A Study to Evaluate the Safety and Efficacy of Denosumab and Ibandronate in Postmenopausal Women Sub-Optimally Treated With Daily or Weekly Bisphosphonates

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00936897
• Collaborator: (none)
• Enrollment: 833
• Arms: 2
• Duration (Months): 30

Study Details

Study Description

Brief Summary

This is a multi-center, randomized, open-label, parallel group, study being conducted in the United States and in Europe in postmenopausal women. Approximately 800 subjects will be randomized across about 65 sites in a 1:1 ratio to either denosumab 60mg SC Q6M, or ibandronate 150mg PO QM.

Condition or Disease	Intervention/Treatment	Phase
Postmenopausal Osteoporosis	Drug: Ibandronate; Drug: Denosumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 833 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Open-Label Study to Evaluate the Safety and Efficacy of Denosumab and Ibandronate in Postmenopausal Women Sub-Optimally Treated With Daily or Weekly Bisphosphonates
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ibandronate Ibandronate 150mg PO QM (tablet)	Drug: Ibandronate; Ibandronate 150mg PO QM (tablet)
Experimental: Denosumab denosumab 60mg Subcutaneous Q6M (pre-filled syringe)	Drug: Denosumab; denosumab 60mg SC Q6M (pre-filled syringe)

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

1. Serum Type-1 C-Telopeptide Percent Change From Baseline at Month 1 [Baseline to month 1]

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

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ambulatory, postmenopausal women (based on medical history) 55 years or older at screening

• Postmenopause will be defined as no vaginal bleeding or spotting for at least 12 months

• If the subject is 55 - 59 years old and there is uncertainty regarding menopausal status, confirmation of serum FSH (>= 50 mIU/mL) and serum estradiol (<= 20 pg/mL) must be obtained

• If the subject is 60 years or older, evaluation of FSH and estradiol levels is not needed to confirm menopausal status

• Have received their first prescription of daily or weekly bisphosphonate therapy at least 1 month prior to screening

• May have received

• raloxifene, calcitonin, prior to initiation of daily orweekly bisphosphonate therapy.

• up to 3 doses of monthly bisphosphonate prior to initiation of daily or weekly bisphosphonate therapy

• calcium, and vitamin D

• Hormone replacement therapy (e.g. estrogen use for mitigation of menopausal symptoms)

• Subject has:

• Stopped daily or weekly bisphosphonate therapy (is denoted as non-persistent) at least one month before the screening visit, or

• Demonstrated low adherence to therapy assessed by a score of less than 6 on the OS-MMAS

• Screening BMD (g/cm2) values, at the lumbar spine OR total hip, that occur within the following ranges, based on the particular scanner that is used:

GE Lunar Lumbar spine 0.700 < or = BMD < and = 0.940 Total hip 0.504 < or = BMD < or = 0.756

Hologic Lumbar spine 0.607 < or = BMD < or = 0.827 Total hip 0.454 < or = BMD < or = 0.698 Both the initial and the repeat DXA scan of the lumbar spine OR the total hip must meet the above eligibility criteria.

• At least 2 lumbar vertebrae must be evaluable by DXA.

• At least one hip must be evaluable by DXA (eg, no history of either bilateral hip replacement or pins in both hips)

• Provide signed informed consent before any study-specific procedures are conducted

Exclusion Criteria:

• Any disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures

• Current or prior use of medications prescribed for osteoporosis treatment other than oral daily or weekly bisphosphonate

• Contraindicated to receive oral ibandronate 150mg PO QM, including

• Hypersensitivity to ibandronate 150mg PO QM or other constituents of ibandronate 150mg PO QM tablets

• Abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia

• Inability to stand or sit upright for at least 60 minutes

• Administration of any of the following treatments within 3 months of screening

• Tibolone

• Anabolic steroids or testosterone

• Glucocorticosteroids (>= 5 mg prednisone equivalent per day for more than 10 days or a total cumulative dose of >= 50 mg)

• Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (<49.9 nmol/L)] - Repletion will be allowed and subjects may be re-screened

• Evidence of any of the following per subject report, chart review or central laboratory result:

• Significantly impaired renal function as determined by estimated Glomerular Filtration Rate less that 30mL/min/1.73 m2 determined by the central laboratory

• Current hypo- or hypercalcemia based on the central laboratory reference ranges

• Active gastric or duodenal ulcer; or any history of significant gastrointestinal bleed requiring hospitalization or transfusion

• Known to have tested positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen

• Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years

• Any metabolic bone disease or secondary cause of bone loss that is not controlled and may interfere with the interpretation of the findings

• Previous participation in clinical trials with denosumab 60mg SC Q6M (regardless of treatment)

• Received any solid organ or bone marrow transplant

• Any laboratory abnormality which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results

• Known sensitivity to mammalian cell derived drug products

• Known intolerance to calcium supplements

• Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial(s)

• Any physical or psychiatric disorder which, in the opinion of the investigator, 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 or completing 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

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00936897
• Other Study ID Numbers: 20080562
• First Posted: Jul 10, 2009
• Last Update Posted: Feb 11, 2013
• Last Verified: Feb 1, 2013

• Additional relevant MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal; Denosumab; Ibandronic Acid

Study Results

Participant Flow

Recruitment Details	Participants were randomized from 29 July 2009 through 5 November 2010

Arm/Group Title	Denosumab 60 mg SC Q6M	Ibandronate 150 mg PO QM
Arm/Group Description	Denosumab 60 mg subcutaneous once every 6 months	Ibandronate 150 mg oral monthly
Period Title: Overall Study
STARTED	417	416
COMPLETED	398	356
NOT COMPLETED	19	60

Baseline Characteristics

Arm/Group Title	Denosumab 60 mg SC Q6M	Ibandronate 150 mg PO QM	Total
Arm/Group Description	Denosumab 60 mg subcutaneous once every 6 months	Ibandronate 150 mg oral monthly	Total of all reporting groups
Overall Participants	417	416	833
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.2 (8.1)	66.2 (7.8)	66.7 (8)
Sex/Gender, Customized (Number) [Number]
Female	417 100%	416 100%	833 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
White or Caucasian	348 83.5%	361 86.8%	709 85.1%
Black or African American	3 0.7%	4 1%	7 0.8%
Hispanic or Latino	54 12.9%	42 10.1%	96 11.5%
Asian	3 0.7%	4 1%	7 0.8%
American Indian or Alaska Native	2 0.5%	0 0%	2 0.2%
Other	1 0.2%	2 0.5%	3 0.4%
Native Hawaiian or Other Pacific Islander	6 1.4%	3 0.7%	9 1.1%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized subjects using regression imputation for missing post baseline data.

Arm/Group Title	Denosumab 60 mg SC Q6M	Ibandronate 150 mg PO QM
Arm/Group Description	Denosumab 60 mg subcutaneous once every 6 months	Ibandronate 150 mg oral monthly
Measure Participants	417	415
Mean (95% Confidence Interval) [Percentage Change From Baseline]	2.2	0.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Denosumab 60 mg SC Q6M, Ibandronate 150 mg PO QM
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 1.0 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Ibandronate

2. Secondary Outcome

Title	Serum Type-1 C-Telopeptide Percent Change From Baseline at Month 1
Time Frame	Baseline to month 1

Outcome Measure Data

Analysis Population Description

Randomized subjects who enrolled in the bone marker substudy

Arm/Group Title	Denosumab 60 mg SC Q6M	Ibandronate 150 mg PO QM
Arm/Group Description	Denosumab 60 mg subcutaneous once every 6 months	Ibandronate 150 mg oral monthly
Measure Participants	134	113
Median (Inter-Quartile Range) [Percentage Change From Baseline]	-81.1	-35.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Denosumab 60 mg SC Q6M, Ibandronate 150 mg PO QM
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized subjects using regression imputation for missing post baseline data

Arm/Group Title	Denosumab 60 mg SC Q6M	Ibandronate 150 mg PO QM
Arm/Group Description	Denosumab 60 mg subcutaneous once every 6 months	Ibandronate 150 mg oral monthly
Measure Participants	417	415
Mean (95% Confidence Interval) [Percentage Change From Baseline]	1.7	0.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Denosumab 60 mg SC Q6M, Ibandronate 150 mg PO QM
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Ibandronate

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized subjects using regression imputation for missing post baseline data

Arm/Group Title	Denosumab 60 mg SC Q6M	Ibandronate 150 mg PO QM
Arm/Group Description	Denosumab 60 mg subcutaneous once every 6 months	Ibandronate 150 mg oral monthly
Measure Participants	417	415
Mean (95% Confidence Interval) [Percentage Change From Baseline]	4.1	2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Denosumab 60 mg SC Q6M, Ibandronate 150 mg PO QM
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; 1.5 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Denosumab - Ibandronate

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. Participant flow includes all subjects randomized to the study. Number of subjects at risk of an adverse events are based on safety population - all randomized subjects who received at least one dose of treatment.
Arm/Group Title	Ibandronate 150 mg PO QM		Denosumab 60 mg SC Q6M
Arm/Group Description	Ibandronate 150 mg oral monthly		Denosumab 60 mg subcutaneous once every 6 months
All Cause Mortality
	Ibandronate 150 mg PO QM		Denosumab 60 mg SC Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ibandronate 150 mg PO QM		Denosumab 60 mg SC Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/410 (5.4%)		39/411 (9.5%)
Cardiac disorders
Atrial fibrillation	0/410 (0%)		2/411 (0.5%)
Atrioventricular block complete	1/410 (0.2%)		0/411 (0%)
Bradycardia	0/410 (0%)		2/411 (0.5%)
Cardiac failure congestive	0/410 (0%)		3/411 (0.7%)
Cardiac tamponade	1/410 (0.2%)		0/411 (0%)
Coronary artery disease	1/410 (0.2%)		0/411 (0%)
Sick sinus syndrome	0/410 (0%)		2/411 (0.5%)
Wolff-Parkinson-White syndrome	1/410 (0.2%)		0/411 (0%)
Eye disorders
Retinal detachment	0/410 (0%)		1/411 (0.2%)
Gastrointestinal disorders
Dysphagia	0/410 (0%)		1/411 (0.2%)
Femoral hernia	0/410 (0%)		1/411 (0.2%)
Haemorrhoids	1/410 (0.2%)		0/411 (0%)
Inguinal hernia	0/410 (0%)		1/411 (0.2%)
Internal hernia	0/410 (0%)		1/411 (0.2%)
Intestinal ischaemia	0/410 (0%)		1/411 (0.2%)
Irritable bowel syndrome	0/410 (0%)		1/411 (0.2%)
Small intestinal obstruction	0/410 (0%)		1/411 (0.2%)
Upper gastrointestinal haemorrhage	0/410 (0%)		1/411 (0.2%)
General disorders
Chest pain	0/410 (0%)		3/411 (0.7%)
Device failure	1/410 (0.2%)		0/411 (0%)
Fatigue	0/410 (0%)		1/411 (0.2%)
Hepatobiliary disorders
Hepatitis acute	0/410 (0%)		1/411 (0.2%)
Immune system disorders
Hypersensitivity	1/410 (0.2%)		0/411 (0%)
Infections and infestations
Bacterial pyelonephritis	0/410 (0%)		1/411 (0.2%)
