| 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 |
| Postmenopausal osteoporosis |
|
| 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 |
|
| 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 determine the effect of treatment with AMG 785 versus placebo at month 12 on the percent change from baseline in bone mineral density (BMD) at the lumbar spine in postmenopausal women with low bone density. |
|
| E.2.2 | Secondary objectives of the trial |
To study the effects of up to 12 months of treatment with AMG 785 versus placebo on the percent change from baseline:
• in BMD at lumbar spine (at month 6), total hip and femoral neck (at months 6 and 12), and distal radius (at month 12), and
• in bone turnover markers (BTMs). |
|
| 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 |
Full Title: Quantitative Computed Tomography (QCT)
Date, Version: 20 March 09, Amendment 4
Related Objectives: To investigate the effect of AMG785 on trabecular and cortical bone as assessed by Quantitative Computed Tomography (QCT) of the spine and/or proximal femur.
Full Title: Iliac Crest Bone Biopsy
Date, Version: 20 March 09, Amendment 4
Related Objectives: To investigate the effect of AMG 785 on bone histology and histomorphometry based on transiliac bone biopsies.
Full Title: 24-Hour Urine Collection
Date, Version: 20 March 09, Amendment 4
Related Objectives: To determine 24 hour calcium levels.
|
|
| E.3 | Principal inclusion criteria |
To be eligible for enrollment into the 24-month AMG 785 treatment phase, subjects must meet the following criteria:
• Ambulatory, postmenopausal women (based on medical history) aged ≥ 55 to ≤ 85. Postmenopausal will be defined as no vaginal bleeding or spotting for at least one year. If there is uncertainty regarding menopausal status:
– Women 60 years of age and older will be considered postmenopausal
– Women 55-59 must have confirmation of serum FSH ≥ 50 mIU/ml and serum estradiol ≤ 20 pg/mL at screening
• Low BMD measured by Dual energy X-ray Absorptiometry (DXA) and assessed by the central imaging vendor (refer to table below for eligible BMD values).
- Subjects must have at least two evaluable vertebrae in the L1-L4 region, and at least one evaluable hip.
- Subjects must not have a BMD value at any anatomical site (lumbar spine, total hip and femoral neck) that is below the lower limit specified for that site.
- Scans will be done in duplicate and the mean of the scans from at least one anatomical site (lumbar spine, total hip or femoral neck) must meet the BMD values defined in table below.
Eligible BMD values
Lunar (g/cm2) Hologic (g/cm2)
Lumbar Spine (a) ≤ 0.940 and ≥ 0.760 ≤ 0.827and ≥ 0.662
Total Hip (b) ≤ 0.756 and ≥ 0.567 ≤ 0.698 and ≥ 0.515
Femoral Neck (b) ≤ 0.760 and ≥ 0.551 ≤ 0.618 and ≥ 0.438
a Values correspond to T-scores between -2.0 and -3.5 as determined by the manufacturer
b Values correspond to T-scores between -2.0 and -3.5 Based on data for Caucasian women from the National Health and Nutritional Examination Survey (NHANES) 1998
• Appropriate written informed consent must be obtained
Inclusion Criteria for the 12 month denosumab extension phase (Month 24 to 36)
• Normocalcemia at or after the Month 21 visit but before the Month 24.
• Appropriate written informed consent must be obtained
Inclusion Criteria for the 12-month AMG 785 retreatment phase (Month 36 to 48)
• Normocalcemia as determined by the central laboratory analysis of albumin adjusted serum calcium of the most recent blood draw at or after the Month 30 visit but before the Month 36 study visit. Calcium repletion is permitted and central laboratory analysis of albumin adjusted serum calcium may be repeated before the Month 36 study visit
• Participation in Group A or B during initial 24 month AMG 785 treatment phase
• Subject has reached Month 36 of the study
• Appropriate written informed consent must be obtained
Inclusion Criteria for the 24-Month Follow-on Phase (Month 48 to Month 72)
- General inclusion criteria for participation in the 24-month follow-on phase
• Subject has reached month 48 of the study
• Appropriate written informed consent must be obtained
- Inclusion criteria for assignment to the no intervention group
• During the 24-month AMG 785 treatment phase, subject was assigned to any AMG 785 treatment group
• During the 12-month denosumab extension phase, subject was assigned to the denosumab treatment group |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria for the 24-Month AMG 785 Treatment Phase
•History of vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis after age 50.
•History of metabolic or bone disease that may interfere with the interpretation of the results, such as Paget’s disease, rheumatoid arthritis, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, Cushing’s disease, hyperprolactinemia, and malabsorption syndrome.
•Vitamin D deficiency. Vitamin D repletion will be permitted and subjects may be re-screened once.
•Evidence of untreated hyper-/hypothyroidism, current hyper-/hypoparathyroidism, elevated transaminases as determined by the central laboratory, significantly impaired renal function as determined by a derived creatinine clearance of less than or equal 30 mL/min using the Modification of Diet in Renal Disease equation, calculated by the central laboratory.
-Current hyper-/hypocalcemia as determined by the central laboratory analysis of albumin adjusted serum calcium.
•History of spinal stenosis.
•History of facial nerve paralysis.
•Known to have tested positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen.
•Malignancy within the last 5 years.
•History of solid organ or bone marrow transplants.
•Use of the following agents affecting bone metabolism:
-Intravenous bisphosphonates at any time in the past.
-Fluoride (for osteoporosis) within the past 24 M.
-Denosumab at any time in the past.
-Bisphosphonates, parathyroid hormone or strontium within the past 12 M.
-Calcitonin, selective estrogen receptor modulators, systemic oral or transdermal estrogen or tibolone within the past 3 M.
-Systemic glucocorticosteroids within the past 3 M.
•Contraindicated or intolerant of alendronic acid therapy; contraindications and potential signs of intolerance for alendronic acid therapy include:
-Abnormalities of the esophagus and other factors which delay esophageal emptying such as stricture or achalasia.
-Inability to stand or sit upright for at least 30 minutes.
-Hypersensitivity to alendronic acid or to any of its components
-Active gastric or duodenal ulcer; history of significant gastrointestinal bleed requiring hospitalization or transfusion, or dyspepsia or gastroesophageal reflux disease that is uncontrolled by medication.
•Contraindicated or intolerant of teriparatide therapy; contraindications for teriparatide therapy include:
-Hypersensitivity to teriparatide or to any of its excipients.
-Unexplained elevations of alkaline phosphatase.
-Prior external beam or implant radiation therapy involving the skeleton.
-Bone metastases or a history of skeletal malignancies.
•Known sensitivity to mammalian cell derived drug products.
•Known intolerance to calcium supplements.
•Previous enrollment in an AMG 785 clinical study.
•Currently enrolled in or has not yet completed at least 1 M since ending other investigational device or drug trial(s).
•Any condition which in the opinion of the investigator.
-Compromises the ability of the subject to give written informed consent.
-Prevents the subject from complying with study procedures, from completing the study.
-Interferes with the interpretation of study results.
Exclusion criteria for the 12 month extension phase
•Incidence of a clinical vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis during the initial 24 M treatment phase of the study
•A BMD loss of ≥ 7.0% from baseline at any time up to the M 18 assessment
•Malignancy
•History of osteonecrosis of the jaw
•Use of proscribed medication during the initial 24 M treatment phase
•Contraindicated or intolerant of denosumab therapy
Exclusion Criteria for the 12-month re-treatment phase
•New malignancy
•Use of proscribed medication during the 12 M extension phase
Exclusion Criteria for the 24-Month Follow-on Phase
-General exclusion criteria
•New malignancy, except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ
•Use of proscribed medication during the 12-M AMG 785 retreatment phase
•Partial withdrawal of consent and discontinuation of IP administration at any time up to the M 48 visit
-Exclusion criteria for assignment to the no intervention group
•Incidence of a clinical vertebral fracture or fragility fracture of the wrist,humerus, hip, or pelvis between the M 24 visit and the M 48 visit
•BMD T-score of ≤ -2.5 at the lumbar spine, total hip, or femoral neck based on local read of the DXA scans at M 48
-Exclusion criteria for assignment to the zolendronic acid treatment group
Contraindicated or intolerant of zoledronic acid therapy; contraindications and potential signs of intolerance to zoledronic acid therapy:Hypocalcemia, Severe renal impairment, Hypersensitivity to zoledronic acid, other bisphosphonates, or to any other components of zoledronic acid |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the percent change from baseline at month 12 in BMD at the lumbar spine for the individual AMG 785 groups and pooled placebo arms. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| To study the effects of treatment with AMG 785 versus placebo on the percent change from baseline in BMD at lumbar spine , total hip femoral neck, distal radius and in bone turnover markers |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Treatment effects of AMG 785 versus placebo on the percent change
from baseline at 12 months
- at month 6 in BMD at the lumbar spine, total hip and femoral neck
- at month 12 in BMD at the total hip, femoral neck and distal radius
- at months 1, 3, 6, 9 and 12 in BTMs (P1NP, CTX, OC, BSAP) |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| After initial 24 month treatment phase, eligible subjects enter a 12 month denosumab extension phase |
|
| 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.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Canada |
| European Union |
| 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
|
LVLS. However, subjects with neutralizing antibodies present at EOS will return to the clinic approximately every 12 weeks to test for presence of neutralizing antibodies. Subjects will be followed for a period of one year or until the neutralizing antibodies are no longer detectable, whichever comes first.
At the end of the initial 24 month treatment phase, eligible subjects will enter a 12 month extension phase (Month 24 to Month 36). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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