment of women in menopause, and testosterone in the same RCT.
The main aim of the study is to show that by targeting LH the investigators can change bone markers and maybe even combat hot flashes and night sweats (VMS) in postmenopausal women. For important biological knowledge purpose, the investigators also investigate the 2 additional treatment arms with estradiol and testosterone to compare the effect against the current gold standard treatment option (estradiol) and to testosterone, which is a common supplement to postmenopausal women off-label. A study by Glaser et al. effectively documents that testosterone can improve most common post-menopausal symptoms.
Sample size calculation and statistics Previous studies have shown that CTX in postmenopausal women is usually between 0.44 ng/mL with a standard diviation on SD 0.2. The sample size is calculated based on a direct comparison between GnRH analog (pamorelin) and placebo on the primary outcome 'change in bone markers' (delta CTX between pamorelin and placebo), using a power of 80% and alpha of 0.05 leads to 44 participants in each group, and the investigators would be able to detect a change in CTX on 30 %. The calculations is based on only two arms, however for comparison reasons the investigators will include two extra arms with estradiol/testosterone and patients will be allocated 1:1:1:1 leading to a total sample size of 176 participants. Our design and analysis principles rely on the intent-to-treat (ITT) approach; the investigators strive to evaluate and include all randomized participants in the primary analysis, regardless of adherence to treatment assignment or protocol requirements.
The investigators estimate to screen 250 to include 192 to be randomized and 176 to complete the study leaving 16 patients for dropout (9%). The design enables us to investigate multiple secondary outcomes where the primary comparison will be between GnRH analog treatment and placebo. The study is not powered to show significant differences between placebo and GnRH treatment for most secondary endpoints and should be considered as a pilot placebo-controlled intervention study for these outcomes. T-tests will be used for the primary endpoint, while Nonresponder imputation will be used for missing response data. Change in mean frequency and severity of VMS per 24 hours will be analyzed for each week using a mixed effect model for repeated measures, with change from baseline as the dependent variable and treatment group, visit, and smoking status as factors and baseline measurement as a covariate, as well as interaction of treatment by week and an interaction of baseline measurement by week.
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
- Single (Participant)
入排标准
- 年龄范围
- 40 Years 至 65 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Women >40 years and ≤65 at screening visit
- •A body mass index between 18-35
- •Confirmed menopause
- •Spontaneous amenorrhea for ≥12 consecutive months
- •Negative urine hCG test
- •Spontaneous amenorrhea for ≥6 months
- •FSH >30 mIU/L
- •Negative urine hCG test
- •Moderate to severe vasomotor symptoms (VMS)
- •Within the 7 days prior to randomization, participants must report ≥ 14 moderate to severe VMS per week
排除标准
- •Current or previous hormone replacement therapy (HRT)
- •Vaginal estradiol/vaginal inserts (e.g. Vagifem®) can be used, but will have to be pause 2 weeks prior to randomization and throughout the study period
- •Menopausal Hormone Therapy (MHT) can be used by participants, but must be paused 6 weeks prior to inclusion.
- •Current or previous cancer diagnosis
- •Except for basal cell carcinoma
- •Known BRCA gene mutation
- •Current hyperthyroid disease
- •Osteoporosis
- •Major psychiatric diagnosis including ongoing medication e.g. selective serotonin re-uptake inhibitors (SSRIs)
- •Known prolonged QT or other known clinically significant abnormal ECG, including taking medication that can prolong QT interval (e.g. sotalol, dronedarone, amiodarone, methadone, and several antipsychotic drugs)
- •Previous myocardial infarction or heart failure
- •Previous thromboembolic event
- •The use of opioids, anticoagulating treatment or unwilling to pause fish oil/Omega-3 supplements 3 days prior visit 1 and 3
- •Current alcohol or drug abuse
- •Hypertension treated with more than two drugs
- •Severe history of allergy, hypersensitivity, or intolerance to drugs
- •Moderate to severe liver and kidney disease (eGFR <60 mL/min)
- •Diagnosed with type 1 or 2 diabetes
- •Chronic diseases requiring immunomodulatory treatments such as rheumatoid arthritis, inflammatory bowel disease, and vasculitis etc.
