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

Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01345019
• Other study ID #: 20090482
• Secondary ID: 2010-020454-34
• Status: Completed
• Phase: Phase 3
• Start date: May 17, 2012
• Est. completion date: March 29, 2019

Study information

• Verified date: November 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1718
• Est. completion date: March 29, 2019
• Est. primary completion date: July 19, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bone Diseases
• Bone Metastases
• Cancer
• Hematologic Malignancies
• Hematologic Neoplasms
• Multiple Myeloma
• Multiple Myeloma Bone Lesions
• Neoplasm Metastasis
• Neoplasms
• Neoplasms, Plasma Cell
• Oncology

Intervention

Drug:
• Denosumab
Administered by subcutaneous injection once every 4 weeks.
• Zoledronic acid
Administered by intravenous infusion over 15 minutes once every 4 weeks
• Placebo to Denosumab
Administered by subcutaneous injection once every 4 weeks.
• Placebo to zoledronic acid
Administered by intravenous infusion over 15 minutes once every 4 weeks
• Denosumab (for the open-label treatment phase)
Administered by subcutaneous injection once every 4 weeks.

Locations

Country	Name	City	State
Australia	Research Site	Clayton	Victoria
Australia	Research Site	Douglas	Queensland
Australia	Research Site	Epping	Victoria
Australia	Research Site	Hobart	Tasmania
Australia	Research Site	Liverpool	New South Wales
Australia	Research Site	Malvern	Victoria
Australia	Research Site	Parkville	Victoria
Australia	Research Site	Prahran	Victoria
Australia	Research Site	South Brisbane	Queensland
Australia	Research Site	Tweed Heads	New South Wales
Austria	Research Site	Graz
Austria	Research Site	Innsbruck
Austria	Research Site	Krems an der Donau
Austria	Research Site	Salzburg
Austria	Research Site	Wels
Austria	Research Site	Wien
Austria	Research Site	Wien
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Canada	Research Site	Barrie	Ontario
Canada	Research Site	Burnaby	British Columbia
Canada	Research Site	Laval	Quebec
Canada	Research Site	Moncton	New Brunswick
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montréal	Quebec
Canada	Research Site	Newmarket	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Sault Ste. Marie	Ontario
Canada	Research Site	St. Johns	Newfoundland and Labrador
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Trois-Rivières	Quebec
Canada	Research Site	Windsor	Ontario
Canada	Research Site	Winnipeg	Manitoba
Czechia	Research Site	Brno
Czechia	Research Site	Ostrava-Poruba
Czechia	Research Site	Plzen
Czechia	Research Site	Praha 10
Czechia	Research Site	Praha 2
France	Research Site	Amiens Cedex 1
France	Research Site	Avignon Cedex 9
France	Research Site	Creteil
France	Research Site	Le Kremlin Bicetre
France	Research Site	Le Mans
France	Research Site	Le Mans Cedex 9
France	Research Site	Lille
France	Research Site	Lyon Cédex 3
France	Research Site	Marseille cedex 5
France	Research Site	Marseille Cedex 9
France	Research Site	Nantes Cedex 1
France	Research Site	Nice Cedex 3
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Paris Cedex 12
France	Research Site	Paris Cedex 14
France	Research Site	Pessac Cedex
France	Research Site	Pierre-Benite cedex
France	Research Site	Pontoise Cedex
France	Research Site	Reims Cedex
France	Research Site	Rouen cedex
France	Research Site	Saint Quentin
France	Research Site	Strasbourg
France	Research Site	Villefranche Sur Saone Cedex
Germany	Research Site	Bonn
Germany	Research Site	Chemnitz
Germany	Research Site	Essen
Germany	Research Site	Hamburg
Germany	Research Site	Kassel
Germany	Research Site	Köln
Germany	Research Site	Leipzig
Germany	Research Site	Münster
Germany	Research Site	Regensburg
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Heraklion
Greece	Research Site	Patra
Greece	Research Site	Piraeus
Greece	Research Site	Thessaloniki
Hong Kong	Research Site	Hong Kong
Hong Kong	Research Site	New Territories
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Gyor
Hungary	Research Site	Gyula
Hungary	Research Site	Kaposvar
Hungary	Research Site	Szeged
Ireland	Research Site	Dublin
Ireland	Research Site	Dublin
Ireland	Research Site	Dublin
Ireland	Research Site	Limerick
Ireland	Research Site	Tullamore
Italy	Research Site	Ancona
Italy	Research Site	Bari
Italy	Research Site	Brescia
Italy	Research Site	Busto Arsizio
Italy	Research Site	Catania
Italy	Research Site	Firenze
Italy	Research Site	Genova
Italy	Research Site	Messina
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Napoli
Italy	Research Site	Novara
Italy	Research Site	Palermo
Italy	Research Site	Pescara
Italy	Research Site	Pisa
Italy	Research Site	Roma
Italy	Research Site	Roma
Italy	Research Site	Rozzano MI
Italy	Research Site	Torino
Italy	Research Site	Udine
Italy	Research Site	Vimercate MB
Japan	Research Site	Akita-shi	Akita
Japan	Research Site	Fukuoka-shi	Fukuoka
Japan	Research Site	Fukuyama-shi	Hiroshima
Japan	Research Site	Gifu-shi	Gifu
Japan	Research Site	Kamogawa-shi	Chiba
Japan	Research Site	Kawagoe-shi	Saitama
Japan	Research Site	Kobe-shi	Hyogo
Japan	Research Site	Kumamoto-shi	Kumamoto
Japan	Research Site	Kyoto-shi	Kyoto
Japan	Research Site	Maebashi-shi	Gunma
Japan	Research Site	Nagoya-shi	Aichi
Japan	Research Site	Ogaki-shi	Gifu
Japan	Research Site	Okayama-shi	Okayama
Japan	Research Site	Shibukawa-shi	Gunma
Japan	Research Site	Shibuya-ku	Tokyo
Japan	Research Site	Shinjuku-ku	Tokyo
Japan	Research Site	Tokushima-shi	Tokushima
Japan	Research Site	Toyama-shi	Toyama
Korea, Republic of	Research Site	Anyang
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Daegu
Korea, Republic of	Research Site	Daejeon
Korea, Republic of	Research Site	Gwangju
Korea, Republic of	Research Site	Incheon
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Lithuania	Research Site	Kaunas
Lithuania	Research Site	Vilnius
Malaysia	Research Site	Ampang
Malaysia	Research Site	Georgetown	Pinang
Malaysia	Research Site	Ipoh	Perak
Malaysia	Research Site	Kuching	Sarawak
New Zealand	Research Site	Christchurch
New Zealand	Research Site	Grafton, Auckland
Poland	Research Site	Legnica
Poland	Research Site	Lublin
Poland	Research Site	Slupsk
Poland	Research Site	Torun
Poland	Research Site	Warszawa
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
Portugal	Research Site	Braga
Portugal	Research Site	Coimbra
Portugal	Research Site	Lisboa
Portugal	Research Site	Matosinhos
Portugal	Research Site	Porto
Russian Federation	Research Site	Dzerzhinsk
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhny Novgorod
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Penza
Russian Federation	Research Site	Petrozavodsk
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Samara
Russian Federation	Research Site	Saratov
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	Volgograd
Singapore	Research Site	Singapore
Singapore	Research Site	Singapore
Singapore	Research Site	Singapore
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Nitra
Slovakia	Research Site	Nove Zamky
Spain	Research Site	Badalona	Cataluña
Spain	Research Site	Barcelona	Cataluña
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Ourense	Galicia
Spain	Research Site	Palma de Mallorca	Baleares
Spain	Research Site	Salamanca	Castilla León
Spain	Research Site	San Sebastian	País Vasco
Spain	Research Site	Sevilla	Andalucía
Spain	Research Site	Valencia	Comunidad Valenciana
Spain	Research Site	Valencia	Comunidad Valenciana
Switzerland	Research Site	Chur
Switzerland	Research Site	Zurich
Switzerland	Research Site	Zurich
Taiwan	Research Site	Changhua
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taoyuan
Turkey	Research Site	Adana
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Ukraine	Research Site	Cherkasy
Ukraine	Research Site	Dnipropetrovsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Khmelnitskiy
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lviv
Ukraine	Research Site	Poltava
United Kingdom	Research Site	Harrow
United Kingdom	Research Site	Inverness
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Oxford
United States	Research Site	Aberdeen	South Dakota
United States	Research Site	Ames	Iowa
United States	Research Site	Anaheim	California
United States	Research Site	Anderson	Indiana
United States	Research Site	Baltimore	Maryland
United States	Research Site	Baltimore	Maryland
United States	Research Site	Baltimore	Maryland
United States	Research Site	Bethesda	Maryland
United States	Research Site	Billings	Montana
United States	Research Site	Bismarck	North Dakota
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boynton Beach	Florida
United States	Research Site	Boynton Beach	Florida
United States	Research Site	Campbell	California
United States	Research Site	Charleston	South Carolina
United States	Research Site	Charleston	South Carolina
United States	Research Site	Chicago	Illinois
United States	Research Site	Christiansburg	Virginia
United States	Research Site	Columbus	Georgia
United States	Research Site	Danvers	Massachusetts
United States	Research Site	Detroit	Michigan
United States	Research Site	Encinitas	California
United States	Research Site	Fairhaven	Massachusetts
United States	Research Site	Fayetteville	Arkansas
United States	Research Site	Fayetteville	North Carolina
United States	Research Site	Fort Wayne	Indiana
United States	Research Site	Fresno	California
United States	Research Site	Goldsboro	North Carolina
United States	Research Site	Greenville	South Carolina
United States	Research Site	Hackensack	New Jersey
United States	Research Site	Hershey	Pennsylvania
United States	Research Site	High Point	North Carolina
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Iowa City	Iowa
United States	Research Site	Jackson	Mississippi
United States	Research Site	Jacksonville	Florida
United States	Research Site	Joliet	Illinois
United States	Research Site	Lake Success	New York
United States	Research Site	Lansing	Michigan
United States	Research Site	Lincoln	Nebraska
United States	Research Site	Lubbock	Texas
United States	Research Site	Maywood	Illinois
United States	Research Site	Memphis	Tennessee
United States	Research Site	Minocqua	Wisconsin
United States	Research Site	Morgantown	West Virginia
United States	Research Site	New Orleans	Louisiana
United States	Research Site	New York	New York
United States	Research Site	Niles	Illinois
United States	Research Site	North Las Vegas	Nevada
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Omaha	Nebraska
United States	Research Site	Paducah	Kentucky
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Pleasant Hill	California
United States	Research Site	Rapid City	South Dakota
United States	Research Site	Rochester	New York
United States	Research Site	Salt Lake City	Utah
United States	Research Site	Santa Barbara	California
United States	Research Site	Santa Maria	California
United States	Research Site	Savannah	Georgia
United States	Research Site	Scarborough	Maine
United States	Research Site	Sioux Falls	South Dakota
United States	Research Site	Skokie	Illinois
United States	Research Site	Skokie	Illinois
United States	Research Site	Spokane	Washington
United States	Research Site	Springfield	Missouri
United States	Research Site	Stamford	Connecticut
United States	Research Site	Tacoma	Washington
United States	Research Site	Tucson	Arizona
United States	Research Site	Washington	District of Columbia
United States	Research Site	Washington	District of Columbia
United States	Research Site	Watertown	South Dakota
United States	Research Site	Wauwatosa	Wisconsin
United States	Research Site	West Reading	Pennsylvania
United States	Research Site	Westminster	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Amgen	Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  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, 

References & Publications (4)

Huang SY, Yoon SS, Shimizu K, Chng WJ, Chang CS, Wong RS, Gao S, Wang Y, Gordon SW, Glennane A, Min CK. Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Randomized Controlled Phase 3 Study-Asian Subgroup Analysis. Adv Ther. 2020 Jul;37(7):3404-3416. doi: 10.1007/s12325-020-01395-x. Epub 2020 Jun 10. — View Citation

Raje N, Roodman GD, Willenbacher W, Shimizu K, García-Sanz R, Terpos E, Kennedy L, Sabatelli L, Intorcia M, Hechmati G. A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America. J Med Econ. 2018 May;21(5):525-536. doi: 10.1080/13696998.2018.1445634. Epub 2018 Mar 5. — View Citation

Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, Legiec W, Krejcí 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. — View Citation

Terpos E, Raje N, Croucher P, Garcia-Sanz R, Leleu X, Pasteiner W, Wang Y, Glennane A, Canon J, Pawlyn C. Denosumab compared with zoledronic acid on PFS in multiple myeloma: exploratory results of an international phase 3 study. Blood Adv. 2021 Feb 9;5(3):725-736. doi: 10.1182/bloodadvances.2020002378. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to First On-study Skeletal Related Event	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.	From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Primary	Percentage of Participants With an On-study Skeletal Related Event	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.	From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Primary	Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event	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.	From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); 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.
Secondary	Time to First On-study Skeletal Related Event - Superiority Analysis	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.	From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Secondary	Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient	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.	From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Secondary	Time to First and Subsequent On-Study Skeletal Related Event - Number of Events	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.	From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Secondary	Overall Survival	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.	From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Secondary	Percentage of Participants Who Died		From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.

External Links

•   AmgenTrials clinical trials website