Micronized Progesterone Versus Norethisterone Acetate in Combination With Estrogen as Menopausal Hormone Therapy

Study Overview
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Brief Summary
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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).

Detailed Description
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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. 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. The gut- and vaginal microbiome will be characterized and compared between groups.

Official Title
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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)

Conditions
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Menopausal Symptoms

Intervention / Treatment
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* Drug: Micronized progesterone in continuous combination with oral estrogen
* Drug: Norethisterone acetate in continuous combination with oral estrogen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Micronized progesterone in continuous combination with oral estrogen<br>Capsule 100 mg mP (Utrogestan®) orally per day in continuous combination with 1 mg encapsulated estradiol (Estrofem®) | Drug: Micronized progesterone in continuous combination with oral estrogen<br>* Capsule 100 mg mP (Utrogestan®) orally per day in continuous combination with 1 mg encapsulated estradiol (Estrofem®)<br>|
| Active Comparator: Norethisterone acetate in continuous combination with oral estrogen<br>Capsule 0.5 mg NETA/ 1 mg estradiol (Activelle®) orally per day (encapsulated and identical to Estrofem® and one matched placebo to Utrogestan. | Drug: Norethisterone acetate in continuous combination with oral estrogen<br>* Capsule 0.5 mg NETA/ 1 mg estradiol (Activelle®) orally per day (encapsulated and identical to Estrofem® and one matched placebo to Utrogestan<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mammographic breast density | Percentage change in mammographic density | 12 months treatment | 
| Endometrial pathology | The incidence of endometrial pathology (hyperplasia or cancer) | 12 months treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast cell proliferation | Percentage change in breast cell proliferation (proliferation marker Ki-67) | 12 months treatment | 
| Endometrial cell proliferation | Percentage change in endometrial cell proliferation (histology classification and proliferation marker Ki-67) | 12 months treatment | 
| Endometrial thickness | Change in endometrial thickness by ultrasound | 12 months treatment | 
| Bleeding pattern | Bleeding patterns registered in diary (number of days of bleedings) | 3, 6, 9 and 12 months | 
| Gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue | Change in gene and protein expression (proliferation and apoptosis markers) | 12 months treatment | 
| Depression (PHQ-9) | Change in score of PHQ-9: A 4-point scale where a larger value reflects more depression. | 12 months treatment | 
| Anxiety (HADS) | Change in score of HADS: A 4-point scale where a larger value reflects more anxiety. | 12 months treatment | 
| Quality of life (PGWB) | Change in score of PGWBI, where a where a higher score reflects more well-being. | 12 months treatment | 
| Menopausal symptoms (WHQ) | WHQ: A 4-point scale where a larger value reflects less menopausal symptoms. | 12 months treatment | 
| Serum levels of hormones, growth factors, lipids and coagulation factors. | Change in serum levels of these markers | 12 months treatment | 
| Gut- and vaginal microbiome | Change in microbiome diversity and relative abundance of different microbial species. | 12 months treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menopausal hormone therapy, Climacteric symptoms, Progesterone, Progestogens, Breast safety, Endometrial safety