Study to Compare the Efficacy and Safety of DenosumAb Versus Placebo in Males With Osteoporosis

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00980174
• Collaborator: (none)
• Enrollment: 242
• Arms: 2
• Actual Duration (Months): 31.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Low Bone Mass; Low Bone Mineral Density; Males With Osteoporosis; Osteopenia; Osteoporosis	Drug: 60 mg denosumab; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 242 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo Controlled Study to Compare the Efficacy and Safety of Denosumab Versus Placebo in Males With Low Bone Mineral Density
• Actual Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jun 21, 2011
• Actual Study Completion Date: May 23, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 2 Subjects will receive placebo for denosumab (SC injection every 6 months) for 1 year (double-blind phase) followed by 60 mg denosumab (SC injection every 6 months) for 1 year (open-label phase)	Drug: 60 mg denosumab; 60 mg denosumab (SC injection every 6 months); Other Names: denosumab ; Other: Placebo; Placebo for denosumab (SC injection every 6 months)
Experimental: 1 60 mg denosumab (SC injection every 6 months) for 1 year (double-blind phase) followed by 60 mg denosumab(SC injection every 6 months) for 1 year (open-label phase). These subjects will be on denosumab for a total of 2 years.	Drug: 60 mg denosumab; 60 mg denosumab (SC injection every 6 months); Other Names: denosumab

Outcome Measures

Primary Outcome Measures

1. Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 [From Baseline to 12 Months]

Secondary Outcome Measures

1. Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 [From Baseline to 12 Months]

2. Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12 [From Baseline to 12 Months]

3. Trochanter Bone Mineral Density Percent Change From Baseline at Month 12 [From Baseline to 12 Months]

4. Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 [From Baseline to 12 Months]

5. Serum Type 1 Collagen C-telopeptide (CTX) Percent Change From Baseline at Day 15 [From Baseline to Day 15]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 85 Years
• Sexes Eligible for Study: Male
• Accepts 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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Langdahl BL, Teglbjærg CS, Ho PR, Chapurlat R, Czerwinski E, Kendler DL, Reginster JY, Kivitz A, Lewiecki EM, Miller PD, Bolognese MA, McClung MR, Bone HG, Ljunggren Ö, Abrahamsen B, Gruntmanis U, Yang YC, Wagman RB, Mirza F, Siddhanti S, Orwoll E. A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial. J Clin Endocrinol Metab. 2015 Apr;100(4):1335-42. doi: 10.1210/jc.2014-4079. Epub 2015 Jan 21.
• Orwoll E, Teglbjærg CS, Langdahl BL, Chapurlat R, Czerwinski E, Kendler DL, Reginster JY, Kivitz A, Lewiecki EM, Miller PD, Bolognese MA, McClung MR, Bone HG, Ljunggren Ö, Abrahamsen B, Gruntmanis U, Yang YC, Wagman RB, Siddhanti S, Grauer A, Hall JW, Boonen S. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012 Sep;97(9):3161-9. doi: 10.1210/jc.2012-1569. Epub 2012 Jun 21.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00980174
• Other Study ID Numbers: 20080098
• First Posted: Sep 18, 2009
• Last Update Posted: Oct 17, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Amgen: men; male; denosumab; BMD; lumbar spine; ADAMO; The ADAMO Trial; male osteoporosis; osteoporosis in men; males with low bone mineral density
• Additional relevant MeSH terms: Osteoporosis; Bone Diseases, Metabolic; Denosumab

Study Results

Participant Flow

Arm/Group Title	Placebo	Denosumab 60 mg Q6M
Arm/Group Description
Period Title: Overall Study
STARTED	121	121
COMPLETED	117	111
NOT COMPLETED	4	10

Baseline Characteristics

Arm/Group Title	Placebo	Denosumab 60 mg Q6M	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	121	121	242
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.0 (9.1)	64.9 (10.5)	65.0 (9.8)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	121 100%	121 100%	242 100%
Race/Ethnicity, Customized (Number) [Number]
White or Caucasian	107 88.4%	121 100%	228 94.2%
Hispanic or Latino	10 8.3%	0 0%	10 4.1%
Asian	2 1.7%	0 0%	2 0.8%
Black or African American	1 0.8%	0 0%	1 0.4%
Native Hawaiian or Pacific Islander	1 0.8%	0 0%	1 0.4%
Region of Enrollment (Number) [Number]
Europe	78 64.5%	87 71.9%	165 68.2%
North America	43 35.5%	34 28.1%	77 31.8%

Outcome Measures

1. Primary Outcome

Title	Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12
Time Frame	From Baseline to 12 Months

Outcome Measure Data

Analysis Population Description

Subjects with baseline and at least one post baseline measurements

Arm/Group Title	Placebo	Denosumab 60 mg Q6M
Arm/Group Description
Measure Participants	118	117
Mean (95% Confidence Interval) [Percent]	0.9	5.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab 60 mg Q6M
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Adjusted by level of baseline bone mineral density T-score
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.8
	Confidence Interval	(2-Sided) 95%; 4.0 to 5.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Placebo

2. Secondary Outcome

Title	Total Hip Bone Mineral Density Percent Change From Baseline at Month 12
Time Frame	From Baseline to 12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Denosumab 60 mg Q6M
Arm/Group Description
Measure Participants	119	117
Mean (95% Confidence Interval) [Percent]	0.3	2.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab 60 mg Q6M
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is adjusted for multiple comparisons by Hochberg method
	Method	ANCOVA
	Comments	Adjusted by level of baseline bone mineral density T-score
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; 1.5 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Placebo

3. Secondary Outcome

Title	Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12
Time Frame	From Baseline to 12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Denosumab 60 mg Q6M
Arm/Group Description
Measure Participants	119	117
Mean (95% Confidence Interval) [Percent]	0.0	2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab 60 mg Q6M
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is adjusted for multiple comparisons by Hochberg method
	Method	ANCOVA
	Comments	Adjusted by level of baseline bone mineral density T-score
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 95%; 1.3 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Placebo

4. Secondary Outcome

Title	Trochanter Bone Mineral Density Percent Change From Baseline at Month 12
Time Frame	From Baseline to 12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Denosumab 60 mg Q6M
Arm/Group Description
Measure Participants	119	117
Mean (95% Confidence Interval) [Percent]	0.8	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab 60 mg Q6M
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is adjusted for multiple comparisons by Hochberg method
	Method	ANCOVA
	Comments	Adjusted by level of baseline bone mineral density T-score
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; 1.4 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Placebo

5. Secondary Outcome

Title	Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12
Time Frame	From Baseline to 12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Denosumab 60 mg Q6M
Arm/Group Description
Measure Participants	118	116
Mean (95% Confidence Interval) [Percent]	-0.3	0.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab 60 mg Q6M
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0144
	Comments	p-value is adjusted for multiple comparisons by Hochberg method
	Method	ANCOVA
	Comments	Adjusted by level of baseline bone mineral density T-score
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.2 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Placebo

6. Secondary Outcome

Title	Serum Type 1 Collagen C-telopeptide (CTX) Percent Change From Baseline at Day 15
Time Frame	From Baseline to Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Denosumab 60 mg Q6M
Arm/Group Description
Measure Participants	116	115
Median (Inter-Quartile Range) [Percent]	-7	-81

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab 60 mg Q6M
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value is adjusted for multiple comparisons by Hochberg method
	Method	Van Elteren Rank Test
	Comments	Adjusted by level of baseline bone mineral density T-score

Adverse Events

Time Frame	12 months
Adverse Event Reporting Description	The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Arm/Group Title	Placebo		Denosumab 60 mg Q6M
Arm/Group Description
All Cause Mortality
	Placebo		Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/120 (8.3%)		11/120 (9.2%)
Cardiac disorders
Acute myocardial infarction	0/120 (0%)		1/120 (0.8%)
Atrial fibrillation	1/120 (0.8%)		0/120 (0%)
Myocardial infarction	0/120 (0%)		1/120 (0.8%)
Congenital, familial and genetic disorders
Skull malformation	1/120 (0.8%)		0/120 (0%)
Eye disorders
Retinal detachment	1/120 (0.8%)		0/120 (0%)
Vitreous haemorrhage	1/120 (0.8%)		0/120 (0%)
Gastrointestinal disorders
Pancreatitis acute	1/120 (0.8%)		1/120 (0.8%)
General disorders
Chest pain	0/120 (0%)		1/120 (0.8%)
Hepatobiliary disorders
Cholecystitis	0/120 (0%)		1/120 (0.8%)
Infections and infestations
Pneumonia	1/120 (0.8%)		0/120 (0%)
Injury, poisoning and procedural complications
Injury	0/120 (0%)		1/120 (0.8%)
Ligament rupture	1/120 (0.8%)		0/120 (0%)
Meniscus lesion	1/120 (0.8%)		0/120 (0%)
Post procedural complication	0/120 (0%)		1/120 (0.8%)
Road traffic accident	0/120 (0%)		1/120 (0.8%)
Vascular pseudoaneurysm	0/120 (0%)		1/120 (0.8%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/120 (0.8%)		0/120 (0%)
Spinal column stenosis	0/120 (0%)		1/120 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	0/120 (0%)		3/120 (2.5%)
Prostatic adenoma	1/120 (0.8%)		0/120 (0%)
Nervous system disorders
Basilar artery thrombosis	1/120 (0.8%)		0/120 (0%)
Cerebral haemorrhage	1/120 (0.8%)		0/120 (0%)
Vascular disorders
Arterial thrombosis limb	0/120 (0%)		2/120 (1.7%)
Peripheral ischaemia	1/120 (0.8%)		1/120 (0.8%)
Other (Not Including Serious) Adverse Events
	Placebo		Denosumab 60 mg Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/120 (22.5%)		23/120 (19.2%)
Gastrointestinal disorders
Constipation	7/120 (5.8%)		0/120 (0%)
Infections and infestations
Nasopharyngitis	7/120 (5.8%)		8/120 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/120 (5.8%)		8/120 (6.7%)
Back pain	8/120 (6.7%)		10/120 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results aftercompletion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.