Trial Outcomes & Findings for A Study to Compare Denosumab With Zoledronic Acid in Subjects With Bone Metastases From Solid Tumors (NCT NCT01920568)

NCT ID: NCT01920568

Last Updated: 2017-01-16

Results Overview

uNTx/uCr is the bone turnover marker correlated with the presence and extent of metastases, and the prognosis and response to bone targeted treatment (trt). uNTx/uCr was expressed in nanomoles bone collagen equivalent per millimole (nM BCE/mM). Primary objective: to compare the effect of denosumab with that of zoledronic acid on % chg from BL in uNTx/uCr at Wk 13 in par. of Asian ancestry with bone metastases from solid tumors. BL value is the most recent, non-missing value prior to or on the 1st study trt dose date. Chg from BL is the value at Wk13 minus BL value. Percent chg from BL is the chg from BL / BL value \* 100. For missing Wk 13 observations, the last post-BL value was carried forward to obtain the Wk 13 value.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

487 participants

Primary outcome timeframe

Baseline (BL) and Week (Wk) 13

Results posted on

2017-01-16

Participant Flow

The study consisted of three phases: Screening period , 49-week Double-blind treatment period and Follow-up period. The total participation time in the study was approximately 77 weeks.

A total of 487 participants (par.) were randomized in a 2:1 ratio to receive one of the two study treatments. A total of 485 participants received at least single dose of investigational products (IP).

Participant milestones

Participant milestones
Measure	Denosumab 120 mg Participants received denosumab 120 milligrams (mg) as subcutaneous (SC) injection for a maximum of 13 doses and placebo as intravenous (IV) infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 international unit (IU) of vitamin D.	Zoledronic Acid 4 mg Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Overall Study STARTED	326	159
Overall Study COMPLETED	175	75
Overall Study NOT COMPLETED	151	84

Reasons for withdrawal

Reasons for withdrawal
Measure	Denosumab 120 mg Participants received denosumab 120 milligrams (mg) as subcutaneous (SC) injection for a maximum of 13 doses and placebo as intravenous (IV) infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 international unit (IU) of vitamin D.	Zoledronic Acid 4 mg Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Overall Study Adverse Event	27	8
Overall Study Protocol Violation	5	3
Overall Study Lost to Follow-up	2	2
Overall Study Physician Decision	13	4
Overall Study Withdrawal by Subject	79	55
Overall Study Death due to disease progression	25	12

Baseline Characteristics

A Study to Compare Denosumab With Zoledronic Acid in Subjects With Bone Metastases From Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Denosumab 120 mg n=326 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=159 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Total n=485 Participants Total of all reporting groups
Age, Continuous	54.0 Years STANDARD_DEVIATION 11.36 • n=5 Participants	53.6 Years STANDARD_DEVIATION 11.45 • n=7 Participants	53.9 Years STANDARD_DEVIATION 11.38 • n=5 Participants
Gender Female	222 Participants n=5 Participants	105 Participants n=7 Participants	327 Participants n=5 Participants
Gender Male	104 Participants n=5 Participants	54 Participants n=7 Participants	158 Participants n=5 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	312 Participants n=5 Participants	158 Participants n=7 Participants	470 Participants n=5 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	14 Participants n=5 Participants	1 Participants n=7 Participants	15 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (BL) and Week (Wk) 13

Population: Full-Analysis-Set Intent-to-Treat (FAS-ITT) Population: comprised of all randomized participants regardless of whether or not study treatment was administered. Only those participants with values at Baseline and Week 13 were included in the analysis.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=322 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=154 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Percent Change (Chg) From Baseline (BL) to Week (Wk)13 in Urinary Amino-terminal Cross-linking Telopeptide of Type I Collagen Corrected for Urine Creatinine (uNTx/uCr)	-81.9 Percent change Interval -83.1 to -80.6	-75.2 Percent change Interval -77.6 to -72.5

SECONDARY outcome

Timeframe: Baseline and Week 13

Population: FAS-ITT Population. Chinese participants.

uNTx/uCr is the bone turnover marker correlated with the presence and extent of metastases, and the prognosis and response to bone targeted treatment. uNTx/uCr was expressed in nanomoles bone collagen equivalent per millimole (nM BCE/mM). Secondary objective: to compare the effect of denosumab with that of zoledronic acid on % chg from BL in uNTx/uCr at Wk 13 in par. of Chinese ancestry with bone metastases from solid tumors. Baseline value is the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline is the value at Week 13 minus Baseline value. Percent chg from BL is the chg from BL / BL value \* 100. For missing Wk 13 observations, the last post-BL value was carried forward to obtain the Wk 13 value.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=296 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=147 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Percentage Change From Baseline to Week 13 in Urinary Amino-terminal Cross-linking Telopeptide of Type I Collagen of Type I Collagen Corrected for Urine Creatinine (uNTx/uCr) in Chinese Participants.	-82.2 Percent change Interval -83.4 to -80.8	-75.6 Percent change Interval -78.0 to -72.9

SECONDARY outcome

Timeframe: Baseline and Week 13

Population: FAS-ITT Population. Participants with advanced breast cancer.

uNTx/uCr is the bone turnover marker correlated with the presence and extent of metastases, and the prognosis and response to bone targeted treatment. uNTx/uCr was expressed in nanomoles bone collagen equivalent per millimole (nM BCE/mM). Secondary objective: to compare the effect of denosumab with that of zoledronic acid on % chg from BL in uNTx/uCr at Wk 13 in breast cancer par. with bone metastases from solid tumors. Baseline value is the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline is the value at Week 13 minus Baseline value. Percent chg from BL is the chg from BL / BL value \* 100. For missing Wk 13 observations, the last post-BL value was carried forward to obtain the Wk 13 value.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=160 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=77 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Percentage Change From Baseline to Week 13 in Urinary Amino-terminal Cross-linking Telopeptide of Type I Collagen of Type I Collagen Corrected for Urine Creatinine (uNTx/uCr) in Participants With Advanced Breast Cancer.	-80.9 Percent change Interval -82.7 to -78.9	-72.4 Percent change Interval -76.1 to -68.2

SECONDARY outcome

Timeframe: Baseline and Week 13

Population: FAS-ITT Population. All participants who were randomized and had a observed values at Baseline and Week 13 were used in the analysis.

Baseline value is the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline is the value at Indicated visit minus Baseline value. Percent change from Baseline is the change from Baseline divided by Baseline value multiplied by 100.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=294 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=134 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Percent Change From Baseline in the Serum Bone-specific Alkaline Phosphatase (s-BALP) at Week 13.	-36.8 Percent change Interval -96.2 to 93.8	-30.3 Percent change Interval -91.7 to 345.9

SECONDARY outcome

Timeframe: From start of IP through the Study Phase (49 weeks post-dose) (assessed up to 73 weeks)

Population: Full-Analysis-Set Safety (FAS-Safety) Population: comprised of all randomized participants who received at least one dose of study treatment and was based on the actual study treatment received (if this differed from that to which the participant was randomized).

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or other events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the outcome listed above, liver injury and impaired liver function and grade 4 laboratory abnormalities. Number of participants with any AEs, non-fatal SAEs, fatal SAEs have been presented.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=326 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=159 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (Non-fatal Serious Adverse Events and Fatal Serious Adverse Events) Any AEs	291 Participants	145 Participants
Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (Non-fatal Serious Adverse Events and Fatal Serious Adverse Events) Any SAEs	46 Participants	14 Participants
Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (Non-fatal Serious Adverse Events and Fatal Serious Adverse Events) Any Fatal SAEs	25 Participants	7 Participants
Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (Non-fatal Serious Adverse Events and Fatal Serious Adverse Events) Any Non-Fatal SAEs	25 Participants	7 Participants

SECONDARY outcome

Timeframe: Baseline and up to last study-related visit (up to 53 weeks)

Population: FAS-Safety Population. Only participants whose indicated on-therapy laboratory values were available (represented by n=X, X in the category title) were analyzed.

Clinical chemistry parameters were measured at the Screening and Weeks 2, 5, 9, 13, 25, 37, and 53 visits. Clinical chemistry parameters measured on-study included albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, calcium (Ca), creatinine, magnesium, and phosphorous (P) inorganic. All reported values are of participants with worst-case on-therapy increase to the specified grade: Any increase, that is, worst-case increase to grade 1, 2, 3, or 4 (any grade); worst-case increase to grade 3 (WC G3); and worst-case increase to grade 4 (WC G4). The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) was used for grading. Participants with missing Baseline grade were assumed to have a Baseline grade of 0. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=326 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=159 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Albumin (hyperalbuminemia), any grade, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Albumin (hyperalbuminemia), WC G3, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Albumin (hyperalbuminemia), WC G4, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Albumin (hypoalbuminemia), any grade, n=324, 156	45 Participants	26 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Albumin (hypoalbuminemia), WC G3, n=324, 156	1 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Albumin (hypoalbuminemia), WC G4, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. ALP, any grade, n=324, 156	67 Participants	31 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. ALP, WC G3, n=324, 156	7 Participants	2 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. ALP, WC G4, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. ALT, any grade, n=324, 156	137 Participants	59 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. ALT, WC G3, n=324, 156	7 Participants	4 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. ALT, WC G4, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. AST, any grade, n=323, 155	117 Participants	61 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. AST, WC G3, n=323, 155	7 Participants	4 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. AST, WC G4, n=323, 155	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Total Bilirubin, any grade, n=324, 155	34 Participants	16 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Total Bilirubin, WC G3, n=324, 155	2 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Total Bilirubin, WC G4, n=324, 155	2 Participants	1 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Calcium (hypercalcemia), any grade, n=324, 156	4 Participants	3 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Calcium (hypercalcemia), WC G3, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Calcium (hypercalcemia), WC G4, n=324, 156	0 Participants	1 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Calcium (hypocalcemia), any grade, n=324,156	78 Participants	28 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Calcium (hypocalcemia), WC G3, n=324, 156	5 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Calcium (hypocalcemia), WC G4, n=324, 156	1 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Creatinine, any grade, n=324, 156	16 Participants	13 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Creatinine, WC G3, n=324, 156	1 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Creatinine, WC G4, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Magnesium (hypermagnesemia), any grade, n=324, 156	4 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Magnesium (hypermagnesemia), WC G3, n=324, 156	2 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Magnesium (hypermagnesemia), WC G4, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Magnesium (hypomagnesemia), any grade, n=324, 156	8 Participants	2 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Magnesium (hypomagnesemia), WC G3, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. Magnesium (hypomagnesemia), WC G4, n=324, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. P,inorganic(hyperphosphatemia),any grade,n=323,156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. P, inorganic (hyperphosphatemia),WC G3, n=323, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. P, inorganic (hyperphosphatemia),WC G4, n=323, 156	0 Participants	0 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. P,inorganic(hypophosphatemia),any grade,n=323, 156	124 Participants	35 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. P, inorganic (hypophosphatemia),WC G3, n=323, 156	35 Participants	9 Participants
Number of Participants With Worst-case (WC) On-therapy Increase in the Indicated Clinical Chemistry Parameters From Baseline Grade to the Indicated Grade. P, inorganic (hypophosphatemia), WC G4, n=323, 156	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline and up to last study-related visit (up to 53 weeks)

Population: FAS-Safety Population. Only participants whose indicated on-therapy lab values were available (represented by n=X, X in the category titles) were analyzed.

Hematology parameters included hemoglobin, lymphocytes, platelet count, total neutrophils, white blood cell (WBC) count. All reported values are of participants with worst-case on-therapy increase to the specified grade: Any increase, that is, worst-case increase to grade 1, 2, 3, or 4 (any grade); worst-case increase to grade 3 (WC G3); and worst-case increase to grade 4 (WC G4). Participants with missing Baseline grade were assumed to have a Baseline grade of 0. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=326 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=159 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Hemoglobin, any grade, n=316, 147	139 Participants	69 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Hemoglobin, WC G3, n=316, 147	24 Participants	11 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Hemoglobin, WC G4, n=316, 147	0 Participants	0 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Lymphocyte count decreased, any grade, n=315, 147	77 Participants	47 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Lymphocyte count decreased, WC G3, n=315, 147	21 Participants	14 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Lymphocyte count decreased, WC G4, n=315, 147	1 Participants	1 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Lymphocyte count increased, any grade, n=315, 147	2 Participants	2 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Lymphocyte count increased, WC G3, n=315, 147	0 Participants	0 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Lymphocyte count increased, WC G4, n=315, 147	0 Participants	0 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Platelet count, any grade, n=314, 144	77 Participants	48 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Platelet count, WC G3, n=314, 144	2 Participants	5 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Platelet count, WC G4, n=314, 144	2 Participants	1 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Total neutrophils, any grade, n=315, 147	124 Participants	58 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Total neutrophils, WC G3, n=315, 147	40 Participants	19 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. Total neutrophils, WC G4, n=315, 147	12 Participants	8 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. WBC count, any grade, n=315, 147	138 Participants	78 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. WBC count, WC G3, n=315, 147	25 Participants	19 Participants
Number of Participants With Worst-case On-therapy Increase in the Indicated Hematology Parameters From Baseline Grade to the Indicated Grade. WBC count, WC G4, n=315, 147	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Day 1, Week 25 and Week 53

Population: FAS-Safety Population. Only those participants on whom anti-denosumab antibody formation was analyzed at specified time point is presented (represented by n=X, X in the category titles).

Anti-denosumab antibody formation was assessed at Day 1, Week 25 and Week 53. Binding antibody assay was used to assess number of participants with anti-denosumab antibody.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=326 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg n=159 Participants Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Number of Participants With Confirmed Anti-denosumab Antibody Formation at Day 1, Week 25 and Week 53. Day 1, n = 326, 158	0 Participants	0 Participants
Number of Participants With Confirmed Anti-denosumab Antibody Formation at Day 1, Week 25 and Week 53. Week 25, n = 256, 115	0 Participants	0 Participants
Number of Participants With Confirmed Anti-denosumab Antibody Formation at Day 1, Week 25 and Week 53. Week 53, n = 180, 76	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Samples were collected at pre-dose (Day 1); 4 hours, 24 hours, 168 hours post-dose; pre-dose at Week 5, Week 9, Week 13, Week 17; Week 19 (at 336 hours); pre-dose at Week 21, Week 25, Week 49

Population: Pharmacokinetic (PK) Population: comprised of participants who signed informed consent to participate in the PK sub-study and who had their PK parameters evaluable according to GSK standards. Only those participants with evaluable parameters are included (represented by n=X in the category titles).

Blood samples were drawn on study Day 1, pre-dose; 4 hours, 24 hours, and at Week 2 (168 hours); then pre-dose at Week 5, Week 9, Week 13, Week 17, Week 19 (no dose), Week 21, Week 25, and Week 49.

Outcome measures

Outcome measures
Measure	Denosumab 120 mg n=26 Participants Participants received denosumab 120 mg as SC injection for a maximum of 13 doses and placebo as IV infusion over a minimum of 15 minutes once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.	Zoledronic Acid 4 mg Participants received zoledronic acid 4 mg as IV infusion over a minimum of 15 minutes for a maximum of 13 doses and placebo as SC once every 4 weeks up to 49 weeks. Participants also received daily oral supplementation of \>= 500 mg elemental calcium and \>=400 IU of vitamin D.
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 25, Predose, n=22	16619.0 micrograms per milliliter (µg/mL) Interval 13354.9 to 20681.0	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Day 1, Pre-dose, n=26	0 micrograms per milliliter (µg/mL) Interval 0.0 to 0.0	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Day 1, 4 hours post-dose, n=26	777.1 micrograms per milliliter (µg/mL) Interval 574.2 to 1051.6	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Day 1, 24 hours post-dose, n=26	5521.6 micrograms per milliliter (µg/mL) Interval 4744.2 to 6426.3	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 2, 168 hours post-dose, n=26	11701.1 micrograms per milliliter (µg/mL) Interval 10554.0 to 12973.0	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 5, Pre-dose, n=25	8658.1 micrograms per milliliter (µg/mL) Interval 7631.1 to 9823.3	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 9, Pre-dose, n=25	12086.4 micrograms per milliliter (µg/mL) Interval 10284.9 to 14203.4	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 13, Pre-dose, n=25	14867.5 micrograms per milliliter (µg/mL) Interval 12515.5 to 17661.6	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 17, Pre-dose, n=24	16543.3 micrograms per milliliter (µg/mL) Interval 13871.8 to 19729.2	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 19, 336 hours, n=22	20802.4 micrograms per milliliter (µg/mL) Interval 16280.7 to 26579.9	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 21, Predose, n=21	14508.0 micrograms per milliliter (µg/mL) Interval 10907.0 to 19297.9	—
Serum Concentration of Denosumab on Day 1, at Week 2, Week 5, Week 9, Week 13, Week 17, Week 19, Week 21, Week 25 and Week 49 Week 49, Predose, n=19	20029.2 micrograms per milliliter (µg/mL) Interval 16282.7 to 24637.9	—

Adverse Events

Denosumab 120 mg

Serious events: 46 serious events

Other events: 268 other events

Deaths: 0 deaths

Zoledronic Acid 4 mg

Serious events: 14 serious events

Other events: 136 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER