Low Bone Mass, Low Bone Mineral Density, Males With Osteoporosis, Osteopenia, Osteoporosis
Conditions
Keywords
men, male, denosumab, BMD, lumbar spine, ADAMO, The ADAMO Trial, male osteoporosis, osteoporosis in men, males with low bone mineral density
Brief summary
The purpose of this study is to assess how effective and safe denosumab is in a population of males with low bone mass at risk of fracture. The primary clinical hypothesis is that in men with low bone mineral density, the mean percent change in lumbar spine bone mineral density at 12 months in subjects receiving denosumab will be greater than in subjects receiving placebo. Denosumab is a fully human monoclonal antibody with a high affinity for Receptor Activator of Nuclear Factor (RANK) Ligand that can bind and neutralize the activity of human RANK Ligand similar to the action of endogenous osteoprotegerin.
Interventions
DRUG60 mg denosumab
60 mg denosumab (SC injection every 6 months)
OTHERPlacebo
Placebo for denosumab (SC injection every 6 months)
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
30 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Bone Mineral Density (BMD) values (g/cm2) assessed by the local site at either the lumbar spine OR femoral neck that occur within the ranges specified in the protocol OR For subjects with a history of a major osteoporotic fracture (clinical vertebral, hip, humerus and distal radius fractures) occurring more than 6 months prior to screening, BMD values (g/cm2) assessed by the local site, at either the lumbar spine OR femoral neck that occur within the ranges specified in the protocol. * At least 2 lumbar vertebrae, at least 1 hip and at least one forearm must be evaluable by Dual X ray Absorptiometry (DXA). * Ambulatory males 30 to 85 years of age inclusive at the start of screening. * Provide the appropriate written informed consent before any study specific procedure.
Exclusion criteria
* BMD values (g/cm2) as specified in the protocol in subjects with or without a history of major osteoporotic fractures, based on the particular scanner that is used. * Any disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures. * Any severe or more than 1 moderate vertebral fractures on screening spinal x ray * Any vertebral fracture diagnosed within the 6 months prior to screening * Any clinical fracture within the last 6 months prior to screening * For males with a partner of childbearing potential: Subject refuses to use 2 highly effective methods of contraception for the duration of the study and for 10 months after the last dose of study medication. * For males with a partner who is pregnant: Subject refuses to use a condom for the duration of the study and for 10 months after the last dose of study medication. * Previous participation in clinical trials with denosumab or administration of commercial denosumab. * Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s). * Vitamin D deficiency \[25(OH) vitamin D level \< 20 ng/mL (\< 49.9 nmol/L)\]. Vitamin D replenishment will be permitted and subjects may be re-screened; see Section 7. * Hyper- or hypothyroidism; however, stable subjects, in the investigator's opinion, on thyroid hormone replacement therapy are allowed. * Hyper- or hypoparathyroidism. Intact parathyroid hormone (iPTH) values outside of the reference range as determined by the central laboratory * Elevated transaminases. Serum aspartate aminotransferase; serum glutamate-oxaloacetic transaminase \> 2.5 x upper limit of normal. Serum alanine aminotransferase; serum glutamate pyruvate transaminase \> 2.5 x upper limit of normal (both as determined by the central laboratory). * Significantly impaired renal function as determined by a derived glomerular filtration rate (using the Modification of Diet in Renal Disease formula) of less than or equal to 30 mL/min/1.73 m2 calculated by the central laboratory. * Hypo- or hypercalcemia based on the central laboratory reference ranges for albumin-adjusted serum calcium. * Known to have tested positive for human immunodeficiency virus, hepatitis C virus, hepatitis B surface antigen or cirrhosis of the liver. * Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma) within the last 5 years. * Any metabolic bone disease, eg osteomalacia, osteogenesis imperfecta, rheumatoid arthritis, Paget's disease, Cushing's disease or, hyperprolactinemia which may interfere with the interpretation of the findings OR evidence of malabsorption syndromes which might interfere with absorption of vitamin D. * Received any solid organ or bone marrow transplant or is on chronic immunosuppression for any reason. * Any laboratory abnormality, which in the opinion of the investigator or Amgen, will prevent the subject from completing the study or interfere with the interpretation of the study results. * Administration of intravenous bisphosphonate, or fluoride (except for dental treatment) or strontium ranelate. * Oral bisphosphonate treatment: * greater than or equal to 3 months cumulatively in the past 2 years, OR * greater than or equal to 1 month in the past year, OR * Any use during the 3-month period prior to randomization * Administration of any of the following treatments 3 months prior to screening: * Anabolic steroids or testosterone * Glucocorticosteroids (greater than or equal to 5 mg prednisone equivalent per day for more than 10 days or a total cumulative dose of greater than or equal to 50 mg) * Calcitonin * Calcitriol or vitamin D derivatives \[vitamin D contained in supplements or multivitamins is allowed\] * Other bone active drugs including anti-convulsives (except benzodiazepines) and heparin * Chronic systemic ketoconazole, adrenocorticotrophic hormone (ACTH), cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists. * Androgen deprivation therapy * Known sensitivity to mammalian cell derived drug products. * Known intolerance to calcium or vitamin D supplements. * Height, weight or girth which may preclude accurate DXA measurements. * Bilateral hip replacements * Any physical or psychiatric disorder which, in the opinion of the investigator or Amgen, will prevent the subject from completing the study or interfere with the interpretation of the study results. * Evidence of alcohol or substance-abuse within the last 12 months which the investigator believes would interfere with understanding of or completion of the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 | From Baseline to 12 Months |
Secondary
| Measure | Time frame |
|---|---|
| Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 | From Baseline to 12 Months |
| Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12 | From Baseline to 12 Months |
| Trochanter Bone Mineral Density Percent Change From Baseline at Month 12 | From Baseline to 12 Months |
| Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 | From Baseline to 12 Months |
| Serum Type 1 Collagen C-telopeptide (CTX) Percent Change From Baseline at Day 15 | From Baseline to Day 15 |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo | 121 |
| Denosumab 60 mg Q6M | 121 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Ineligibility determined | 2 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo | Denosumab 60 mg Q6M | Total |
|---|---|---|---|
| Age, Continuous | 65.0 years STANDARD_DEVIATION 9.1 | 64.9 years STANDARD_DEVIATION 10.5 | 65.0 years STANDARD_DEVIATION 9.8 |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 10 Participants | 0 Participants | 10 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White or Caucasian | 107 Participants | 121 Participants | 228 Participants |
| Region of Enrollment Europe | 78 Participants | 87 Participants | 165 Participants |
| Region of Enrollment North America | 43 Participants | 34 Participants | 77 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 121 Participants | 121 Participants | 242 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 120 | 23 / 120 |
| serious Total, serious adverse events | 10 / 120 | 11 / 120 |
Outcome results
Primary
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12
Time frame: From Baseline to 12 Months
Population: Subjects with baseline and at least one post baseline measurements
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 | 0.9 Percent |
| Denosumab 60 mg Q6M | Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 | 5.7 Percent |
p-value: <0.000195% CI: [4, 5.6]ANCOVA
Secondary
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12
Time frame: From Baseline to 12 Months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 | -0.3 Percent |
| Denosumab 60 mg Q6M | Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 | 0.6 Percent |
p-value: 0.014495% CI: [0.2, 1.6]ANCOVA
Secondary
Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12
Time frame: From Baseline to 12 Months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12 | 0.0 Percent |
| Denosumab 60 mg Q6M | Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12 | 2.1 Percent |
p-value: <0.000195% CI: [1.3, 3]ANCOVA
Secondary
Serum Type 1 Collagen C-telopeptide (CTX) Percent Change From Baseline at Day 15
Time frame: From Baseline to Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Serum Type 1 Collagen C-telopeptide (CTX) Percent Change From Baseline at Day 15 | -7 Percent |
| Denosumab 60 mg Q6M | Serum Type 1 Collagen C-telopeptide (CTX) Percent Change From Baseline at Day 15 | -81 Percent |
p-value: <0.0001Van Elteren Rank Test
Secondary
Total Hip Bone Mineral Density Percent Change From Baseline at Month 12
Time frame: From Baseline to 12 Months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 | 0.3 Percent |
| Denosumab 60 mg Q6M | Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 | 2.4 Percent |
p-value: <0.000195% CI: [1.5, 2.6]ANCOVA
Secondary
Trochanter Bone Mineral Density Percent Change From Baseline at Month 12
Time frame: From Baseline to 12 Months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Trochanter Bone Mineral Density Percent Change From Baseline at Month 12 | 0.8 Percent |
| Denosumab 60 mg Q6M | Trochanter Bone Mineral Density Percent Change From Baseline at Month 12 | 3.1 Percent |
p-value: <0.000195% CI: [1.4, 3.2]ANCOVA