E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Post Menopausal Osteoporosis |
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E.1.1.1 | Medical condition in easily understood language |
Post Menopausal 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 | 18.0 |
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 |
Evaluate the effect of treatment with romosozumab for 12 months, compared with teriparatide (TPTD), 12 months on total hip bone mineral density (BMD), as assessed by dual energy X-ray absorptiometry (DXA), in postmenopausal women with osteoporosis, previously treated with bisphosphonate (BP) therapy. |
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E.2.2 | Secondary objectives of the trial |
Evaluate the effect of treatment with romosozumab for 12 months, compared with TPTD, on the following:
• integral and cortical BMD at the total hip, as assessed by quantitative computed tomography (QCT)
• QCT bone mineral content (BMC) and estimated strength by finite element analysis (FEA) at the total hip
• BMD by DXA at the femoral neck and lumbar spine |
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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 |
Ileac Crest Bone Biopsy
Up to 20 romosozumab-treated subjects will be recruited to undergo a transiliac bone biopsy at month 12 to assess the effect of romosozumab treatment on parameters of bone histology and histomorphometry.
Subjects will need to provide separate informed consent specific to the biopsy procedure in order to participate. |
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E.3 | Principal inclusion criteria |
- Ambulatory, postmenopausal women, aged ≥ 55 to ≤ 90 at randomization. Postmenopause is defined as no vaginal bleeding or spotting for 12 consecutive months prior to screening.
- Received oral bisphosphonate therapy at a dose approved for postmenopausal osteoporosis for at least 3 years immediately prior to screening.
- At least 75% compliant (as reported by the subject) with bisphosphonate administration over the previous 3 years immediately prior to screening.
- At least 75% compliant (as reported by the subject) with alendronate (70 mg weekly or equivalent) administration during the 1 year immediately prior to screening.
- BMD T-score ≤ -2.50 at the lumbar spine, total hip or femoral neck, as assessed by the central imaging vendor at the time of screening, based on DXA scans.
- History of nonvertebral fracture after age 50, or vertebral fracture.
- At least 2 vertebrae in the L1-L4 region and at least one hip that are evaluable by DXA
- Subject has provided informed consent |
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E.4 | Principal exclusion criteria |
- Use of the following agents affecting bone metabolism:
• Strontium ranelate or fluoride (for osteoporosis): more than 1 month of cumulative use within 5 years prior to randomization
• IV bisphosphonates:
zoledronic acid
- any dose received within 3 years prior to randomization
- more than 1 dose received within 5 years prior to randomization
IV ibandronate or IV pamidronate
- any dose received within 12 months prior to randomization
- more than 3 years of cumulative use, unless last dose received ≥5 years prior to randomization
• Denosumab or any cathepsin inhibitor, sucha as odanacatib (MK-0822): dose received within 18 months prior to randomization
• TPTD or any PTH analogs: more than 12 months of cumulative use or dose received within 12 months prior to randomization
• Systemic oral or transdermal estrogen, or SERMs: more than 1 month of cumulative use within 6 months prior to randomization
• Hormonal ablation therapy: more than 1 month of cumulative use within 6 months prior to randomization
• Tibolone, cinacalcet, or calcitonin: dose received within 3 months prior to randomization
• Systemic glucocorticosteroids: ≥ 5 mg prednisone equivalent per day for more than 14 days within 3 months prior to randomization
- History of metabolic or bone disease (except osteoporosis) that may interfere with the interpretation of study results, such as sclerosteosis, Paget’s disease, rheumatoid arthritis, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, Cushing’s disease, hyperprolactinemia, and malabsorption syndrome
- Vitamin D insufficiency, defined as 25 (OH) vitamin D levels < 20 ng/mL, as determined by the central laboratory. Vitamin D repletion will be permitted and subjects may be rescreened.
- Current hyper- or hypocalcemia, defined as albumin adjusted serum calcium outside the normal range, as determined by the central laboratory. Albumin-adjusted serum calcium levels may eb retested once in case of an elevated albumin-adjusted serum calcium level within 1.1x the upper limit of normal as assessed by the central laboratory.
- Current, uncontrolled hyper- or hypothyroidism, defined as thyroid-stimulating hormone and thyroxine outside of the normal range, per subject report or chart review
- Current, uncontrolled, hyper- or hypoparathyroidism, defined as PTH outside the normal range, per subject report or chart review
- Subjects with reported history of hearing loss associated with cranial nerve VIII compression due to excessive bone growth (eg, as seen in conditions such as Paget’s disease, sclerosteosis and osteopetrosis)
- History of solid organ or bone marrow transplants
- Known to have human immunodeficiency virus hepatitis C virus, or hepatitis B infection
TPTD-related exclusion criteria (for all subjects)
- Hypersensitivity to TPTD or any of the excipients (eg, glacial acetic acid, sodium acetate, mannitol, metacresol, hydrochloric acid, sodium hydroxide)
- Severe renal impairment, (as assessed by the central laboratory based on a derived creatinine clearance of < 35 mL/min using the Modification of Diet in Renal Disease equation [Levey et al, 2006]). The estimated glomerular filtration rate is calculated as follows: estimated glomerular filtration rate (mL/min/1.73m2) = 175 x [Serum creatinine (mg/dL)]-1.154 x [Age]-0.203 x [0.742 if subject is female] x [1.212 if subject is black].
- Unexplained elevations of alkaline phosphatase (> 1.5x ULN)
- Skeletal malignancies or bone metastases
- Prior external-beam or implant radiation therapy
- Known active or recent urolithiasis
General exclusion criteria (for all subjects)
- 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 are excluded.
- Malignancy within the last 5 years, except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ.
- Known sensitivity to any of the products or known intolerance to any of the products or components to be administered (calcium supplements, vitamin D products, or mammalian cell derived products)
- Pregnant or planning to become pregnant within 3 months after the last dose of IP
- Previous participation in this study or prior participation in a study with a sclerostin antibody product
- 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.
- Metal implants or hardware at either hip (ie, sliding nail, total endoprosthesis) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the percent change from baseline in DXA BMD at the total hip through Month 12. |
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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) |
Key secondary endpoints, which will be included in the test sequence, are as follows:
• Percent change from baseline in BMD by DXA at the total hip at Month 6
• Percent change from baseline in BMD by DXA at the total hip at Month 12
• Percent change from baseline in cortical BMD by QCT at the total hip at Month 6
• Percent change from baseline in cortical BMD by QCT at the total hip at Month 12
• Percent change from baseline in BMD by QCT at the total hip at Month 6
• Percent change from baseline in BMD by QCT at the total hip at Month 12
• Percent change from baseline in estimated strength by FEA at the total hip at Month 6
• Percent change from baseline in estimated strength by FEA at the total hip at Month 12
Other secondary endpoints, which will not be included in the test sequence, are as follows:
• Percent change from baseline in QCT BMC at the total hip at Month 6 and Month 12
• Percent change from baseline in BMD by DXA at the femoral neck at Month 6 and Month 12
• Percent change from baseline in BMD by DXA at the lumbar spine at Month 6 and Month 12 |
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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) | 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 | 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) | 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
Belgium |
Canada |
Colombia |
Czech Republic |
Denmark |
Hungary |
Poland |
Spain |
United Kingdom |
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 | 3 |
E.8.9.1 | In the Member State concerned days | |
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 | 3 |