| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal osteoporosis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.1 |
| 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 |
|
| 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 |
For the primary analysis period (randomization to primary analysis)
• To assess the effect of romosozumab treatment for 12 months followed by alendronate (ALN) treatment compared with ALN treatment alone on the subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) in postmenopausal women with osteoporosis
• To assess the effect of romosozumab treatment for 12 months followed by ALN treatment compared with ALN treatment alone on the subject incidence of new vertebral fracture in postmenopausal women with osteoporosis |
|
| E.2.2 | Secondary objectives of the trial |
Primary analysis period
To assess the effect of romosozumab treatment for 12months followed
by ALN treatment vs ALN treatment alone on:
•Subject incidence of fractures (all fractures [nonvertebral(…)] new…
fracture [pelvis(…) hip],(…) fracture and clinical vertebral fracture)
12month double-blind ALN-controlled study period
To assess the effect of romosozumab treatment for 12months vs ALN
treatment on:
•Subject incidence of fractures (clinical fracture [nonvertebral(…)]
(…)[nonvertebral(…) fractures] nonvertebral fracture, hip fracture,
clinical vertebral fracture, and major osteoporotic fracture [hip, forearm,
humerus, and clinical vertebral])
Overall study period-randomization to end of study
To assess the effect of romosozumab treatment for 12months followed
by ALN treatment vs ALN treatment alone on subject incidence of hip
fracture, major nonvertebral fracture [pelvis, distal femur, proximal
tibia, ribs, proximal humerus, forearm and hip](…)
See PA5 for complete wording |
|
| 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 |
Imaging and Pharmacokinetics (PK) / Bone Turnover Marker (BTM) / Biomarker Sub-study
Objectives:
For the 12-month double-blind ALN-controlled study period
• To characterize the serum romosozumab concentration
• To assess the effect of romosozumab treatment for 12 months compared with ALN treatment on:
- Percent changes in bone formation markers Procollagen Type 1 N-telopeptide (P1NP), Bone Specific Alkaline Phosphatase (BSAP), and Osteocalcin (OC) and in bone resorption marker serum Type I collagen C-telopeptide (sCTX)
- Percent changes in sclerostin and intact Parathyroid Hormone (iPTH)
- For subjects participating in the imaging components:
- Percent changes in integral (total) and trabecular volumetric BMD (vBMD) at the lumbar spine by Quantitative Computed Tomography (QCT)
- Percent changes in lumbar spine strength as assessed by Finite Element Analysis (FEA)
•For subjects participating in the imaging components: To assess the effect of romosozumab treatment for 6 months compared with ALN treatment for 6 months on percent changes in DXA BMD at the lumbar spine, total hip, and femoral neck
• To enable exploratory assessments of novel biomarkers through prospective collection of blood samples
For the primary analysis period
• To assess the effect of romosozumab treatment for 12 months followed by ALN treatment compared with ALN treatment alone on:
- Percent changes in bone formation marker P1NP and bone resorption marker sCTX
- Percent changes in sclerostin and iPTH
-For subjects participating in the imaging components:
- Percent changes in integral (total) and trabecular vBMD at the lumbar spine by QCT
- Percent changes in lumbar spine strength as assessed by FEA
• For subjects participating in the imaging components:To assess the effect of romosozumab treatment for 12 months followed by ALN treatment for 6 months compared with ALN treatment alone on percent changes in DXA BMD at the lumbar spine, total hip, and femoral neck
• To enable exploratory assessments of novel biomarkers through prospective collection of blood samples |
|
| E.3 | Principal inclusion criteria |
4.1.1 Ambulatory postmenopausal women, age ≥ 55 to ≤ 90 years at randomization. Postmenopausal status is defined as no vaginal bleeding or spotting for 12 consecutive months prior to screening.
4.1.2 Subject meets at least one of the following BMD and fracture criteria
BMD T-score ≤ -2.50 at the total hip or femoral neck AND EITHER at least one moderate (SQ2) or severe (SQ3) vertebral
fracture OR at least 2 mild (SQ1) vertebral fractures
or
BMD T-score ≤ -2.00 at the total hip or femoral neck AND EITHER at least 2 moderate (SQ2) or severe (SQ3) vertebral fractures OR a fracture of the proximal femur that occurred within 3 to 24 months prior to randomization
BMD T-scores at the time of screening will be assessed by the central imaging vendor based on DXA scans and using data for Caucasian women from the National Health and Nutritional Examination Survey (NHANES) 1998.
Vertebral fractures at the time of screening will be assessed by the
central imaging vendor based on lateral spine x-rays.
History of proximal femur fracture will be assessed by the principal
investigator based on discharge summary, radiology report, or
comparable documentation of type and date of fracture.
4.1.3 At least one hip is evaluable by DXA, as assessed by the principal investigator
4.1.4 Subject has provided informed consent |
|
| E.4 | Principal exclusion criteria |
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
Oral bisphosphonates:
•More than 3 years of cumulative use, unless last dose received ≥ 5
years prior to randomization
•Any dose received within 3 months prior to randomization
•More than 1 month of cumulative use between 3 and 12 months prior to
randomization
Denosumab or any cathepsin K inhibitor,such as odanacatib:any dose
received within 18 months prior to randomization
Teriparatide or any PTH analogs:
•any dose received within 3 months prior to randomization
•more than 1 month of cumulative use between 3 and 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:any 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 the results, such as sclerosteosis,
Paget's disease, osteomalacia, osteogenesis imperfecta, osteopetrosis,
ankylosing spondylitis, Cushing's disease, hyperprolactinemia, and
malabsorption syndrome
History of solid organ or bone marrow transplants
-25(OH) vitamin D levels <20 ng/mL as assessed by the central
laboratory.
