E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on mammographic breast density. |
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E.2.2 | Secondary objectives of the trial |
To compare the effects of one-year treatment with mP versus NETA, both in combination with estradiol, on the secondary outcomes below: - Breast cell proliferation - Endometrial cell proliferation - Endometrial thickness using ultrasound - Bleeding pattern Gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue - Depression and anxiety symptoms (PHQ-9, HADS) - Health-related quality of life (PGWB) - Women’s Health Questionnaire (WHQ) - Blood lipid profile, serum hormones, growth and metabolic factors
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
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)
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). |
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E.3 | Principal inclusion criteria |
- 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. - 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 |
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E.4 | Principal exclusion criteria |
- Previous history of breast cancer or abnormal mammogram at baseline as assessed clinically by a radiology expert - Previous history of 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 cardiovascular disease including thromboembolic disorder or cerebrovascular disease - History or presence of liver 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 - 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
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E.5 End points |
E.5.1 | Primary end point(s) |
-Percentage change in mammographic density compared between the groups. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 12 months of treatment |
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E.5.2 | Secondary end point(s) |
- Incidence of endometrial proliferation (proliferation marker (Ki67) - Endometrial thickness on ultrasound - Bleeding pattern as documented in a bleeding diary - Gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue - Depression and anxiety symptoms (Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS)) - Health-related quality of life (Psychological General Well-Being Index (PGWB)) - Women’s Health Questionnaire (WHQ) - 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).
Incidence of endometrial hyperplasia and cancer.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 12 months of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |