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

Sponsor

Angelica Lindén Hirschberg (Other)

Overall Status

Recruiting

CT.gov ID

NCT05586724

Collaborator

(none)

390

Enrollment

Location

Arms

69.2

Anticipated Duration (Months)

5.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Menopausal Symptoms	Drug: Micronized progesterone in continuous combination with oral estrogen Drug: Norethisterone acetate in continuous combination with oral estrogen	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

390 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Feb 25, 2022

Anticipated Primary Completion Date :

Sep 1, 2026

Anticipated Study Completion Date :

Dec 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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®)	Drug: 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®)
Active Comparator: 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.	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

Arm

Intervention/Treatment

Active Comparator: 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®)

Drug: 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®)

Active Comparator: 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.

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

Outcome Measures

Primary Outcome Measures

Mammographic breast density [12 months treatment]
Percentage change in mammographic density
Endometrial pathology [12 months treatment]
The incidence of endometrial pathology (hyperplasia or cancer)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 60 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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