E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of postmenopausal osteoporosis |
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E.1.1.1 | Medical condition in easily understood language |
Postmenopausal Osteoporosis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10031285 |
E.1.2 | Term | Osteoporosis postmenopausal |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue 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 |
To describe the safety and tolerability of up to 10 years or 7 years of denosumab administration as measured by adverse event monitoring, immunogenicity, and safety laboratory parameters in subjects who previously received denosumab or placebo, respectively.
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E.2.2 | Secondary objectives of the trial |
To describe the
-effect of denosumab administration on changes in lumbar spine, total hip and distal radius Bone Mineral Density (BMD) in subjects who previously received denosumab and in subjects who previously received placebo.
-incidence of vertebral and non vertebral fractures following denosumab administration in subjects who previously received denosumab and in subjects who previously received placebo.
-effect of denosumab administration on markers of bone turnover in subjects who previously received denosumab and in subjects who previously received placebo.
-change in serum calcium values between the Baseline and Day 10 visit in subjects who previously received denosumab and in subjects who previously received placebo.
-effect of up to 10 yrs denosumab administration on bone histology in subjects who previously received denosumab . |
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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 |
Bone turnover markers sub-study (29 May 2007) – Serum for biochemical markers (Type 1 CTX, iPTH, RANKL, OPG, BALP, P1NP) will be collected in a subset of subjects who participated in the 20030216 bone marker substudy at Day 10, month 6, month 12 and month 24 visits to assess the effect of denosumab treatment on bone turnover and other bone parameters. At month 24, month 36, month 48, month 60, month 72 and month 84 serum for biochemical markers (CTX-1, P1NP) will be collected in subjects currently in the Bone Turnover Markers sub-study and in new subjects continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
DXA sub-study (29 May 2007) – Subjects who participated in the 20030216 DXA sub-study will be requested to undergo additional bone densitometry assessments of the distal radius at the month 12 and month 24 visits. At the month 24 visit new subjects and subjects currently in the DXA Radius sub-study will be requested to undergo additional bone densitometry assessments of the distal radius at the month 48, month 72 and month 84 visits.
Transiliac bone biopsy sub-study (29 May 2007) - A target of approximately 50 subjects who received denosumab therapy for 5 and/or 10 years will be approached to undergo a transiliac bone biopsy to be obtained prior to or during the subject’s Month 24 and Month 84 visits.
Pharmacokinetics (PK) and Pharmacodynamics (PD) Sub-Study (25 October 2007) – Serum for denosumab levels (PK) and CTX-1 (PD) will be collected at Day 10, months 3, 4 and 6 in approximately 225 subjects who previously participated in the 20030216 PK sub-study. |
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E.3 | Principal inclusion criteria |
Subjects must sign the informed consent before any study specific procedures are performed and agree to receive denosumab 60mg SC injection every 6 months.
Subjects must not have discontinued investigational product during the 20030216 study and must have attended the 20030216 study month 36 visit.
Subjects must be re-consented prior to (or at) the 24 month visit for participation beyond month 24. |
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E.4 | Principal exclusion criteria |
- Permanently non-ambulatory subjects (use of an assistive device e.g. cane, walker etc is permitted)
- Missed two or more investigational product doses during the 20030216 study
- Any disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures
- Developed sensitivity to mammalian cell derived drug products during the 20030216 study
- Unable to tolerate calcium supplementation during the last 6 months of participation in the 20030216 study (between the month 30 and month 36 20030216 study visits)
- Currently receiving any investigational product other than denosumab or having received any investigational product during the 20030216 study
- Current use of the following osteoporosis agents: bisphosphonates, calcitonin, fluoride, parathyroid hormone, selective estrogen receptor modulators, systemic oral or transdermal estrogen (except vaginal preparations and estrogen creams which are acceptable), strontium or tibolone
- For bone biopsy sub-study subjects only: known or suspected sensitivity or contraindication to tetracycline derivatives |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is safety monitoring, including adverse event incidence, serious adverse event incidence, changes in safety laboratory analytes (serum chemistry, hematology) and subject incidence of anti-denosumab antibody formation. |
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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) |
• Actual values, changes and percent changes in BMD of the
lumbar spine, total hip and distal radius from baseline
• Actual values, changes and percent changes in BMD of the
lumbar spine, total hip and distal radius from study 20030216
baseline
• Subject incidence of vertebral fractures
• Subject incidence of non-vertebral fractures during the study
markers from baseline
• Actual values, changes and percent changes in bone turnover
markers from study 20030216 baseline
• Actual value, change and percent change from baseline in
albumin-adjusted serum calcium
• Serum denosumab concentrations
• Actual values of bone biopsy measurements
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Values and changes in BMD of the at all timepoints
• Values and changes in BMD of the from study 20030216
baseline at all timepoints
• Subject incidence of vertebral fractures at months 24, 36, 60,
and 84
• Subject incidence of non-vertebral fractures during the study
markers from baseline at all timepoints
• Values and changes in bone turnover markers from study 20030216 baseline at all timepoints
• Values and changes from baseline in albumin-adjusted serum calcium at Day 10
• Serum denosumab concentrations at all timepoints
• Values of bone biopsy measurements at months 24 and 84 |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 148 |
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 |
European Union |
Argentina |
Brazil |
Canada |
Mexico |
Switzerland |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |