| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10027309 |
| E.1.2 | Term | Menopause and related conditions |
| E.1.2 | System Organ Class | 10038604 - Reproductive system and breast disorders |
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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 |
Primary Safety Objective: To confirm the endometrial safety of BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg based on an endometrial hyperplasia incidence of less than 1% at year 1.
Primary Efficacy Objective: To assess the effect of BZA/CE in preventing postmenopausal osteoporosis at year 1 (osteoporosis substudy)
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| E.2.2 | Secondary objectives of the trial |
To assess the effect of BZA/CE compared to BZA 20 mg on the change in bone mineral density (osteoporosis substudy).
To assess the effect of BZA/CE versus placebo and CE/MPA on uterine bleeding/spotting.
To assess the effect of BZA/CE versus placebo and CE/MPA on breast tenderness.
To demonstrate non-inferiority of BZA/CE to placebo on quantitative changes in mammographic breast density at year 1 (breast density substudy).
To assess the effect of BZA/CE versus placebo and BZA 20 mg on bone turnover markers (osteoporosis substudy).
To assess the effect of BZA/CE versus placebo on sleep parameters in a subset of women (sleep substudy) with bothersome VMS at baseline.
To provide a descriptive comparison of BZA/CE to conjugated estrogens/medroxyprogesterone acetate (CE/MPA).
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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 |
Osteoporosis substudy (20 Nov 08)
To assess the effect of BZA/CE in preventing postmenopausal osteoporosis at year 1.
To assess the effect of BZA/CE compared to BZA 20 mg on the change in bone mineral density (BMD).
To assess the effect of BZA/CE versus placebo and BZA 20 mg on bone turnover markers (BTM).
Breast density substudy (20 Nov 08)
To demonstrate non-inferiority of BZA/CE to placebo on quantitative changes in mammographic breast density in postmenopausal women at year 1 (breast density substudy).
Sleep substudy (20 Nov 08)
To assess the effect of BZA/CE versus placebo on sleep parameters in a subset of women.
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| E.3 | Principal inclusion criteria |
1. Generally healthy, postmenopausal female subjects between the ages of ≥ 40 and < 65 years, seeking treatment for menopausal symptoms, with at least:
• 12 months of spontaneous amenorrhea, or
• 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/mL.
2. Intact uterus.
3. Endometrial biopsy report at screening of one of the following by each of the central pathologists: proliferative endometrium; weakly proliferative endometrium; secretory endometrium; endometrial tissue, other (including benign, inactive or atrophic fragments of endometrial epithelium, glands, stroma, etc); endometrial tissue insufficient for diagnosis; no endometrium identified; or no tissue identified. In addition, at least 1 pathologist must identify sufficient tissue to evaluate the biopsy;
see exclusion criterion 4d.
4. Body mass index (BMI) less than or equal to 34.0 kg/m2.
5. In the opinion of the investigator, the subject will comply with the protocol and has a high probability of completing the study.
6. For the osteoporosis substudy, last natural menstrual cycle must be less than 5 years before screening.
7. For the osteoporosis substudy, subjects must have 2 evaluable BMD scans, at screening, of the lumbar spine and of 1 hip (the left hip will be measured unless prevented by pathology). The lumbar spine scans must differ by less than 5% and total hip scans must differ by less than 7.5%.
8. For the sleep substudy, subjects must respond yes to the following questions:
• Are you very bothered by hot flushes or night sweats?
• Do you often awake during sleep time and have trouble falling asleep again?
• Do you feel that you often do not get the amount of sleep needed during sleep time?
9. For the breast density substudy, subjects must have a digital mammogram that is technically acceptable for reading at screening.
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| E.4 | Principal exclusion criteria |
1. Use of oral estrogen-, progestin-, androgen-, or SERM-containing drug products.
2.
a. Hypersensitivity to estrogens or progestins, undiagnosed vaginal bleeding, endometrial hyperplasia, known or suspected estrogen-dependent neoplasia.
b. Chronic renal or hepatic disease.
c. Deep vein or superficial thrombophlebitis, thrombosis or thromboembolic disorders, including retinal vein thrombosis.
d. Cerebrovascular accident, stroke, or transient ischemic attack.
e. Neuroocular disorders.
f. Myocardial infarction or ischemic heart disease.
g. Malignancy, or treatment for malignancy, within the previous 5 years, with the exception of basal cell carcinoma of the skin or successfully removed squamous cell carcinoma of the skin; a history of breast cancer, melanoma or any gynecologic cancer, at any time, excludes the subject.
h. Gallbladder disease (subjects who have had a cholecystectomy may be enrolled).
i. Untreated known osteoporosis.
3.
a. Malabsorption disorders.
b. Endocrine disease (except for controlled hypothyroidism or diet-controlled diabetes mellitus).
c. Known alcohol or drug abuse.
d. Heavy smoking (more than 15 cigarettes per day).
e. Use of an intrauterine device within 12 weeks before screening.
f. Received any investigational drugs or devices within 60 days before screening.
4.
a. Unresolved cervical smear report of atypical glandular cells (AGC) or atypical squamous cells of undetermined significance (ASC-US); cervical cytology smear of low-grade squamous intraepithelial lesion (LSIL) or greater, any reported dysplasia. Subjects with reported ASC-US may be considered if high risk human papilloma virus result is negative.
b. Unresolved findings suspicious for malignancy on the breast examination.
c. On the screening transvaginal ultrasound examination, nonmeasurable endometrial thickness, double-walled endometrial thickness greater than 4 mm, focal endometrial abnormality (other than fluid), complex ovarian cyst of any diameter, or simple ovarian cyst with diameter greater than 20 mm.
d. Endometrial biopsy report at screening of any of the following, by both of the primary central pathologists: endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified.
e. Endometrial polyps with atypical nuclei reported by at least 1 of the primary central pathologists.
f. Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) levels greater than 1.5 times the upper limit of normal for the laboratory reference range.
g. Uncontrolled hypertension; subjects with elevated sitting blood pressure, greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic, must seek treatment of hypertension, be controlled on therapy before randomization and not be using more than 3 antihypertensive medications for the treatment of hypertension.
h. Fasting total cholesterol greater than 300 mg/dL (7.77 mmol/L) or triglycerides greater than 300 mg/dL (3.39 mmol/L).
i. Fasting blood glucose greater than 125 mg/dL (6.94 mmol/L).
j. ECG findings suggestive of ischemia.
5. Osteoporosis substudy:
a. History or active presence of osteoporosis or low traumatic fracture; clinically active rheumatoid arthritis, diseases of both hips or of the spine at L1 to L4 that preclude obtaining evaluable BMD measurements, bone metabolic diseases such as hypercalcemia, hypocalcemia, hyperparathyroidism (intact parathyroid hormone [PTH] level above the normal range for the assay used), vitamin D deficiency (25-hydroxy-vitamin D level less than 20 ng/ml), osteogenesis imperfecta, chronic gastrointestinal disease affecting absorption or Paget disease.
b. Lumbar spine or total hip T-score at screening exceeding 2.5 standard deviations (SD) below the mean for healthy young women based on the reference population database for the densitometry equipment used.
c. Use of medications that affect bone metabolism.
6. Breast density substudy:
a. Subjects with breasts that may make the interpretation of the mammogram difficult.
b. Use of prolactin releasing medications within 6 months before screening.
7. Sleep substudy:
a. Use of medications thought to treat VMS within 4 weeks before screening.
b. Use of hypnotic and/or sedative medications within 2 weeks before screening.
8. Enrollment has completed and closed.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence of endometrial hyperplasia at year 1.
For the osteoporosis substudy, percent change from baseline in BMD of the lumbar spine at year 1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. To assess the effect of BZA/CE compared with BZA 20 mg on the change in bone mineral density (BMD); osteoporosis substudy.
2. To assess the effect of BZA/CE versus placebo and CE/ medroxyprogesterone acetate (MPA) on uterine bleeding/spotting.
3. To assess the effect of BZA/CE versus placebo and CE/MPA on breast tenderness.
4. To demonstrate noninferiority of BZA/CE to placebo on quantitative changes in mammographic breast density (BD) in postmenopausal women at Year 1 (BD substudy).
5. To assess the effect of BZA/CE versus placebo and BZA 20 mg on bone turnover markers (BTM; osteoporosis substudy).
6. To assess the effect of BZA/CE versus placebo on sleep parameters in a subset of women (sleep substudy) with bothersome vasomotor symptoms (VMS) at baseline.
7. To provide a descriptive comparison of BZA/CE to CE/MPA.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At 6-Months and 12-Months.
2. Weeks 1-12, weeks 13-26, weeks 27-39, and weeks 40-52.
3. During each 4-week period.
4. 1 year (Month 12).
5. At Month 3, Month 6, and Month 12.
6. Week 13 and Week 52. |
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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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life (Sleep Quality) |
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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 | Information not present in EudraCT |
| 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 | 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 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 | No |
| 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 |
| Argentina |
| Australia |
| Chile |
| Colombia |
| Denmark |
| European Union |
| Finland |
| Hungary |
| Mexico |
| New Zealand |
| Norway |
| Poland |
| United States |
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| 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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| The end of the study is the last follow-up 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 | |
| E.8.9.1 | In the Member State concerned months | 32 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial months | 32 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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