Cellulitis	0/410 (0%)		1/411 (0.2%)
Clostridial infection	1/410 (0.2%)		0/411 (0%)
Clostridium difficile colitis	0/410 (0%)		1/411 (0.2%)
Diverticulitis	0/410 (0%)		2/411 (0.5%)
Gastroenteritis	1/410 (0.2%)		1/411 (0.2%)
Gastroenteritis viral	1/410 (0.2%)		0/411 (0%)
Pneumonia	1/410 (0.2%)		0/411 (0%)
Pneumonia bacterial	1/410 (0.2%)		0/411 (0%)
Postoperative wound infection	1/410 (0.2%)		0/411 (0%)
Urinary tract infection	0/410 (0%)		1/411 (0.2%)
Injury, poisoning and procedural complications
Aortic injury	1/410 (0.2%)		0/411 (0%)
Cardiac vein perforation	1/410 (0.2%)		0/411 (0%)
Femur fracture	1/410 (0.2%)		0/411 (0%)
Fracture	0/410 (0%)		1/411 (0.2%)
Gun shot wound	1/410 (0.2%)		0/411 (0%)
Heart injury	1/410 (0.2%)		0/411 (0%)
Lumbar vertebral fracture	1/410 (0.2%)		0/411 (0%)
Thoracic vertebral fracture	1/410 (0.2%)		1/411 (0.2%)
Metabolism and nutrition disorders
Dehydration	1/410 (0.2%)		0/411 (0%)
Diabetes mellitus inadequate control	0/410 (0%)		1/411 (0.2%)
Hypoglycaemia	0/410 (0%)		1/411 (0.2%)
Hypokalaemia	0/410 (0%)		1/411 (0.2%)
Musculoskeletal and connective tissue disorders
Foot deformity	1/410 (0.2%)		0/411 (0%)
Lumbar spinal stenosis	0/410 (0%)		1/411 (0.2%)
Osteoarthritis	0/410 (0%)		1/411 (0.2%)
Rotator cuff syndrome	0/410 (0%)		1/411 (0.2%)
Tendonitis	0/410 (0%)		1/411 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	0/410 (0%)		1/411 (0.2%)
Basal cell carcinoma	1/410 (0.2%)		0/411 (0%)
Breast cancer	1/410 (0.2%)		1/411 (0.2%)
Colon adenoma	1/410 (0.2%)		0/411 (0%)
Colon cancer	1/410 (0.2%)		1/411 (0.2%)
Lung neoplasm malignant	1/410 (0.2%)		0/411 (0%)
Malignant melanoma in situ	0/410 (0%)		1/411 (0.2%)
Renal cell carcinoma	0/410 (0%)		1/411 (0.2%)
Thyroid neoplasm	1/410 (0.2%)		0/411 (0%)
Nervous system disorders
Cerebrovascular accident	0/410 (0%)		2/411 (0.5%)
Transient ischaemic attack	1/410 (0.2%)		0/411 (0%)
Psychiatric disorders
Mental status changes	1/410 (0.2%)		1/411 (0.2%)
Renal and urinary disorders
Bladder prolapse	0/410 (0%)		1/411 (0.2%)
Renal failure acute	0/410 (0%)		1/411 (0.2%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/410 (0%)		1/411 (0.2%)
Chronic respiratory failure	0/410 (0%)		1/411 (0.2%)
Dyspnoea	0/410 (0%)		1/411 (0.2%)
Hypoxia	0/410 (0%)		1/411 (0.2%)
Obstructive airways disorder	0/410 (0%)		1/411 (0.2%)
Pleural effusion	0/410 (0%)		1/411 (0.2%)
Surgical and medical procedures
Aortic valve repair	0/410 (0%)		1/411 (0.2%)
Vascular disorders
Deep vein thrombosis	0/410 (0%)		1/411 (0.2%)
Hypertension	1/410 (0.2%)		1/411 (0.2%)
Other (Not Including Serious) Adverse Events
	Ibandronate 150 mg PO QM		Denosumab 60 mg SC Q6M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/410 (7.6%)		42/411 (10.2%)
Infections and infestations
Upper respiratory tract infection	9/410 (2.2%)		21/411 (5.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	23/410 (5.6%)		25/411 (6.1%)

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.