Current hyper- or hypocalcemia, defined as albumin-adjusted serum
calcium outside the normal range, as assessed by the central laboratory.
Serum calcium levels may be retested once in case of an elevated serum
calcium level within 1.1x the ULN as assessed by the central laboratory.
Current, uncontrolled hyper- or hypothyroidism, per subject report or
chart review. Uncontrolled hyperthyroidism is defined as TSH and T4
outside the normal range. Uncontrolled hypothyroidism is defined as TSH>10
Current, uncontrolled hyperparathyroidism or history of
hypoparathyroidism, per subject report or chart review. Uncontrolled
hyperparathyroidism is defined as: PTH outside the normal range in
subjects with concurrent hypercalcemia; or PTH values >20% above the
ULN in normocalcemic subjects
Possible diagnosis of multiple myeloma or related lymphoproliferative
disorder, as assessed by serum protein electrophoresis performed by the
local laboratory
Exclusion criteria related to contraindications or possible signs of
intolerance to ALN; contraindications and potential signs of intolerance
for ALN therapy include:
•Hypocalcemia
•Abnormalities of the esophagus, which delay esophageal emptying such
as stricture or achalasia
•Inability to stand or sit upright for at least 30 min
•Hypersensitivity to ALN or other constituents of ALN tablets
•Pregnancy and lactation
•Other contraindications to ALN based on the country-specific product
insert applicable to the specific study center
•Significantly impaired renal function.
General
•Subject is currently enrolled in another investigational device or drug
study, or less than 30 days since ending another investigational device
or drug study(s), or receiving other investigational agent(s)
•Subject has previously entered this study or has previously participated
in a study with a sclerostin antibody product
•Other investigational procedures are excluded
•Malignancy within the last 5 years except non-melanoma skin cancers,
cervical or breast ductal carcinoma in situ within the last 5 years
•Subject has known sensitivity to any of the products or components to
be administered (calcium supplements, vitamin D products, or
mammalian cell derived products)
•Subject is pregnant or is planning to become pregnant within 3 months
after the last dose of IP
•Subject will not be available for protocol-required study visits or
procedures, to the best of the subject and investigator's knowledge
•Subject has any kind of disorder that, in the opinion of the investigator,
may compromise the ability of the subject to give written informed
consent and/or to comply with all required study procedures
•Subject is known to have human immunodeficiency virus, HCV, or HBV
infection
•Subject has any condition or illness, which in the opinion of the
Investigator might interfere with the evaluation of the safety of the
study product or may otherwise compromise the safety of the subject
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
During the primary analysis period
• Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) at primary analysis
• Subject incidence of new vertebral fracture through Month 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
During the primary analysis period
•Subject incidence of nonvertebral fracture at primary analysis
•Subject incidence of all fractures (nonvertebral fracture and new or
worsening vertebral fracture) at primary analysis
•Subject incidence of new or worsening vertebral fracture through
Month 24
•Subject incidence of major nonvertebral fracture (pelvis, distal femur,
proximal tibia, ribs, proximal humerus, forearm, and hip) at primary
analysis
•Subject incidence of hip fracture at primary analysis
•Subject incidence of multiple new or worsening vertebral fractures
through Month 24
•Subject incidence of clinical fracture (nonvertebral fracture and clinical
vertebral fracture) through Month 24
•Subject incidence of nonvertebral fracture through Month 24
•Subject incidence of hip fracture through Month 24
•Subject incidence of clinical vertebral fracture through Month 24
•Percent change from baseline in BMD at the lumbar spine, total hip, and
femoral neck at Months 24 and 36
During the 12-month double-blind ALN-controlled study period
•Subject incidence of clinical fracture (nonvertebral fracture and clinical
vertebral fracture) through Month 12
•Subject incidence of new vertebral fracture through Month 12
•Subject incidence of all fractures (nonvertebral fracture and new or
worsening vertebral fracture) through Month 12
•Subject incidence of nonvertebral fracture through Month 12
•Subject incidence of hip fracture through Month 12
•Subject incidence of major osteoporotic fracture (hip, forearm,
humerus, and clinical vertebral) through Month 12
•Subject incidence of clinical vertebral fracture through Month 12
•Percent change from baseline in BMD at the lumbar spine, total hip and
femoral neck at Month 12
For the overall study period
•Subject incidence of nonvertebral fracture at final analysis (after 440
events)
•Subject incidence of major nonvertebral fracture (pelvis, distal femur,
proximal tibia, ribs, proximal humerus, forearm, and hip) at final
analysis
•Subject incidence of hip fracture at final analysis |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 162 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Czech Republic |
| Denmark |
| Dominican Republic |
| Estonia |
| Finland |
| France |
| Germany |
| Greece |
| Guatemala |
| Hong Kong |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
End of study: Last subject is assessed or receives an intervention for
evaluation in the study (after nonvertebral fracture events confirmed
for at least 440 subjects unless the primary analysis demonstrates
superiority)
Primary Completion: Last subject is assessed or receives an
intervention for the purposes of final collection of data for the primary
analysis (clinical fracture events confirmed for at least 330 subjects and Month 24 study visits complete). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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