Safety of Oral Micronized Progesterone Versus Norethisterone Acetate in Continuous Combination With Oral Estrogen as Menopausal Hormone Therapy - a Double-blind Randomized Study- PROBES Study (Progesterone Breast Endometrial Safety Study)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 520
- 试验地点
- 1
- 主要终点
- Mammographic breast density
研究概览
简要总结
About one third of all women during menopausal transition have significant climacteric symptoms with considerable impact on quality of life. Meta-analysis has shown a beneficial risk profile with menopausal hormone therapy (MHT) for women 50 to 60 years. Still, there is a great need to find safe MHT able to control excessive endometrial stimulation by estrogen without stimulatory effects on the breast by the combination of estrogen/progestogen. Recent observational studies indicate a lower risk for breast cancer using micronized progesterone (mP) combined with estrogen but increased risk of endometrial cancer than by standard MHT. In a randomized trial, the balance between benefits and risks of mP vs. progestogens (norethisterone (NETA)) in combination with estrogen will be explored. For apparent reasons, long-term largescale clinical trials with endometrial and breast cancer as the primary endpoints, are not feasible. However, much knowledge can be obtained using relevant surrogate markers. Mammographic breast density is a strong risk factor for breast cancer, and endometrial hyperplasia is a strong risk factor for endometrial cancer. The primary objective is to compare the effects of one year treatment with mP versus progestogen, in combination with estradiol on mammographic breast density. Furthermore, to evaluate the effect of one year treatment with mP in continuous combination with estradiol on endometrial pathology (hyperplasia and cancer).
详细描述
Postmenopausal women with climacteric symptoms will be randomized (1:1) to double blind treatment with oral mP or NETA in combination with oral estradiol. For the breast part, a power analysis revealed that 91 women/group would be sufficient to detect a significant difference in mammographic breast density between the groups at the 5%-level (two-sided) with 80% power. Considering the estimated rate of discontinuation and incomplete data, the target sample for the breast part is 260 patients. For the endometrial part, it is estimated that two or less women with serious adverse endometrial outcomes would result in an annual incidence of endometrial pathology of 0.67% or less with an upper bound of the one-sided 95% CI of 2.08% or less. Considering the estimated rate of discontinuation and incomplete data in the mP + estradiol group, the target sample for this part of the study is 390 patients. The total number of patients in part 1 and 2 will be 520.
Mammography at baseline and after 12 months of treatment will be assessed by independent radiologists at the Karolinska University Hospital blinded to treatment. In addition to visual judgment, a computer based quantitative assessment will be performed. All mammograms will be anonymous so that the operator will be unaware of the patient's identity and type of treatment. Percentage change in mammographic density will be evaluated and compared between the groups.
Endometrial biopsies at baseline and after 12 months of treatment will be evaluated by two independent pathologists at the Karolinska University Hospital for the incidence of endometrial pathology (hyperplasia or cancer) in the mP + estradiol group. Furthermore, immunostaining of the proliferation marker Ki-67, and other markers related to proliferation and apoptosis will be analyzed and compared between groups.
Different validated self-assessment questionnaires will be used for screening of mood disorders like depression and anxiety, as well as quality of life and menopausal symptoms. The Patient Health Questionnaire (PHQ-9) is a tool for screening, diagnosing, and measuring the severity of depression. The Hospital Anxiety and Depression Scale (HADS) is an instrument for detecting states of depression and anxiety in the setting of a hospital or medical outpatient clinic. Health related quality of life is measured using the Psychological General Well-Being Index (PGWB). The Women's Health Questionnaire (WHQ) measures menopausal symptoms. The change in scores will be compared between the groups.
Blood lipid profile, serum hormones, growth and metabolic factors, and coagulation factors will be analyzed.
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
- 45 Years 至 60 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Healthy and naturally postmenopausal women (more than one year since last menstruation or FSH > 40 IE/L) with climacteric symptoms (sweating, hot flush and/or sleep problems) that adversely affect the quality of life
- •Age 45-60 years
- •BMI > 19 kg/m2 and ≤ 32 kg/m2
- •Intact uterus
- •In case of previous MHT use, washout 8 weeks for oral MHT and 4 weeks for transdermal MHT or local estrogen treatment before screening
- •Written informed consent
排除标准
- •Previous history or risk factors for breast cancer, breast cancer in situ or abnormal mammogram at baseline as assessed clinically by a radiology expert
- •Previous history or risk factors for endometrial cancer or hyperplasia or abnormal/proliferative endometrial biopsy at baseline
- •Vaginal bleeding
- •Any concomitant medical treatment except for well-controlled hypertension, non-insulin treated type 2 diabetes, asthma and hypothyroidism
- •History or presence of or risk factor for cardiovascular disease including thromboembolic disorder or cerebrovascular disease
- •History or presence of liver and gallbladder disease, familial hyperlipidemia, epilepsy or classical migraine with aura
- •History or presence of clinically significant depression or other psychiatric disorder that might in anyway compromise the performance of the trial or undermine its scientific validity
- •Porphyria, Systemic lupus erythematosus and otosclerosis
- •Current use of MHT or local estrogen treatment
- •Alcohol and/or drug abuse
- •Clinically significant findings on physical and/or gynecological examination at baseline
- •Hypersensitivity to any of the study treatments
研究组 & 干预措施
Micronized progesterone in continuous combination with oral estrogen
Capsule 100 mg mP (Utrogestan®) orally per day in continuous combination with 1 mg encapsulated estradiol (Estrofem®)
干预措施: Micronized progesterone in continuous combination with oral estrogen (Drug)
Norethisterone acetate in continuous combination with oral estrogen
Capsule 0.5 mg NETA/ 1 mg estradiol (Activelle®) orally per day (encapsulated and identical to Estrofem® and one matched placebo to Utrogestan.
干预措施: Norethisterone acetate in continuous combination with oral estrogen (Drug)
结局指标
主要结局
Mammographic breast density
时间窗: At baseline and 12 months treatment
Percentage change in mammographic density
Endometrial pathology
时间窗: At baseline and 12 months treatment
The incidence of endometrial pathology (hyperplasia or cancer)
次要结局
- Breast cell proliferation(At baseline and 12 months treatment)
- Endometrial histology and cell proliferation(At baseline and 12 months treatment)
- Bleeding pattern(3, 6, 9 and 12 months)
- Quality of life (PGWB)(At baseline and 12 months treatment)
- Depression (PHQ-9)(At baseline and 12 months treatment)
- Endometrial thickness(At baseline and 12 months treatment)
- Gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue(At baseline and 12 months treatment)
- Anxiety (HADS)(At baseline and 12 months treatment)
- Serum levels of hormones, growth factors, lipids and coagulation factors.(At baseline and 12 months treatment)
- Gut- and vaginal microbiome(At baseline and 12 months treatment)
- Menopausal symptoms (WHQ)(At baseline and 12 months treatment)
研究者
Angelica Lindén Hirschberg
Professor, MD, PhD
Karolinska University Hospital