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

NCT05586724 | Recruiting Phase 3

• 1 other identifier: 2021-001624-17
• Study Type: interventional
• Target: 520
• Locations: 1 country
• Sites: 1

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).

Conditions

Menopausal Symptoms

Keywords

Menopausal hormone therapy; Climacteric symptoms; Progesterone; Progestogens; Breast safety; Endometrial safety

Outcome Measures

Primary Outcomes (2)

• Mammographic breast density

  Percentage change in mammographic density

  At baseline and 12 months treatment

• Endometrial pathology

  The incidence of endometrial pathology (hyperplasia or cancer)

  At baseline and 12 months treatment

Secondary Outcomes (11)

• Breast cell proliferation

  At baseline and 12 months treatment

• Endometrial histology and cell proliferation

  At baseline and 12 months treatment

• Endometrial thickness

  At baseline and 12 months treatment

• Bleeding pattern

  3, 6, 9 and 12 months

• Gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue

  At baseline and 12 months treatment

Study Arms (2)

Micronized progesterone in continuous combination with oral estrogen

ACTIVE COMPARATOR

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

Norethisterone acetate in continuous combination with oral estrogen

ACTIVE COMPARATOR

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

Interventions

Micronized progesterone in continuous combination with oral estrogen DRUG

Capsule 100 mg mP (Utrogestan®) orally per day in continuous combination with 1 mg encapsulated estradiol (Estrofem®)

Micronized progesterone in continuous combination with oral estrogen

Norethisterone acetate in continuous combination with oral estrogen DRUG

Capsule 0.5 mg NETA/ 1 mg estradiol (Activelle®) orally per day (encapsulated and identical to Estrofem® and one matched placebo to Utrogestan

Norethisterone acetate in continuous combination with oral estrogen

Eligibility Criteria

• Age: 45 Years - 60 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Angelica Lindén Hirschberg: lead

Study Sites (1)

Karolinska University Hospital

Stockholm, 171 76, Sweden

RECRUITING

Related Publications (2)

• Bofill Rodriguez M, Yong LN, Mirkov S, Bekos C, Lethaby A, Farquhar C. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2025 Nov 27;11(11):CD004143. doi: 10.1002/14651858.CD004143.pub6.

  PMID: 41307293 DERIVED

• Lundell C, Stergiopoulos N, Blomberg L, Ujvari D, Schuppe-Koistinen I, Kopp-Kallner H, Iliadis SI, Skalkidou A, Hirschberg AL. Breast and endometrial safety of micronised progesterone versus norethisterone acetate in menopausal hormone therapy (PROBES): study protocol of a double-blind randomised controlled trial. BMJ Open. 2024 Oct 23;14(10):e082749. doi: 10.1136/bmjopen-2023-082749.

  PMID: 39448218 DERIVED

MeSH Terms

Interventions

Progesterone; Estrogens; Norethindrone Acetate

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Norethindrone; Norpregnenes; Norpregnanes; Norsteroids

Central Study Contacts

Angelica L Hirschberg, MD, PhD

CONTACT

+46 70 255 99 24; angelica.linden-hirschberg@regionstockholm.se

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, MD, PhD

Study Record Dates

• First Submitted: October 9, 2022
• First Posted: October 19, 2022
• Study Start: March 15, 2022
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2027
• Last Updated: June 4, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: Earliest from January 2028 and for ten years ahead.
• Access Criteria: Investigators whose proposed use of the data has been approved by the study management team. To achieve aims in the approved proposal. Proposals should be directed to angelica.hirschberg.linden@ki.se. To gain access, data requestors will need to sign a data access agreement.

Locations

SE (1)