E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
postmenopausal women with high risk for osteoporosis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 7.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050213 |
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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 |
The aim of this study is to evaluate the efficacy and safety of 2 different low-dose E2 preparations (SHT04170E – 100 µg E2; SHT04170F – 190 µg E2) for the prevention of postmenopausal osteoporosis in women who are at least 5 years postmenopausal over a treatment period of 2 years (26 cycles of 28 days) compared to placebo. Efficacy will be assessed by BMD measurements of the lumbar spine (L1-L4), femoral neck, and total hip. |
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E.2.2 | Secondary objectives of the trial |
A secondary objective will be endometrial safety and the evaluation of differences in E2 and E1 exposure between the treatment groups. This evaluation will be based on population pharmacokinetic analyses of E2 and E1 concentrations in the targeted patient population. The relationship of E2 and E1 with SHBG will be studied in an explorative way. Additionally, the influence of covariates (i.e., age, weight, race, and concomitant medication) on pharmacokinetic parameters of E2 and E1, like clearance (CL) and volume of distribution (V), will be explored.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Age ≥ 55 years and ≤ 80 years (at visit 1) 2. Last (regular) menstrual period ≥ 5 years ago (at visit 2) 3. Intact, normal uterus and an endometrial biopsy result confirming absence of hyperplasia or any relevant pathology 4. Evaluable BMD by DXA of the lumbar spine (AP view, L1-L4; at least 2 vertebrae should be evaluable), femoral neck, and total hip 5. Mean pretreatment BMD T score ≤-1 and ≥-2.5 at the lumbar spine (L1-L4) 6. Presence of at least one additional risk factor to develop osteoporosis as listed below: - Mother, father or sister with history of low trauma fracture or osteoporosis - Body mass index (BMI) < 19 kg / m2, or weight less than 58 kg - Previous low trauma fracture - Menopause before age 45 years - Current smoking - Alcohol intake of more than 3 units per day (e.g. 1 unit = 1 glass of beer or 1 small glass of wine or 1 shot (25ml) of spirit) - Little or no (less than 1 hour per day) weight bearing exercise (e.g., sport activity, speedy gardening, heavy shopping) - Inadequate intake of calcium (less than 750 mg per day as estimated by the intake of milk, milk products and cheese) - History of use of corticosteroid therapy for more that 3 months - Hyperthyroidism (medicinally controlled) 7. Signed informed consent form.
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E.4 | Principal exclusion criteria |
1. Current bone and musculoskeletal diseases, e.g., Morbus Scheuermann, osteogenesis imperfecta, hypo- or hyper-parathyroidism, Paget’s disease, osteomalacia, or other metabolic disease of bone; hypo- or hypercalcemia, vitamin D deficiencies 2. History of immobilization > 2 months in the last 6 months before visit 1 3. History of clinically significant vertebral fracture within the last 12 months before visit 1 4. Patients requiring specific anti-osteoporotic treatment according to the investigator’s judgement 5. Any uterine bleeding within the last year before visit 1 6. Cervical smear with abnormal result (Pap: C III or worse) 7. Pre-existing cardiovascular disease - Uncontrolled hypertension; sitting systolic blood pressure ≥ 180 mm Hg or sitting diastolic blood pressure ≥ 105 mm Hg after at least 10 minutes rest (at either visits 1 or 2) - History of stroke, transient ischemic attacks and myocardial infarction, or angiographic evidence of 50% narrowing of one or more coronary arteries, or heart disease requiring anti-arrhythmic or anti-anginal drug treatment, or congestive heart failure - History or planned coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, coronary stenting - Existing or history of venous thromboembolic event (including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis) at any time and any condition which might increase the risk to suffer from any of the mentioned disorders, or known or suspected genetical component thereof (e.g., positive family history, event that occurred in a sibling or a parent at an early age), or current treatment with anticoagulants 8. Laboratory values as defined as clinically significant by the sponsor (see 7.5.1.3.10 and protocol attachment 3) and/or assessed as significantly abnormal by the investigator 9. Uncontrolled diabetes mellitus or diabetes mellitus currently treated with insulin 10. Uncontrolled thyroid disorders, or initiation or change in dose of thyroid replacement therapy within 6 months 11. Relevant renal disorder or significant liver dysfunction (including cholestasis and porphyria) 12. Current or past history of clinically significant depression 13. Malignant or premalignant disease within the last 5 years (except for superficial skin cancer) 14. Sex steroid (hormone)-dependent malignant disease at any time 15. Any other systemic or gynecologic disorder, laboratory finding, or ultrasound finding which might worsen under study drug treatment, might interfere with the conduct of the study or the interpretation of the results 16. Any disease or condition that compromises the function of the body system and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study medication 17. Intake or use of the following medications (before visit 1 or during the study) - Within 4 weeks before visit 1: estrogen or progestin therapy (oral, transdermal, intrauterine or intravaginal administration, or estrogen implants), for intramuscular depot injections wash-out phase of 6 months - Within 3 months before visit 1: raloxifene, fluoride, or calcitonin - If taken for a duration > 3 months within the past 2 years: bisphosphonates, parathyroid hormone - Currently taking GnRH agonists or antagonists, therapeutic vitamin D analogues - Currently taking: systemic corticosteroids, high dose multivitamins, or other agents which are known or suspected to affect bone metabolism - Currently taking: medication which may alter the plasma concentration of estrogen, e.g., St. John’s Wort (Hypericum perforatum), phenobarbital, carbamazepine, rifampicin, erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir 18. History of alcohol or drug abuse (within the last 2 years) 19. Known allergic reaction or hypersensitivity to any components of the study drugs 20. Participation in another clinical study within 1 month or use / administration of an investigational drug within the last 3 months before visit 1 21. Patient is a dependent person, e.g., a relative / family member and / or is a member of the investigator’s staff.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the percent change in the BMD at the lumbar spine (L1-L4) from pretreatment to the final visit (visit 7). With respect to the 2 pretreatment measurements, the arithmetic mean of the BMD measurements by DXA from screening (visit 1) will be used. With respect to the 2 final visit measurements, the arithmetic mean of the BMD measurements by DXA after 2 years of treatment at the final visit (visit 7) will be used. |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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) | Yes |
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 | 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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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End of study is defined to be last patient last visit (LPLV) according to protocol. It is expected that LPLV is in July 2007. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |