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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

April 28, 2011
April 29, 2011
January 17, 2018
March 7, 2018
March 7, 2018
May 17, 2012
July 19, 2016   (Final data collection date for primary outcome measure)
  • 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. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
  • 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. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
  • 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. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
Time to the first on-study skeletal related event (SRE) (non-inferiority test) [ Time Frame: until approximately 800 subjects have experienced at least one on-study SRE (anticipated to be approximately 48 months) ]
Complete list of historical versions of study NCT01345019 on ClinicalTrials.gov Archive Site
  • 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. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
  • 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. ]

    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE.

    A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The average number of events per patient is reported.

  • 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. ]

    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE.

    A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The total number of events is reported.

  • 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. ]
    Overall survival was defined as the time interval (in days) from the randomization date to the date of death. If a participant was still alive at the primary analysis data cut-off date or was lost to follow-up by the primary analysis data cut-off date, survival time was censored at their last contact date or the primary analysis data cut-off date, whichever was first.
  • 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. ]
  • Time to the first on-study SRE (superiority test) [ Time Frame: until approximately 800 subjects have experienced at least one on-study SRE (anticipated to be approximately 48 months) ]
  • Time to the first-and-subsequent SRE (superiority test, using multiple event analysis) [ Time Frame: until approximately 800 subjects have experienced at least one on-study SRE (anticipated to be approximately 48 months) ]
Not Provided
Not Provided
 
Denosumab Compared to Zoledronic Acid in the Treatment of Bone Disease in Patients With Multiple Myeloma
A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Disease in Subjects With Newly Diagnosed Multiple Myeloma
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone disease from multiple myeloma.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
  • Cancer
  • Hematologic Malignancies
  • Multiple Myeloma
  • Oncology
  • Bone Metastases
  • Multiple Myeloma Bone Lesions
  • Drug: Denosumab
    Administered by subcutaneous injection once every 4 weeks.
    Other Names:
    • XGEVA®
    • AMG 162
  • Drug: Zoledronic acid
    Administered by intravenous infusion over 15 minutes once every 4 weeks
    Other Name: Zometa®
  • Drug: Placebo to Denosumab
    Administered by subcutaneous injection once every 4 weeks.
  • Drug: Placebo to zoledronic acid
    Administered by intravenous infusion over 15 minutes once every 4 weeks
  • Active Comparator: Zoledronic acid
    Participants received zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneous injection once every 4 weeks until the required number of events was reached.
    Interventions:
    • Drug: Zoledronic acid
    • Drug: Placebo to Denosumab
  • Experimental: Denosumab
    Participants received denosumab 120 mg subcutaneous injection and placebo to zoledronic acid intravenously once every 4 weeks until the required number of events was reached.
    Interventions:
    • Drug: Denosumab
    • Drug: Placebo to zoledronic acid
Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, Legieć W, Krejčí M, Laribi K, Zhu L, Cheng P, Warner D, Roodman GD. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018 Mar;19(3):370-381. doi: 10.1016/S1470-2045(18)30072-X. Epub 2018 Feb 9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
1718
1520
February 1, 2019
July 19, 2016   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Documented evidence of multiple myeloma (per local assessment):
  • Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma, and
  • Monoclonal protein present in the serum and/or urine
  • Radiographic (X-ray, or computer tomography [CT]) evidence of at least 1 lytic bone lesion (or at least 1 focal lesion per magnetic resonance imaging [MRI])
  • Plan to receive or is receiving primary frontline anti-myeloma therapies
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Age ≥ 18 years
  • Adequate organ function, as defined by the following criteria (per central or local laboratory values):

    • Serum aspartate aminotransferase (AST) ≤ 2.0 x upper limit of normal (ULN)
    • Serum alanine aminotransferase ≤ (ALT) 2.0 x ULN
    • Serum total bilirubin ≤ 2.0 x ULN
    • Creatinine clearance ≥ 30 mL/min
    • Serum calcium or albumin-adjusted serum calcium 2.0 mmol/L (8.0 mg/dL) and 2.9 mmol/L (11.5 mg/dL)
  • Written informed consent before any study-specific procedure is performed

Exclusion Criteria:

  • Nonsecretory multiple myeloma based upon standard M-component criteria (ie, measurable serum/urine M-component) unless the baseline serum free light chain level is elevated
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Plasma cell leukemia
  • More than 30 days of previous treatment (before screening) with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 60 mg/day for 4 days]).
  • Planned radiation therapy or surgery to the bone (does not include procedures performed before randomization)
  • Prior administration of denosumab
  • Use of oral bisphosphonates with a cumulative exposure of more than 1 year
  • More than 1 previous dose of IV bisphosphonate administration
  • Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
  • Active dental or jaw condition which requires oral surgery, including tooth extraction
  • Non-healed dental/oral surgery, including tooth extraction
  • Planned invasive dental procedures
  • Evidence of any of the following conditions per subject self-report or medical chart review:

    • Any prior invasive malignancy within 5 years before randomization
    • Any non-invasive malignancy not treated with curative intent or with knownactive disease within 5 years before randomization
    • Major surgery or significant traumatic injury occurring within 4 weeks before randomization
    • Active infection with Hepatitis B virus or Hepatitis C virus
    • Known infection with human immunodeficiency virus (HIV)
    • Active infection requiring IV anti-infective therapy
  • Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after end of treatment
  • Female subject of child bearing potential is not willing to use highly effective contraception during treatment and for 5 months after the end of treatment (see section 6.3)
  • Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium or vitamin D)
  • Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication)
  • Subject will not be available for follow-up assessment
  • Any major medical or psychiatric disorder that in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Austria,   Bulgaria,   Canada,   Czechia,   France,   Germany,   Greece,   Hong Kong,   Hungary,   Ireland,   Italy,   Japan,   Korea, Republic of,   Lithuania,   Malaysia,   New Zealand,   Poland,   Portugal,   Russian Federation,   Singapore,   Slovakia,   Spain,   Switzerland,   Taiwan,   Turkey,   Ukraine,   United Kingdom,   United States
Czech Republic
 
NCT01345019
20090482
2010-020454-34 ( EudraCT Number )
Yes
Not Provided
Not Provided
Amgen
Amgen
Daiichi Sankyo, Inc.
Study Director: MD Amgen
Amgen
March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP