E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Post Menospausal Osteoporosis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10031282 |
E.1.2 | Term | Osteoporosis |
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 |
The primary objective of this study is to evaluate if the effect of administering denosumab (60 mg subcutaneously [SC] every 6 months [Q6M]) is not inferior to that of zoledronic acid (5 mg
intravenously [IV] once yearly) in postmenopausal women with osteoporosis previously treated with oral bisphosphonates with respect to change in bone mineral density (BMD) by dual energy
x-ray absorptiometry (DXA) of lumbar spine at 12 months. |
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E.2.2 | Secondary objectives of the trial |
Compare the efficacy of administering denosumab (60 mg SC Q6M), with that of zoledronic acid
(5 mg IV once yearly), on the following:
• BMD by DXA of total hip at 12 months (non - inferiority)
• BMD by DXA of lumbar spine at 12 months (superiority)
• BMD by DXA of total hip at 12 months (superiority) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Subject or subject’s legally acceptable representative has provided informed consent prior to any study specific procedure(s)
- Ambulatory postmenopausal women. Ambulatory is defined as women who are able to walk, not bedridden; postmenopause is defined as no vaginal bleeding or spotting for at least 12 months prior to screening.
- Age 55 years or older
- Received oral bisphosphonate therapy for OP for at least 2 years immediately prior to screening visit
- Screening BMD (g/cm2) values at the lumbar spine, total hip or femoral neck; values of equal to or less than those listed in the protocol. Eligibility will be determined by a local reading of the DXAs at the investigator site. At least 2 lumbar vertebrae and one hip must be evaluable by DXA at the screening visit.
- Serum CTX value of ≤ 0.5 ng/mL at the screening visit as determined by central laboratory |
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E.4 | Principal exclusion criteria |
- Height, weight or girth which may preclude accurate DXA measurements
- Received other OP treatment or bone active treatment with the following guidelines
• administration of denosumab or zoledronic acid at any time
• administration of the following within the last 5 years
o IV bisphosphonate other than zoledronic acid
o fluoride or strontium at doses approved for OP
o PTH or PTH derivatives within the last year
Abnormalities of the following per central laboratory reference ranges:
• vitamin D deficiency (25[OH] vitamin D level < 20 ng/mL), repletion will be allowed and subjects may be re-screened
• hypercalcemia
• elevated transaminases ≥ 2.0 x upper limits of normal (ULN)
Administration of any of the following treatment within 3 months of screening:
• any selective estrogen receptor modulator (estrogen agonist antagonist)
• tibolone
• anabolic steroids or testosterone
• glucocorticosteroids (≥ 5 mg prednisone equivalent per day for more than 10 days or a total cumulative dose of ≥ 50 mg)
• systemic hormone replacement therapy (HRT) (subjects stable on HRT for more than 3 months prior is permitted)
• calcitonin
• other bone active drugs including anti-convulsants (except
benzodiazepines) and heparin
• cathepsin K inhibitor
• anti-sclerostin antibody
• chronic systemic ketoconazole, androgens, adrenocorticotrophic
hormone, cinacalcet, aluminum, lithium, protease inhibitors,
gonadotropin- releasing hormone agonists
- Evidence of history of any of the following:
• hyperthyroidism (stable on antithyroid therapy is allowed)
• hypothyroidism (stable on thyroid replacement therapy is allowed)
• hypo- or hyperparathyroidism
• hypo- or hypercalcemia based on the central laboratory reference ranges
• known to have tested positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen
• osteomalacia (chart review)
• osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures (eg, tooth extraction, dental implants, oral surgery in the past 6 months), poor oral hygiene, periodontal and/or pre-existing dental disease
• recent tooth extraction (within 6 months of screening visit)
• Paget disease of bone (subject report or chart review)
• other bone diseases which affect bone metabolism (eg, osteopetrosis, osteogenesis imperfecta) (chart review)
History of any solid organ or bone marrow transplant
- Malignancy (except nonmelanoma skin cancers, cervical or breast ductal carcinoma in situ) within the last 5 years
- Contraindicated or poorly tolerant of denosumab therapy; contraindications include
• hypocalcemia
• hypersensitivity to drug or any component of the drug
- Contraindicated or poorly tolerant of zoledronic acid therapy;
contraindications include the following:
• hypocalcemia
• subjects with creatinine clearance of <35 mL/min and in those with evidence of acute renal impairment (calculated using Cockcroft Gault equation)
• hypersensitivity to any component of zoledronic acid solution
- Known intolerance to calcium or vitamin D supplements
- For women of child bearing potential: refusal to use 2 highly effective forms of contraception and to continue this practice for 7 months after last injection of study medication
- Self-reported alcohol or drug abuse within 12 months prior to screening
- Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s)
- Other investigational procedures while participating in this study are excluded
- Known sensitivity to any of the products or components to be administered during dosing or known sensitivity to mammalian cell derived drug products.
- Has previously entered this study
- Subject likely to not be available to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and Investigator’s knowledge.
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint:
• percent change from baseline in lumbar spine BMD at month 12 (non-inferiority) |
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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) |
Secondary Endpoints:
• percent change from baseline in total hip BMD at month 12 (non-inferiority)
• percent change from baseline in lumbar spine BMD at month 12 (superiority)
• percent change from baseline in total hip BMD at month 12 (superiority) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 10 |
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 | 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 |
Australia |
Belgium |
Canada |
Denmark |
Germany |
Poland |
Spain |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |