| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Reduction of new vertebral fractures in osteoporotic postmenopausal women- Osteoporosis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10031282 |
| E.1.2 | Term | Osteoporosis |
|
| 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 evaluate the efficacy of bazedoxifene acetate 20 mg and bazedoxifene acetate 40 mg in comparison to placebo in reduction of new vertebral fractures in osteoporotic postmenopausal women after 36 months and after 60 months of therapy and after 84 months of therapy.
To compare the safety profile of bazedoxifene acetate to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
| Compare BZA to placebo & raloxifene (RLX) after 36months on: breast cancer (BC) incidence; clinical vertebral fractures (VF);worsening VF; nonvertebral fractures (NVF); height changes; Bone Mineral Density (BMD) of lumbar spine & hip; serum bone markers; impact on lipid parameters & quality of life; endometrial assessment (substudy[ss]); bone histomorphometry (ss); effect on cardiac repolarization (electrocardiogram ss). Compare RLX 60mg to placebo in reducing the incidence of new VFs & other fractures after 36months of treatment will also be conducted. Compare BZA to placebo after 60months & 84months of therapy on: BC incidence; clinical VFs; worsening VFs; NVF; height changes; BMD of lumbar spine & hip; endometrial assessment (ss); serum bone markers (ss); bone histomorphometry (substudy II). Determine effect of test article discontinuation in the 6th & 7th yr of study on changes in BMD by comparing BMD values off therapy to BMD values observed on therapy (Observational ss). |
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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 |
All substudies mentioned here will be conducted under the same protocol and objectives.
1) Approx 2,400 subjects (4 treatment groups of 600 subjects) will be enrolled into
the Endometrial Safety Substudy, which will be conducted at approximately 100 sites.
2) Approx 200 subjects will participate in the Bone Histomorphometry Substudy
at 20 sites. An anterior iliac crest bone biopsy will be performed after completing 24 months of treatment or if the subject withdraws early and has received at least 12 months of therapy.
3) Approx 400 subjects will be enrolled into the Electrocardiogram Substudy at 6 sites. Three (3) standardized 12-lead serial ECGs will be obtained at two (2) minute intervals, including rhythm strips from lead II. Subjects will undergo on-therapy ECG testing following Visit 5 (12 months) through Visit 9 (36 months).
4) Approx 4300 subjects (approx 1050 per arm) may participate in the Study Extension. Subjects from the raloxifene arm (approx 1050 subjects entering the Study Extension I) will participate in the extension until the last subject has completed the Core Study, and the database for the 3-year analysis is frozen. Up to approx 3200 subjects from the bazedoxifene and placebo arm may participate in the full Study Extension I.
5) In extension phase Approx 600 subjects will participate in the long-term Bone Markers Substudy, which will be conducted at up to 20 sites.
60 Up to 30 subjects will participate in the Bone histomorphometry substudy II in approximately 20 sites which were participating in the Bone hystomorphometry substudy during the Core study. An anterior iliac crest bone biopsy will be performed at the five-year visit Consent for this substudy may be obtained up to the time of the Visit 13 and subjects should sign the Bone Histomorphometry Substudy II informed consent form.
7)Up to approximately 2000 subjects from the bazedoxifene and placebo arms may participate in the Study Extension II
8)Approximately 200 subjects will participate in an observational substudy of subjects entering Study Extension II who have discontinued test article and did not meet the visit window for visit 13 specified for Extension II. These subjects will be followed on the normal visit schedule of Study Extension II. They will not be dispensed test article during Extension II, but will receive calcium/vitamin D supplements. The amount of calcium / vitamin D supplements these subjects will receive will be similar to the amount of calcium/vitamin D supplements as subjects also receiving test article. |
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| E.3 | Principal inclusion criteria |
Inclusion Criteria in the Core Study
1. Generally healthy postmenopausal women
· from 55 to 85 years of age in non-US countries
· from 55 to 80 years of age in US only.
2. Subjects must be at least 2 years postmenopausal defined by any of the following:
a. Last natural menstrual cycle at least 2 years before screening; or,
b. Subject is over 60 years of age; or,
c. Surgical menopause (bilateral oophorectomy with or without hysterectomy) at least 2 years before screening.
3. a. Osteoporotic subjects without vertebral fracture:
· In non-US countries: BMD T-score at the femoral neck or lumbar spine of –2.5 or worse without the presence of a vertebral fracture.
· In US only BMD T-score at the femoral neck or lumbar spine between –2.5 and –4.0 (inclusive) without the presence of a vertebral fracture. or
b. Osteoporotic subjects with vertebral fracture:
· In non-US countries: the presence of 1 to 5 mild or moderate asymptomatic vertebral fracture(s) and a lumbar spine and femoral neck BMD T-score not worse than –3.5.
· In US only: the presence of 1 mild asymptomatic vertebral fracture and a lumbar spine and femoral neck BMD T-score not worse than -4.0.
4. In the opinion of the investigator, the subject will be compliant and have a high
probability of completing the study.
5. Subjects must sign and date a written Institutional Review Board–approved
informed consent before any screening procedures are performed.
6. Subjects in the Endometrial Safety Substudy must have a uterus accessible to
endometrial sampling.
7. Subjects participating in the Electrocardiogram Substudy must have an original
copy of the baseline ECG available for comparison.
Inclusion Criteria in the Study Extension I
1. Completion of the Core Study.
2. In the opinion of the investigator, the subject will be compliant and have a high
probability of completing the Study Extension.
3. Subjects must sign and date a written Institutional Review Board IRB) /Independent Ethics Committee (IEC) - approved informed consent, before any Study Extension procedures are performed.
Inclusion Criteria in the Study Extension II:
1. Completion of the Study Extension I.
2. In the opinion of the investigator, the subject will be compliant and have a high probability of completing the Study Extension II.
3. Subjects must sign and date a written Institutional Review Board (IRB)/Independent Ethics Committee (IEC) - approved informed consent, before any Study Extension II procedures are performed |
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| E.4 | Principal exclusion criteria |
Core Study: 1. Diseases that may affect bone metabolism (e.g., hypercalcemia, hypocalcemia, osteogenesis imperfecta, chronic gastrointestinal disease, Paget’s disease or hyperparathyroidism).
2. Women from whom satisfactory thoracic & lumbar spine radiographs cannot be obtained, or with fewer than 4thoracic & 2lumbar vertebrae that are evaluable.
3. Non-US countries: women with more than 5mild or moderate prevalent vertebral fractures.
US only, women with more than 1 mild prevalent vertebral fracture.
4. Non-US countries: women with 1 or more severe prevalent vertebral fracture(s).
US only: women with 1 or more moderate or severe prevalent vertebral fracture(s).
5. US only, women with vertebral or hip fractures known or suspected to have occurred within 2years of baseline.
6. Any conditions that can substantially interfere with obtaining lumbar spine BMD (e.g., degenerative diseases of the spine, severe scoliosis).
7. In non-hysterectomized women, known history of or suspected endometrial hyperplasia or carcinoma. For subjects in the Endometrial Safety Substudy, endometrial thickness at baseline greater than 5mm (double-wall, fluid excluded) as measured by transvaginal ultrasonography or endometrial hyperplasia or carcinoma (as determined by either of the 2 pathologists) at the baseline biopsy.
8. Abnormal vaginal bleeding at baseline.
9. Vasomotor symptoms requiring treatment.
10. Pathologic vertebral fractures.
11. Known history or suspected cancer of the breast.
12. Unresolved cervical cytology smear report of atypical glandular cells of undetermined significance, atypical squamous cells of undetermined significance favoring low-grade squamous intraepithelial lesions, or low-grade squamous intraepithelial lesions or higher.
13. Malignancy, or treatment for malignancy, within the previous 10years. A history or active presence of basal cell carcinoma of the skin does not exclude the subject.
14. Active or past history of venous thromboembolic events, including DVT, pulmonary embolism, or retinal vein thrombosis.
15. A BMI above 35.
16. Elevated sitting (after 5minutes) blood pressure (180mmHg systolic or 90mmHg diastolic).
17. Aspartate aminotransferase &/or alanine aminotransferase @1.5 times the upper limit of normal for the laboratory used.
18. Serum creatinine @2 times the upper limit of normal for the laboratory used.
19. Active renal lithiasis
20. Alkaline phosphatase @2 times the upper limit of normal for the laboratory used.
21. Total bilirubin @1.5 times the upper limit of normal for the laboratory used. Subjects with a preexisting diagnosis of Gilbert’s syndrome may be included after approval by the medical monitor.
22. Fasting total cholesterol >8.00mmol/L (310mg/dL) or triglycerides >3.40mmol/L (300mg/dL).
23. Endocrine disorders requiring treatment (except well-controlled Type II diabetes mellitus or hypothyroidism).
24. Untreated malabsorption disorders.
25. In the opinion of the investigator, any serious underlying disease or clinically significant abnormal physical finding precluding subject participation in a 3year study.
26. Use of the following drugs within 6months of screening:Systemic estrogen (except estriol 2mg/d);Topical estrogen more often than 3times a week; Progestogens; &rogens;Calcitonin; Bisphosphonates;Parathyroid hormone; SERMs; Cholecalciferol (more than 50,000IU a week);Antiseizure drugs
27. Systemic fluoride treatment (other than topical dental) for more than 1 month within 6months before screening.
28. Systemic corticosteroid equivalent to or greater than 10 mg per day of prednisone, for periods longer than 10days within 6months before screening.
29. Known allergy to raloxifene.
30. Subjects in the Bone Histomorphometry Substudy must not be allergic to tetracycline.
31. Use of any other investigational drug or participation in any other clinical research study during screening.
32. Known alcohol or drug abuse.
Extension I: 1. Withdrawal before 36months in the Core Study
2. Any venous thromboembolic events including DVT, pulmonary embolism, retinal vein thrombosis, or spontaneous superficial thrombosis or any stroke or transient ischemic attack, during the Core study.
3. In the opinion of the investigator, any disease or clinically significant abnormal physical finding developed during the Core Study that would preclude subject participation in the Study Extension.
Extension II 1. Withdrawal before 60months in the Study ExtensionI.
2. Any venous thromboembolic events including DVT, pulmonary embolism, retinal vein thrombosis, or spontaneous superficial thrombosis or any stoke or transient ischemic attack, during the Extension Study I.
3. In the opinion of the investigator, any disease or clinically significant abnormal physical finding developed during the first 5years of the Study that would preclude subject participation in the Study Extension II. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of interest is reduction in the incidence of new vertebral fractures |
|
| 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 | Yes |
| E.6.5 | Efficacy | Yes |
| 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) | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 105 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 105 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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