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 |
Prevention of osteoporosis |
Voorkomen van botontkalking |
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E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
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 investigate the effect of low-dose rhythmic transdermal 17-β-estradiol on serum P1NP (marker of bone formation) and CTX (marker for bone resorption), versus continuous low-dose and standard-dose continuous transdermal 17-β-estradiol administration. |
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E.2.2 | Secondary objectives of the trial |
1. To assess the effect of low-dose rhythmic transdermal 17-β-estradiol on fasting glucose, fasting insulin, insulin resistance (HOMA-IR), and post-OGTT glucose and insulin, versus continuous low-dose and standard-dose continuous transdermal 17-β-estradiol. 2. To assess the effect of low-dose rhythmic transdermal 17-β-estradiol on liver steatosis (CAP score), versus continuous low-dose and standard-dose continuous transdermal 17-β-estradiol. 3. To assess the effect of low-dose rhythmic transdermal 17-β-estradiol versus continuous low-dose and standard-dose continuous transdermal 17-β-estradiol on sleep quality. 4. In a subgroup: To assess the effect of low-dose rhythmic transdermal 17-β-estradiol versus continuous low-dose and standard-dose continuous transdermal 17-β-estradiol on 17-β-estradiol transcriptional regulation in adipose tissue. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Postmenopausal, defined as final menstrual cycle more than 12 months prior to inclusion and FSH>30 IU/L - Final menstrual cycle < 10 years prior to inclusion - Age 45-60 years |
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E.4 | Principal exclusion criteria |
• Contra-indication for estrogen and/or progesterone therapy: Presence or suspicion or history of breast cancer, endometrial cancer, ovarian cancer, presence or history of venous thromboembolism, arterial thrombosis (e.g. myocardial infarction, angina pectoris) inherited or acquired thrombophilia, presence of liver disease, untreated endometrial hyperplasia, abnormal vaginal bleeding, porphyria, uncontrolled or severe hypertension) • First-grade family member with inherited thrombophilia or history of VTE under the age of 60 years • Hysterectomy • Premature menopause (menopause age <40 years) • Known hypersensitivity to the excipients in the estradiol patch: acrylate copolymer, polyethylene terephthalate, α-tocopherol, soy allergy or peanut allergy (component of progesterone capsule) • Hormonal contraception or hormone replacement therapy use (estradiol with or without progesterone) in the past 12 months • Presence or history of any clinically relevant metabolic, endocrinological, hepatic, renal, cardiovascular, gastrointestinal, or respiratory conditions, history of bone disease or bone marrow disease, known vitamin D deficiency (25-OH vitamin D <30 nmol/L) • Recent fracture (<12 months) • BMI <20 or BMI ≥30 • Use of drugs including herbal medicine known to affect bone metabolism (e.g. corticosteroids) or to interfere with cytochrome P450 enzyme (CYP) pathways. Exceptions are occasional use of paracetamol, ibuprofen, acetylsalicylic acid or topical medication • For adipose tissue biopsy: anticoagulant treatment, allergy to lidocaine |
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E.5 End points |
E.5.1 | Primary end point(s) |
The endpoint is the interaction between treatment and time on serum P1NP levels. (Does the change over time differ between the treatment arms?) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every two weeks in from baseline until week 16 |
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E.5.2 | Secondary end point(s) |
1. The secondary endpoint is the interaction between treatment and time on serum CTX levels. (Does the change over time differ between the treatment arms?) 2. Change in fasting glucose, fasting insulin, insulin resistance (HOMA-IR), and 2 hours post-OGTT glucose and insulin in relation to baseline after 16 weeks of treatment. 3. Change in liver steatosis (CAP score) in relation to baseline after 16 weeks of treatment. 4. Sleep quality (PSQI) and chronotype (MCTQ) and menopausal symptoms (GCS) after 16 weeks in relation to baseline. 5. In a subgroup: To assess the effect of low-dose rhythmic transdermal 17-β-estradiol versus continuous low-dose and standard-dose continuous transdermal 17-β-estradiol on 17-β-estradiol transcriptional regulation in adipose tissue using ChipSeq and RNA seq analysis (hypothesis-generating).. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Every two weeks in from baseline until week 16 2. At baseline and after 16 weeks 3. At baseline and after 16 weeks 4. At baseline and after 16 weeks 5. At baseline and after 16 weeks |
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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 | No |
E.6.4 | Safety | No |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 participants' last visit |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |