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Safety and Efficacy Study to Evaluate Denosumab Compared With Zoledronic Acid in Postmenopausal Women With Osteoporosis

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ClinicalTrials.gov Identifier: NCT01732770
Recruitment Status : Completed
First Posted : November 26, 2012
Results First Posted : January 25, 2016
Last Update Posted : March 10, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Post Menopausal Osteoporosis
Interventions Biological: Denosumab
Drug: Zoledronic Acid
Drug: Placebo to Denosumab
Drug: Placebo to Zoledronic Acid
Enrollment 643
Recruitment Details This study was conducted at 37 centers in Belgium, Denmark, Poland, Spain, Canada, United States of America, and Australia. The first participant enrolled on 07 November 2012 and the last participant enrolled on 15 January 2014.
Pre-assignment Details Participants were randomized in a 1:1 allocation ratio to receive either denosumab or zoledronic acid. Randomization was stratified by screening serum type I collagen C-telopeptide (sCTX) values (< 0.3 ng/mL, 0.3 to 0.5 ng/mL).
Arm/Group Title Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Hide Arm/Group Description Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6. Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Period Title: Overall Study
Started 322 321
Received Study Treatment 320 320
Completed 312 313
Not Completed 10 8
Reason Not Completed
Lost to Follow-up             2             3
Withdrawal by Subject             5             3
Decision by Sponsor             2             2
Death             1             0
Arm/Group Title Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M Total
Hide Arm/Group Description Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6. Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1. Total of all reporting groups
Overall Number of Baseline Participants 322 321 643
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 322 participants 321 participants 643 participants
69.5  (7.7) 68.5  (7.1) 69.0  (7.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 322 participants 321 participants 643 participants
Female
322
 100.0%
321
 100.0%
643
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 322 participants 321 participants 643 participants
White 314 309 623
Asian 4 5 9
Other 2 4 6
Native Hawaiian or Other Pacific Islander 1 2 3
Black or African American 0 1 1
Multiple 1 0 1
Screening serum CTX  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 322 participants 321 participants 643 participants
< 0.3 ng/mL 242 239 481
≥ 0.3 ng/mL 78 82 160
Missing 2 0 2
Lumbar Spine Bone Mineral Density (BMD) T-score   [1] 
Mean (Standard Deviation)
Unit of measure:  T-score
Number Analyzed 322 participants 321 participants 643 participants
-2.64  (0.86) -2.74  (0.83) -2.69  (0.84)
[1]
Measure Description: BMD was measured using dual-energy x-ray absorptiometry (DXA) of the lumbar spine. The T-score is a comparison of a person's bone density with that of a healthy 30-year-old of the same sex. Lower scores (more negative) mean lower bone density: A T-score of -2.5 or lower qualifies as osteoporosis and a T-score of -1.0 to -2.5 signifies osteopenia, meaning below-normal bone density without full osteoporosis.
Total Hip BMD T-score  
Mean (Standard Deviation)
Unit of measure:  T-score
Number Analyzed 322 participants 321 participants 643 participants
-1.93  (0.80) -1.93  (0.74) -1.93  (0.77)
Femoral Neck BMD T-score  
Mean (Standard Deviation)
Unit of measure:  T-score
Number Analyzed 322 participants 321 participants 643 participants
-2.17  (0.68) -2.17  (0.66) -2.17  (0.67)
Prior Oral Bisphosphonate Duration  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 322 participants 321 participants 643 participants
6.35  (3.68) 6.21  (3.84) 6.28  (3.76)
Historical Fractures   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 322 participants 321 participants 643 participants
Any prior fracture 159 169 328
Prior osteoporotic fracture 121 120 241
[1]
Measure Description: An osteoporotic fracture is defined as a reported fracture excluding skull fracture, facial bones fracture, fingers fracture and toes fracture, fractures with high trauma severity, and pathological fractures.
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m²
Number Analyzed 322 participants 321 participants 643 participants
24.31  (4.18) 24.27  (3.99) 24.29  (4.08)
1.Primary Outcome
Title Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis
Hide Description Bone mineral density (BMD) of the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging facility.
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analysis set includes all randomized participants who have a baseline BMD measurement and at least one postbaseline BMD measurement. Any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, last observation carried forward [LOCF]).
Arm/Group Title Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Hide Arm/Group Description:
Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.
Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Overall Number of Participants Analyzed 312 314
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
1.1
(0.7 to 1.5)
3.2
(2.8 to 3.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
Comments A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%.
Type of Statistical Test Non-Inferiority or Equivalence (legacy)
Comments The lower bound of the 2-sided 95% confidence interval (CI) of (denosumab - zoledronic acid) was compared with the non-inferiority margin of -0.46% for assessing non-inferiority.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 2.1
Confidence Interval (2-Sided) 95%
1.6 to 2.6
Estimation Comments Treatment difference = denosumab - zoledronic acid
2.Secondary Outcome
Title Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis
Hide Description BMD of the hip was measured by DXA. DXA scans were analyzed by a central imaging facility.
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
Arm/Group Title Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Hide Arm/Group Description:
Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.
Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Overall Number of Participants Analyzed 309 311
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
0.6
(0.3 to 0.8)
1.9
(1.7 to 2.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
Comments A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%.
Type of Statistical Test Non-Inferiority or Equivalence (legacy)
Comments The lower bound of the 2-sided 95% CI) of (denosumab - zoledronic acid) was compared with the non-inferiority margin of -0.51% for assessing non-inferiority.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
1.0 to 1.7
Estimation Comments Treatment difference = denosumab - zoledronic acid
3.Secondary Outcome
Title Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis
Hide Description [Not Specified]
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
Arm/Group Title Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Hide Arm/Group Description:
Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.
Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Overall Number of Participants Analyzed 312 314
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
1.1
(0.7 to 1.5)
3.2
(2.8 to 3.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
Comments A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 2.1
Confidence Interval (2-Sided) 95%
1.6 to 2.6
Estimation Comments Treatment difference = denosumab - zoledronic acid
4.Secondary Outcome
Title Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis
Hide Description [Not Specified]
Time Frame Baseline and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
Arm/Group Title Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Hide Arm/Group Description:
Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6.
Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
Overall Number of Participants Analyzed 309 311
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
0.6
(0.3 to 0.8)
1.9
(1.7 to 2.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Zoledronic Acid 5 mg Q12M, Denosumab 60 mg Q6M
Comments A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments The model included treatment, screening sCTX, baseline BMD, DXA machine type (Hologic or Lunar), and baseline BMD-by-machine type interaction.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
1.0 to 1.7
Estimation Comments Treatment difference = denosumab - zoledronic acid
Time Frame 12 months
Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Hide Arm/Group Description Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6. Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1.
All-Cause Mortality
Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Affected / at Risk (%) Affected / at Risk (%)
Total   29/320 (9.06%)   25/320 (7.81%) 
Blood and lymphatic system disorders     
Febrile neutropenia  1  0/320 (0.00%)  1/320 (0.31%) 
Cardiac disorders     
Acute myocardial infarction  1  1/320 (0.31%)  0/320 (0.00%) 
Atrial fibrillation  1  0/320 (0.00%)  1/320 (0.31%) 
Atrial flutter  1  0/320 (0.00%)  1/320 (0.31%) 
Coronary artery disease  1  0/320 (0.00%)  1/320 (0.31%) 
Myocardial infarction  1  0/320 (0.00%)  1/320 (0.31%) 
Endocrine disorders     
Goitre  1  0/320 (0.00%)  1/320 (0.31%) 
Gastrointestinal disorders     
Diverticulum  1  0/320 (0.00%)  1/320 (0.31%) 
Dysphagia  1  0/320 (0.00%)  1/320 (0.31%) 
Gastrointestinal obstruction  1  1/320 (0.31%)  0/320 (0.00%) 
Inguinal hernia  1  1/320 (0.31%)  0/320 (0.00%) 
General disorders     
Drug interaction  1  1/320 (0.31%)  0/320 (0.00%) 
Hepatobiliary disorders     
Autoimmune hepatitis  1  1/320 (0.31%)  0/320 (0.00%) 
Hepatic failure  1  1/320 (0.31%)  0/320 (0.00%) 
Infections and infestations     
Bronchitis  1  0/320 (0.00%)  1/320 (0.31%) 
Cellulitis  1  0/320 (0.00%)  1/320 (0.31%) 
Clostridium difficile infection  1  1/320 (0.31%)  0/320 (0.00%) 
Diverticulitis  1  1/320 (0.31%)  0/320 (0.00%) 
Herpes zoster  1  0/320 (0.00%)  1/320 (0.31%) 
Laryngitis  1  1/320 (0.31%)  0/320 (0.00%) 
Pneumonia  1  0/320 (0.00%)  1/320 (0.31%) 
Sepsis  1  1/320 (0.31%)  0/320 (0.00%) 
Urinary tract infection  1  2/320 (0.63%)  1/320 (0.31%) 
Vulval abscess  1  0/320 (0.00%)  1/320 (0.31%) 
Injury, poisoning and procedural complications     
Concussion  1  1/320 (0.31%)  0/320 (0.00%) 
Femoral neck fracture  1  1/320 (0.31%)  0/320 (0.00%) 
Femur fracture  1  2/320 (0.63%)  2/320 (0.63%) 
Radius fracture  1  0/320 (0.00%)  1/320 (0.31%) 
Subdural haematoma  1  0/320 (0.00%)  1/320 (0.31%) 
Tendon rupture  1  1/320 (0.31%)  0/320 (0.00%) 
Metabolism and nutrition disorders     
Hyponatraemia  1  0/320 (0.00%)  1/320 (0.31%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/320 (0.00%)  1/320 (0.31%) 
Intervertebral disc disorder  1  1/320 (0.31%)  0/320 (0.00%) 
Osteoarthritis  1  1/320 (0.31%)  0/320 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer  1  1/320 (0.31%)  0/320 (0.00%) 
Breast cancer female  1  0/320 (0.00%)  1/320 (0.31%) 
Colon cancer  1  0/320 (0.00%)  1/320 (0.31%) 
Lung adenocarcinoma stage I  1  0/320 (0.00%)  1/320 (0.31%) 
Lung neoplasm malignant  1  1/320 (0.31%)  0/320 (0.00%) 
Malignant melanoma  1  1/320 (0.31%)  0/320 (0.00%) 
Non-small cell lung cancer  1  1/320 (0.31%)  0/320 (0.00%) 
Pituitary tumour benign  1  1/320 (0.31%)  0/320 (0.00%) 
Pleomorphic adenoma  1  0/320 (0.00%)  1/320 (0.31%) 
Uterine leiomyoma  1  1/320 (0.31%)  0/320 (0.00%) 
Nervous system disorders     
Cerebral thrombosis  1  1/320 (0.31%)  0/320 (0.00%) 
Cerebrovascular accident  1  1/320 (0.31%)  2/320 (0.63%) 
Ischaemic stroke  1  1/320 (0.31%)  0/320 (0.00%) 
Transient ischaemic attack  1  1/320 (0.31%)  0/320 (0.00%) 
Reproductive system and breast disorders     
Cystocele  1  1/320 (0.31%)  0/320 (0.00%) 
Rectocele  1  1/320 (0.31%)  0/320 (0.00%) 
Uterine prolapse  1  1/320 (0.31%)  0/320 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1/320 (0.31%)  0/320 (0.00%) 
Dyspnoea  1  1/320 (0.31%)  0/320 (0.00%) 
Skin and subcutaneous tissue disorders     
Skin ulcer  1  1/320 (0.31%)  0/320 (0.00%) 
Surgical and medical procedures     
Knee operation  1  1/320 (0.31%)  0/320 (0.00%) 
Tendon operation  1  0/320 (0.00%)  1/320 (0.31%) 
Varicose vein operation  1  0/320 (0.00%)  1/320 (0.31%) 
Vascular disorders     
Hypertension  1  1/320 (0.31%)  0/320 (0.00%) 
Peripheral artery thrombosis  1  1/320 (0.31%)  0/320 (0.00%) 
Varicose vein  1  0/320 (0.00%)  1/320 (0.31%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Zoledronic Acid 5 mg Q12M Denosumab 60 mg Q6M
Affected / at Risk (%) Affected / at Risk (%)
Total   22/320 (6.88%)   15/320 (4.69%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  22/320 (6.88%)  15/320 (4.69%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
Layout table for additonal information
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01732770    
Other Study ID Numbers: 20110153
2012-001821-28 ( EudraCT Number )
First Submitted: November 20, 2012
First Posted: November 26, 2012
Results First Submitted: December 9, 2015
Results First Posted: January 25, 2016
Last Update Posted: March 10, 2020