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Denosumab Compared to Zoledronic Acid in the Treatment of Bone Disease in Patients With Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT01345019
Recruitment Status : Active, not recruiting
First Posted : April 29, 2011
Results First Posted : March 7, 2018
Last Update Posted : March 7, 2018
Sponsor:
Collaborator:
Daiichi Sankyo, Inc.
Information provided by (Responsible Party):
Amgen

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Supportive Care
Conditions: Cancer
Hematologic Malignancies
Multiple Myeloma
Oncology
Bone Metastases
Multiple Myeloma Bone Lesions
Interventions: Drug: Denosumab
Drug: Zoledronic acid
Drug: Placebo to Denosumab
Drug: Placebo to zoledronic acid

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

This study was an international study conducted at 259 centers across 29 countries in Europe, North America, Asia, Australia/New Zealand, and Japan. Participants were enrolled from 17 May 2012 to 29 March 2016.

The data cutoff date for the primary analysis results reported here was 19 July 2016.


Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Randomization was stratified according to:

  • intent to undergo autologous peripheral blood stem cell (PBSC) transplantation
  • the antimyeloma agent being utilized/planned to be utilized in first-line therapy
  • stage (International Staging System [ISS]) at diagnosis
  • previous SRE (yes or no)
  • region (Japan yes or no)

Reporting Groups
  Description
Zoledronic Acid Participants randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneous injection once every 4 weeks until the required number of events was reached.
Denosumab Participants randomized to receive denosumab 120 mg subcutaneous injection and placebo to zoledronic acid intravenously once every 4 weeks until the required number of events was reached.

Participant Flow:   Overall Study
    Zoledronic Acid   Denosumab
STARTED   859   859 
Received Treatment   852   850 
COMPLETED   596 [1]   587 [1] 
NOT COMPLETED   263   272 
Death                127                120 
Withdrawal by Subject                82                107 
Completed Survival Follow-up                16                4 
Disease Progression                11                8 
Adverse Event                4                13 
Administrative Decision                8                5 
Noncompliance                4                4 
Ineligibility Determined                1                6 
Lost to Follow-up                4                2 
Protocol Deviation                5                0 
Other                1                3 
[1] Still on study as of the data cut-off date



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Zoledronic Acid Participants randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneous injection once every 4 weeks until the required number of events was reached.
Denosumab Participants randomized to receive denosumab 120 mg subcutaneous injection and placebo to zoledronic acid intravenously once every 4 weeks until the required number of events was reached.
Total Total of all reporting groups

Baseline Measures
   Zoledronic Acid   Denosumab   Total 
Overall Participants Analyzed 
[Units: Participants]
 859   859   1718 
Age 
[Units: Years]
Mean (Standard Deviation)
 63.3  (10.5)   63.5  (10.6)   63.4  (10.6) 
Age, Customized 
[Units: Participants]
Count of Participants
     
< 65 years      464  54.0%      472  54.9%      936  54.5% 
≥ 65 years      395  46.0%      387  45.1%      782  45.5% 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      386  44.9%      397  46.2%      783  45.6% 
Male      473  55.1%      462  53.8%      935  54.4% 
Ethnicity (NIH/OMB) 
[Units: Participants]
Count of Participants
     
Hispanic or Latino      35   4.1%      35   4.1%      70   4.1% 
Not Hispanic or Latino      819  95.3%      823  95.8%      1642  95.6% 
Unknown or Not Reported      5   0.6%      1   0.1%      6   0.3% 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
     
White      699  81.4%      711  82.8%      1410  82.1% 
Asian      101  11.8%      107  12.5%      208  12.1% 
Black or African American      36   4.2%      29   3.4%      65   3.8% 
Other      19   2.2%      10   1.2%      29   1.7% 
American Indian or Alaska Native      3   0.3%      0   0.0%      3   0.2% 
Native Hawaiian or Other Pacific Islander      0   0.0%      1   0.1%      1   0.1% 
Multiracial      0   0.0%      1   0.1%      1   0.1% 
Missing      1   0.1%      0   0.0%      1   0.1% 
Eastern Cooperative Oncology Group (ECOG) Performance Status [1] 
[Units: Participants]
Count of Participants
     
0 (Fully active)      259  30.2%      263  30.6%      522  30.4% 
1 (Restricted but ambulatory)      413  48.1%      400  46.6%      813  47.3% 
2 (Ambulatory but unable to work)      187  21.8%      196  22.8%      383  22.3% 
[1] A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
Skeletal Related Event History 
[Units: Participants]
     
Any Skeletal Related Event   577   567   1144 
Pathological fracture   463   479   942 
Spinal cord compression   115   92   207 
Radiation therapy to bone   139   118   257 
Surgery to bone   144   142   286 
Summary of Randomization Stratifications [1] 
[Units: Participants]
     
Intent to undergo PBSC transplantation: Yes   465   465   930 
Intent to undergo PBSC transplantation: No   394   394   788 
Anti-myeloma agent utilized/planned: Novel   821   819   1640 
Anti-myeloma agent utilized/planned: Non-novel   38   40   78 
ISS stage at diagnosis: I   268   263   531 
ISS stage at diagnosis: II   313   319   632 
ISS stage at diagnosis: III   278   277   555 
Previous SRE : Yes   484   481   965 
Previous SRE : No   375   378   753 
Region: Japan   18   24   42 
Region: Non-Japan   841   835   1676 
[1]

Randomization was stratified by

  • Intent to undergo autologous peripheral blood stem cell (PBSC) transplantation: yes or no
  • The anti-myeloma agent being utilized/planned to be utilized in first-line therapy: novel therapy (included bortezomib, lenalidomide, or thalidomide) based or non-novel therapy-based,
  • International Staging System (ISS) stage at diagnosis: I (serum β2 microglobulin < 3.5 mg/L; serum albumin ≥ 3.5 g/dL) or II (neither stage I or III) or III (serum β2 microglobulin ≥ 5.5 mg/L),
  • Previous skeletal-related event (SRE): yes or no,
  • Region (Japan, non-Japan).


  Outcome Measures

1.  Primary:   Time to First On-study Skeletal Related Event   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

2.  Primary:   Percentage of Participants With an On-study Skeletal Related Event   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

3.  Primary:   Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported. ]

4.  Secondary:   Time to First On-study Skeletal Related Event - Superiority Analysis   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

5.  Secondary:   Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

6.  Secondary:   Time to First and Subsequent On-Study Skeletal Related Event - Number of Events   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

7.  Secondary:   Overall Survival   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

8.  Secondary:   Percentage of Participants Who Died   [ Time Frame: From randomization until the data cut-off date of 19 July 2016; median time on study was 17.6 and 17.3 months in each treatment group respectively. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

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 agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Amgen Inc.
phone: 866-572-6436


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01345019     History of Changes
Other Study ID Numbers: 20090482
2010-020454-34 ( EudraCT Number )
First Submitted: April 28, 2011
First Posted: April 29, 2011
Results First Submitted: January 17, 2018
Results First Posted: March 7, 2018
Last Update Posted: March 7, 2018