- •Known uterine fibroids, Endometriosis, Systemic lupus erythematosus (SLE), otosclerosis, severe migraine or sleep apnea
- •Known Epilepsy or previous seizures or convulsive disorder
研究组 & 干预措施
GnRH analog
Pamorelin 11.25 mg intramuscular injection once + Daily placebo gel
干预措施: Triptorelin 11.25 mg (Drug)
GnRH analog
Pamorelin 11.25 mg intramuscular injection once + Daily placebo gel
干预措施: Placebo gel (Drug)
Placebo
Saline intramuscular injection once + Daily placebo gel
干预措施: Sodium Chloride 0.9% (Drug)
Placebo
Saline intramuscular injection once + Daily placebo gel
干预措施: Placebo gel (Drug)
Transdermal Estrogen
Saline intramuscular injection once + Estreva gel 1.5 mg daily
干预措施: Sodium Chloride 0.9% (Drug)
Transdermal Estrogen
Saline intramuscular injection once + Estreva gel 1.5 mg daily
干预措施: Estradiol (E2) (Drug)
Transdermal testosterone
Saline intramuscular injection once + Tostran gel 10 mg every other day + placebo gel every other day
干预措施: Sodium Chloride 0.9% (Drug)
Transdermal testosterone
Saline intramuscular injection once + Tostran gel 10 mg every other day + placebo gel every other day
干预措施: Testosterone (Drug)
Transdermal testosterone
Saline intramuscular injection once + Tostran gel 10 mg every other day + placebo gel every other day
干预措施: Placebo gel (Drug)
结局指标
主要结局
Change in bone remodeling from baseline to week 8.
时间窗: From baseline to week 8
Change in bone remodeling defined by change in bone marker (ΔCTX) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1. GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2. Combined analysis of all 4 arms of the RCT 3. GnRH analog and estradiol 4. GnRH analog and testosterone 5. Estradiol and placebo 6. Testosterone and placebo 7. Estradiol and testosterone
Change in bone remodeling from baseline to week 8
时间窗: From baseline to week 8
Change in bone remodeling defined by change in bone marker-ratios (ΔCTX/ΔP1NP, and ΔBBI) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone
次要结局
- Change in sexual function evaluated with female sexual function index from baseline to week 8(Baseline to week 8)
- Change in sexual function evaluated with female sexual distress scale-revised from baseline to week 8(Baseline to week 8)
- Change in serum levels of Hypothalamic-Pituitary-Adrenal (HPA) axis from baseline to week 8(Baseline to week 8)
- Change in depressive symptoms evaluated by MDI from baseline to week 8(Baseline to week 8)
- Change in serum levels of Hypothalamic-Pituitary-Gonadal (HPG) axis from baseline to week 8(Baseline to week 8)
- Change in serum levels of Hypothalamic-Pituitary-Thyroid (HPT) axis from baseline to week 8(Baseline to week 8)
- Change in quality of life evaluated with MENQOL-1 from baseline to week 8(Baseline to week 8)
- Change in depressive symptoms evaluated by CES-D from baseline to week 8(Baseline to week 8)
- Change in anxiety symptoms evaluated by GAD-7 from baseline to week 8(Baseline to week 8)
- Change in The Mean Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) from baseline to week 8(Baseline to week 8)
- Change in thyroid hormones from baseline to week 4 and 8(Baseline to week 4 and 8.)
- Change in urine calcium from baseline to weeks 4 and 8(Baseline to weeks 4 and 8)
- Change in urine creatinine from baseline to weeks 4 and 8(Baseline to weeks 4 and 8.)
- Change in urine phosphate from baseline to weeks 4 and 8(Baseline to weeks 4 and 8)
- Change in urine magnesium from baseline to weeks 4 and 8(Baseline to weeks 4 and 8)
- Change in urine sodium from baseline to weeks 4 and 8(Baseline to weeks 4 and 8)
- Change in urine cortisol and other hormones from baseline to weeks 4 and 8(Baseline to weeks 4 and 8.)
- Change in serum ionized calcium from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in serum calcium from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in serum albumin from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in serum PTH from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in serum phosphate from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in serum vitamin D metabolites from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in serum hCG from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in thyroid hormone conversion (DIO2 activity) in fat cells determined by their conversion of T4 to T3 from baseline to week 8(Baseline to week 8)
- Change in adrenal hormones from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in the mean frequency of moderate to severe VMS from Baseline to week 8(Baseline to week 8)
- Change in the mean frequency of moderate to severe VMS from Baseline to week 4(Baseline to week 4)
- Change in the mean severity-score from Baseline to week 8(Baseline to week 8)
- Change in the mean severity-score from Baseline to week 4(Baseline to week 4)
- Change in VMS measured by the Greene Climacteric Scale (GCS) from baseline to week 8(Baseline to week 8)
- Change in serum LH from baseline to weeks 4 and 8(Baseline to weeks 4 and 8)
- Change in serum FSH from baseline to weeks 4 and 8(Baseline to weeks 4 and 8)
- Change in serum estradiol from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in serum SHGB from baseline to week 4 and 8(Baseline to week 4 and 8)
- Change in physical strength tests from baseline to weeks 4 and 8.(Baseline to weeks 4 and 8.)
- Change in androgens from baseline to weeks 4 and 8(Baseline to weeks 4 and 8.)
研究者
Martin Blomberg Jensen
Professor
Copenhagen University Hospital at Herlev