| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal Osteoporosis/osteopenia |
|
| 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 |
| The primary objective is to evaluate the effect of denosumab 60 mg q 6 months on total hip bone mineral density (BMD) at 12 months in postmenopausal women with low BMD previously treated with alendronate 70 mg QW or equivalent compared to that in subjects continuing on alendronate therapy. |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the effects of transitioning to denosumab in comparison to treatment with continuing alendronate therapy on:
• Bone turnover markers (serum Type 1 CTX, P1NP, BSAP and uNTX) at post-Day 1 (each subject will be assigned to one visit at 5, 10, or 15 days post dose), and Months 1, 3, 6, post-Month 6 (each subject will be assigned to one visit at 5, 10, or 15 days post dose), Months 9 and 12.
• BMD at the lumbar spine, femoral neck, hip trochanter and distal 1/3 radius at 12 months • BMD at the total hip, lumbar spine, femoral neck, hip trochanter and distal 1/3 radius at 6 months
• Safety and tolerability measured by evaluating adverse events, laboratory parameters, and immunogenicity to denosumab over 12 months. |
|
| 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 |
Date - 31 May 2006
Title - Transiliac Bone Biopsy Sub-study
Objective - Histologic and histomorphometric assessment of transiliac bone biopsies.
A target of 50 subjects enrolled at approximately 12 selected study sites will be requested to undergo a cross-sectional transiliac bone biopsy within 30 days before their month 12 visit. All subjects scheduled for the biopsy will follow a double tetracycline/demeclocycline labeling procedure prior to undergoing the biopsy. The double tetracycline/demeclocycline labeling procedure may be initiated up to 55 days prior to the scheduled month 12 dose, as long as the timing allows the actual biopsy to be performed within the 30 days before the month 12 visit. |
|
| E.3 | Principal inclusion criteria |
Inclusion Criteria from Section 4.1 of the Protocol
4.1.1 ≥ 55 years of age at the start of screening.
4.1.2 Ambulatory postmenopausal women based on medical history.
• Postmenopause will be defined as no vaginal bleeding or spotting for at least 12 months.
• If there is uncertainty regarding menopausal status, confirmation of serum FSH (≥ 50 mIU/mL) and serum estradiol (≤ 20 pg/mL) must be obtained.
4.1.3 Have received alendronate treatment at a dose of 70 mg/week or equivalent (ie, 10 mg/day) for at least the past 6 months prior to screening.
4.1.4 Screening BMD (g/cm2) values, at the lumbar spine OR total hip, that occur within the following ranges, based on the particular scanner that is used:
• GE Lunar Hologic
Lumbar spine 0.700 ≤ BMD ≤ 0.940 0.607≤ BMD ≤ 0.827
Total hip 0.504 ≤ BMD ≤ 0.756 0.454 ≤ BMD ≤ 0.698
• Both the initial and the repeat DXA scan of the lumbar spine OR the total hip must meet the above eligibility criteria. At least 2 lumbar vertebrae must be evaluable by DXA.
4.1.5 At least one hip must be evaluable by DXA (eg, no history of either bilateral hip replacement or pins in both hips).
4.1.6 Provide the appropriate written informed consent before any study-specific procedure. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria from Section 4.2 of the Protocol
4.2.1 Any disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.
4.2.2 Evidence of any of the following per subject report, chart review or central laboratory result:
1. Hyper- or hypothyroidism; however, subjects on stable thyroid hormone replacement therapy may be allowed per the following criteria:
• If TSH level is normal, subject is eligible for the study.
• If TSH level is below normal range, subject is not eligible for the study.
• If TSH level is elevated (> 5.5 µIU/mL to 10.0 µIU/mL), serum T4 should be measured. If serum T4 is within normal range, subject is eligible. If serum T4 is outside of normal range, subject is not eligible for the study.
• If TSH level is above 10.0 µIU/mL , subject is not eligible.
2. Current hyper- or hypoparathyroidism.
3. Elevated transaminases
• Serum aspartate aminotransferase (AST; serum glutamate-oxaloacetic transaminase [SGOT]) ≥ 2.0 x upper limit of normal (ULN).
• Serum alanine aminotransferase (ALT; serum glutamate-pyruvate transaminase [SGPT]) ≥ 2.0 x ULN.
4. Significantly impaired renal function as determined by a derived creatinine clearance (using the Cockroft-Gault formula) of ≤ 35 mL/min calculated by the central laboratory.
5. Current hypo- or hypercalcemia based on the central laboratory reference ranges. 6. Active gastric or duodenal ulcer; or any history of significant gastrointestinal bleed requiring hospitalization or transfusion.
7. Rheumatoid arthritis, Paget’s disease, Cushing’s disease, hyperprolactinemia, or cirrhosis of the liver.
8. Known to have tested positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen.
9. Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years.
10. Any metabolic bone disease, eg, osteomalacia or osteogenesis imperfecta, which may interfere with the interpretation of the findings.
11. Malabsorption syndrome or any gastrointestinal disorder that is associated with malabsorption.
4.2.3 Previous participation in clinical trials with denosumab.
4.2.4 Received any solid organ or bone marrow transplant.
4.2.5 Any laboratory abnormality, which in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results.
4.2.6 Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (< 49.9 nmol/L)]. Vitamin D repletion will be permitted and subjects may be re-screened; see Section 7.
4.2.7 Contraindicated or poorly tolerant of ALN therapy; contraindications for ALN therapy include:
a) Abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia.
b) Inability to stand or sit upright for at least 30 minutes.
c) Hypersensitivity to ALN or other constituents of ALN tablets.
4.2.8 Known sensitivity to mammalian cell derived drug products.
4.2.9 Known intolerance to calcium supplements.
4.2.10 Administration of intravenous bisphosphonate, or fluoride (except for dental treatment) or strontium ranelate.
4.2.11 Administration of PTH or PTH derivatives (eg, teriparatide) within the last year.
4.2.12 Administration of any of the following treatments within 3 months of screening:
a) Any SERM (eg, raloxifene)
b) Tibolone
c) Anabolic steroids or testosterone
d) Glucocorticosteroids (≥ 5 mg prednisone equivalent per day for more than 10 days)
e) Systemic (oral, transdermal, topical, vaginal) hormone replacement therapy (low dose local vaginal estrogen preparation will be allowed)
f) Calcitonin
g) Calcitriol or vitamin D derivatives [vitamin D (cholecalciferol) < 800 IU/day or equivalent is allowed; vitamin D contained in supplements or multivitamins is allowed]
h) Other bone active drugs including anti-convulsives (except benzodiazepines) and heparin
i) Chronic systemic ketoconazole, androgens, ACTH, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists.
4.2.13 Administration of any bisphosphonate other than ALN within 1 year of screening.
4.2.14 Height, weight or girth which may preclude accurate DXA measurements.
4.2.15 Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s).
4.2.16 Any physical or psychiatric disorder which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results.
4.2.17 Evidence of alcohol or substance-abuse within the last 12 months which the investigator believes would interfere with understanding of or completion of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change in total hip BMD from baseline to 12 months |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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.8.3 |
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.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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