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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Karolinska University Hospital

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Decision date (initial)

2025-01-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-520435-33-00

EudraCT number

2021-001624-17

ClinicalTrials.gov

NCT05586724

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

Part 1 Breast safety - a double-blind, randomized study design: To compare the effects of one year treatment with mP versus NETA, both in combination with estradiol, on mammographic breast density.

Part 2 Endometrial safety – open, single arm, study design: To evaluate the effect of one-year treatment with mP in continuous combination with estradiol on endometrial pathology (hyperplasia and cancer).

Secondary objectives 9

1. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on breast cell proliferation
2. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on endometrial cell proliferation
3. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on endometrial thickness using ultrasound
4. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on bleeding pattern
5. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue
6. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on depression and anxiety symptoms (PHQ-9, HADS)
7. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on health-related quality of life (PGWB)
8. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on women’s Health Questionnaire (WHQ)
9. To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on blood lipid profile, serum hormones, growth and metabolic factors, and coagulation factors

Conditions and MedDRA coding

Climacteric symptoms

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Healthy and naturally postmenopausal women (more than one year since last menstruation or FSH > 40 IE/L) with climacteric symptoms (sweating, hot flush and sleep problems) that adversely affect quality of life.
2. Age 45-60 years
3. BMI > 19 kg/m2 and ≤ 32 kg/m2
4. Intact uterus
5. In case of previous MHT use, washout 8 weeks for oral MHT and 4 weeks for transdermal MHT or local estrogen treatment before screening
6. Written informed consent

Exclusion criteria 12

1. Previous history or risk factors for breast cancer, breast cancer in situ or abnormal mammogram at baseline as assessed clinically by a radiology expert
2. Previous history or risk factors for endometrial cancer or hyperplasia or abnormal/proliferative endometrial biopsy at baseline
3. Vaginal bleeding
4. Any concomitant medical treatment except for well-controlled hypertension, non-insulin treated type 2 diabetes, asthma and hypothyroidism
5. History or presence of or risk factor for cardiovascular disease including thromboembolic disorder or cerebrovascular disease
6. History or presence of liver and gallbladder disease, familial hyperlipidemia, epilepsy or classical migraine with aura
7. 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
8. Porphyria, Systemic lupus erythematosus and otosclerosis
9. Current use of MHT or local estrogen treatment
10. Alcohol and/or drug abuse
11. Clinically significant findings on physical and/or gynecological examination at baseline
12. Hypersensitivity to any of the study treatments

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage change in mammographic density compared between the groups.

Secondary endpoints 8

1. Incidence of endometrial proliferation (proliferation marker (Ki67)
2. Endometrial thickness on ultrasound
3. Bleeding pattern as documented in a bleeding diary
4. Gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue
5. Depression and anxiety symptoms (Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS))
6. Health-related quality of life (Psychological General Well-Being Index (PGWB))
7. Women’s Health Questionnaire (WHQ)
8. Blood lipid profile, serum hormones, growth and metabolic factors (follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, sex hormone-binding globulin, IGF–I and its binding proteins), and coagulation factors (antitrombin, factor V Leiden, factor II mutation, cardiolipin-ab, Lupus anticoagulant, Protein C activity, Protein S free, APT-time, fibrinogen, prothrombin complex, thrombocytes).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karolinska University Hospital

Sponsor organisation

Karolinska University Hospital

Address

Eugeniavagen 3

City

Solna

Postcode

171 64

Country

Sweden

Scientific contact point

Organisation

Karolinska University Hospital

Contact name

Angelica Lindén Hirschberg

Public contact point

Organisation

Karolinska University Hospital

Contact name

Angelica Lindén Hirschberg

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications