Trial Outcomes & Findings for Study of Denosumab in Subjects With Giant Cell Tumor of Bone (NCT NCT00680992)

Last Updated: 2022-09-22

Results Overview

AE defined as any untoward medical occurrence in a clinical trial participant. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v3.0) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. Investigator assessed AEs for relatedness to study drug. Results are presented for treatment-emergent events (TEAEs) and included all AEs occurring from first dose in initial treatment phase to end of initial treatment phase (or for participants entering retreatment, from first dose in initial treatment phase until end of retreatment phase).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

535 participants

Primary outcome timeframe

From first dose of study drug up to last study visit for treatment-emergent period (a maximum of approximately 111 months).

Results posted on

2022-09-22

Participant Flow

Adults and skeletally mature adolescents (≥12 years of age) were enrolled in this open-label single-arm study. The study was conducted at 30 centers in North America, Europe, and Australia from 09 Sep 2008 to study completion on 17 May 2018. The planned study duration for each participant was at least 60 months (following protocol amendment 7).

3 participants from study 20040215 (NCT00396279) were enrolled directly into safety follow-up phase without retreatment. They were excluded from all defined analysis sets and results are reported for the 532 participants enrolled into the treatment phase. Non-completion reasons are summarized for the on-study period (ie, initial treatment phase).

Participant milestones

Participant milestones
Measure	Cohort 1 (Denosumab 120 mg Q4W) Participants with surgically unsalvageable disease (eg, sacral, spinal giant cell tumor of bone (GCTB), or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 milligrams (mg) subcutaneously (SC) once every 4 weeks (Q4W), starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Overall Study STARTED	268	252	12
Overall Study Safety Analysis Set	265	249	12
Overall Study Efficacy Analysis Set	260	242	11
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	268	252	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 (Denosumab 120 mg Q4W) Participants with surgically unsalvageable disease (eg, sacral, spinal giant cell tumor of bone (GCTB), or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 milligrams (mg) subcutaneously (SC) once every 4 weeks (Q4W), starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Overall Study Complete Resection (as per protocol)	25	121	0
Overall Study Administrative Decision	83	42	5
Overall Study End of Trial	32	12	3
Overall Study Withdrawal by Subject	33	11	1
Overall Study Adverse Event	21	19	1
Overall Study Other	19	14	1
Overall Study Disease Progression	21	9	0
Overall Study Lost to Follow-up	12	14	0
Overall Study Noncompliance	4	6	0
Overall Study Requirement for Alternative Therapy	8	2	0
Overall Study Pregnancy	5	0	1
Overall Study Death	5	1	0
Overall Study Ineligibility Determined	0	1	0

Baseline Characteristics

Study of Denosumab in Subjects With Giant Cell Tumor of Bone

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 (Denosumab 120 mg Q4W) n=268 Participants Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) n=252 Participants Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) n=12 Participants Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.	Total n=532 Participants Total of all reporting groups
Age, Categorical <=18 years	14 Participants n=5 Participants	14 Participants n=7 Participants	0 Participants n=5 Participants	28 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	238 Participants n=5 Participants	231 Participants n=7 Participants	12 Participants n=5 Participants	481 Participants n=4 Participants
Age, Categorical >=65 years	16 Participants n=5 Participants	7 Participants n=7 Participants	0 Participants n=5 Participants	23 Participants n=4 Participants
Age, Continuous	36.4 Years STANDARD_DEVIATION 14.6 • n=5 Participants	35.1 Years STANDARD_DEVIATION 13.5 • n=7 Participants	36.1 Years STANDARD_DEVIATION 14.9 • n=5 Participants	35.8 Years STANDARD_DEVIATION 14.1 • n=4 Participants
Sex: Female, Male Female	154 Participants n=5 Participants	142 Participants n=7 Participants	5 Participants n=5 Participants	301 Participants n=4 Participants
Sex: Female, Male Male	114 Participants n=5 Participants	110 Participants n=7 Participants	7 Participants n=5 Participants	231 Participants n=4 Participants
Race/Ethnicity, Customized White or Caucasian	221 Participants n=5 Participants	208 Participants n=7 Participants	11 Participants n=5 Participants	440 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	18 Participants n=5 Participants	12 Participants n=7 Participants	0 Participants n=5 Participants	30 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic or Latino	13 Participants n=5 Participants	13 Participants n=7 Participants	1 Participants n=5 Participants	27 Participants n=4 Participants
Race/Ethnicity, Customized Asian	11 Participants n=5 Participants	14 Participants n=7 Participants	0 Participants n=5 Participants	25 Participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Other	5 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	9 Participants n=4 Participants
GCTB Disease Type Primary resectable	0 Participants n=5 Participants	167 Participants n=7 Participants	0 Participants n=5 Participants	167 Participants n=4 Participants
GCTB Disease Type Primary unresectable	93 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	95 Participants n=4 Participants
GCTB Disease Type Recurrent resectable	0 Participants n=5 Participants	85 Participants n=7 Participants	0 Participants n=5 Participants	85 Participants n=4 Participants
GCTB Disease Type Recurrent unresectable	175 Participants n=5 Participants	0 Participants n=7 Participants	10 Participants n=5 Participants	185 Participants n=4 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to last study visit for treatment-emergent period (a maximum of approximately 111 months).

Population: The safety analysis set included all enrolled participants who received at least one dose of denosumab on the study.

Outcome measures

Outcome measures
Measure	Cohort 1 (Denosumab 120 mg Q4W) n=265 Participants Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) n=249 Participants Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) n=12 Participants Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Fatal TEAE	8 Participants	3 Participants	0 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) TEAE leading to treatment phase discontinuation	27 Participants	24 Participants	1 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) TEAE leading to study drug discontinuation	27 Participants	23 Participants	1 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) CTCAE Grade 3, 4, or 5	121 Participants	59 Participants	6 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Any TEAE	260 Participants	231 Participants	12 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Serious TEAE	98 Participants	39 Participants	5 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Any TEAE related to study drug	184 Participants	136 Participants	9 Participants

PRIMARY outcome

Timeframe: Baseline (day 1) up to last study visit for initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 months).

Population: The safety analysis set included all enrolled participants who received at least one dose of denosumab on the study.

Serum samples for clinical chemistry were collected on study day 1 (baseline), day 15, week 5 and each study visit Q4W thereafter until last study visit for the on-study period (ie, until end of initial treatment phase). The parameters included albumin, calcium (albumin-adjusted), creatinine, magnesium and phosphate. Results are presented for number of participants who experienced the maximum toxicity grade for each of these clinical parameters. The maximum toxicity grade experienced by each participant was based on CTCAE, v3.0, and are summarized for Grade 3 and 4. Increases and decreases in relationship to the normal parameter ranges are indicated as 'Above' and 'Below' respectively.

Outcome measures

Outcome measures
Measure	Cohort 1 (Denosumab 120 mg Q4W) n=265 Participants Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) n=249 Participants Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) n=12 Participants Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Calcium corrected Grade 4 (Above)	1 Participants	1 Participants	0 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Calcium corrected Grade 3 (Below)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Calcium corrected Grade 4 (Below)	2 Participants	0 Participants	0 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Phosphate Grade 3 (Below)	60 Participants	41 Participants	4 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Magnesium Grade 3 (Above)	4 Participants	5 Participants	2 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Magnesium Grade 3 (Below)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Creatinine Grade 3 (Above)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Calcium corrected Grade 3 (Above)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters Albumin Grade 3 (Below)	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From first dose of study drug up to the end of the initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 months).

Population: The efficacy analysis set included all enrolled participants who were eligible for the study, and who received at least one dose of denosumab on the study. Analysis was performed on cohort 1 only.

Time to disease progression or recurrence during the on-study period was defined as the time interval (in days) from the date of first dose of study drug to the date of earliest Progressive Disease (PD) during the initial treatment phase. PD was defined as the response of progressive disease, locally recurrent disease or relapse as captured in the Disease Status page of the Case Report Form. If a participant had not had PD by the end of the initial treatment phase date, time to disease progression or recurrence were censored at her/his end of initial treatment phase date. Since median time to disease progression or recurrence for participants in cohort 1 was not reached, Kaplan-Meier estimates for the probability (expressed as a percentage) of participants in cohort 1 to have disease progression or recurrence at months 6, 12, 24, 36 and 60 are presented.

Outcome measures

Outcome measures
Measure	Cohort 1 (Denosumab 120 mg Q4W) n=260 Participants Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability Month 36	8.2 Percent probability Interval 4.6 to 11.8	—	—
Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability Month 6	1.9 Percent probability Interval 0.3 to 3.6	—	—
Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability Month 24	6.1 Percent probability Interval 3.1 to 9.0	—	—
Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability Month 12	4.3 Percent probability Interval 1.8 to 6.8	—	—
Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability Month 60	11.7 Percent probability Interval 7.1 to 16.2	—	—

SECONDARY outcome

Timeframe: At month 6.

The percentage of participants without any surgery at month 6 was equivalent to the number of participants without any surgery by month 6 divided by the number of cohort 2 participants who had an opportunity to complete 6 months of treatment, expressed as a percentage.

Outcome measures

Outcome measures
Measure	Cohort 1 (Denosumab 120 mg Q4W) n=238 Participants Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2	92.0 Percentage of participants Interval 87.8 to 95.1	—	—

SECONDARY outcome

Timeframe: Blood samples were collected at baseline (day 1), days 8 and 15 and weeks 5, 9, 13 and 25.

Population: The PK analysis set included all participants who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement. Only participants with available data at each time point were included in the analysis.

Blood samples for determination of serum denosumab concentration levels were obtained from participants included in the pharmacokinetic (PK) substudy at baseline (prior to administration of study drug on day 1) and at scheduled time points during the study up to week 25.

Outcome measures

Outcome measures
Measure	Cohort 1 (Denosumab 120 mg Q4W) n=10 Participants Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 2 (Denosumab 120 mg Q4W) n=15 Participants Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Cohort 3 (Denosumab 120 mg Q4W) Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Mean Serum Denosumab Trough Concentrations Day 1	0.0 nanograms / milliliter Standard Deviation 0.0	0.0 nanograms / milliliter Standard Deviation 0.0	—
Mean Serum Denosumab Trough Concentrations Day 8	11800 nanograms / milliliter Standard Deviation 4130	12000 nanograms / milliliter Standard Deviation 4300	—
Mean Serum Denosumab Trough Concentrations Day 15	21800 nanograms / milliliter Standard Deviation 5620	24200 nanograms / milliliter Standard Deviation 9050	—
Mean Serum Denosumab Trough Concentrations Week 5	30400 nanograms / milliliter Standard Deviation 6150	33500 nanograms / milliliter Standard Deviation 8970	—
Mean Serum Denosumab Trough Concentrations Week 9	25100 nanograms / milliliter Standard Deviation 6450	30000 nanograms / milliliter Standard Deviation 10300	—
Mean Serum Denosumab Trough Concentrations Week 13	22300 nanograms / milliliter Standard Deviation 6840	29100 nanograms / milliliter Standard Deviation 10000	—
Mean Serum Denosumab Trough Concentrations Week 17	23600 nanograms / milliliter Standard Deviation 4370	28300 nanograms / milliliter Standard Deviation 11600	—
Mean Serum Denosumab Trough Concentrations Week 25	22400 nanograms / milliliter Standard Deviation 6690	25400 nanograms / milliliter Standard Deviation 10800	—

Adverse Events

Denosumab 120 mg Q4W (All Cohorts)

Serious events: 176 serious events

Other events: 480 other events

Deaths: 26 deaths

Serious adverse events

Serious adverse events
Measure	Denosumab 120 mg Q4W (All Cohorts) n=526 participants at risk All participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ganglioneuroma	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive ductal breast carcinoma	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Blood and lymphatic system disorders Anaemia	1.5% 8/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Blood and lymphatic system disorders Febrile neutropenia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Blood and lymphatic system disorders Leukopenia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Blood and lymphatic system disorders Microcytic anaemia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Blood and lymphatic system disorders Thrombocytopenia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Cardiac disorders Bradycardia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Cardiac disorders Cardiac failure	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Cardiac disorders Coronary artery disease	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Cardiac disorders Supraventricular tachycardia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Congenital, familial and genetic disorders Aplasia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Endocrine disorders Hyperparathyroidism	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Endocrine disorders Toxic nodular goitre	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Abdominal pain	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Abdominal pain upper	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Colitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Diarrhoea	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Enterocolitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Gastritis	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Large intestine perforation	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Melaena	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Nausea	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Pancreatic failure	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Peptic ulcer	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Small intestinal obstruction	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Vomiting	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Asthenia	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Chest pain	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Death	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Disease recurrence	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Hernia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Impaired healing	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Malaise	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Mucosal inflammation	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Non-cardiac chest pain	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Pyrexia	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Hepatobiliary disorders Cholecystitis	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Hepatobiliary disorders Cholelithiasis	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Abdominal abscess	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Abdominal wall infection	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Abscess	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Abscess jaw	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Abscess neck	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Abscess oral	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Appendicitis	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Arthritis infective	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Aspergillus infection	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Bacteraemia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Bacteroides bacteraemia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Bone abscess	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Catheter site infection	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Cellulitis	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Device related infection	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Gastroenteritis	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Infected cyst	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Infected skin ulcer	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Infection	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Infectious colitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Muscle abscess	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Orchitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Osteomyelitis	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Osteomyelitis bacterial	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Peritonsillar abscess	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Pharyngitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Pneumonia	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Postoperative wound infection	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Pyelonephritis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Scrotal abscess	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Sepsis	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Staphylococcal infection	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Staphylococcal osteomyelitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Subcutaneous abscess	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Tooth infection	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Urinary tract infection	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Wound infection	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Wound infection staphylococcal	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Ankle fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Atypical femur fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Cervical vertebral fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Endotracheal intubation complication	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Femoral neck fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Femur fracture	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Fracture displacement	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Gun shot wound	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Joint dislocation	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Meniscus injury	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Overdose	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Post procedural fistula	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Postoperative respiratory failure	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Procedural haemorrhage	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Pubis fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Radiation myelopathy	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Spinal compression fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Stress fracture	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Tibia fracture	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Upper limb fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Vena cava injury	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Wound	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Wound dehiscence	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Wrist fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Metabolism and nutrition disorders Decreased appetite	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Metabolism and nutrition disorders Hypercalcaemia	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Metabolism and nutrition disorders Hypertriglyceridaemia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Metabolism and nutrition disorders Hypokalaemia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Arthralgia	0.95% 5/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Back pain	0.95% 5/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Bone pain	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Exposed bone in jaw	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Muscular weakness	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Myositis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Osteitis	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Osteonecrosis	0.76% 4/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	4.8% 25/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Pain in extremity	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Pain in jaw	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Pathological fracture	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Pseudarthrosis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Tendonitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bone giant cell tumour	3.6% 19/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bone neoplasm	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bone sarcoma	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer stage I	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myeloproliferative neoplasm	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine tumour	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal adenocarcinoma	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oncologic complication	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Osteosarcoma	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pelvic neoplasm	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cancer	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rhabdomyosarcoma	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Sarcoma	0.95% 5/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Second primary malignancy	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Spindle cell sarcoma	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer metastatic	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Cauda equina syndrome	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Central nervous system lesion	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Cerebrovascular accident	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Dizziness	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Facial neuralgia	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Headache	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Lethargy	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Nerve compression	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Peripheral sensory neuropathy	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Presyncope	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Seizure	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Spinal cord compression	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Syncope	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Transient ischaemic attack	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Product Issues Device breakage	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Product Issues Device failure	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Product Issues Device loosening	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Product Issues Device occlusion	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Psychiatric disorders Completed suicide	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Psychiatric disorders Suicide attempt	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Acute kidney injury	0.57% 3/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Bladder prolapse	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Dysuria	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Nephrolithiasis	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Renal colic	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Renal failure	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Urethral fistula	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Renal and urinary disorders Urge incontinence	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Reproductive system and breast disorders Dysmenorrhoea	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Reproductive system and breast disorders Pelvic pain	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Bronchial haemorrhage	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Lung disorder	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Pharyngeal fistula	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Skin and subcutaneous tissue disorders Dermatitis psoriasiform	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Surgical and medical procedures Bone lesion excision	0.38% 2/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Surgical and medical procedures Leg amputation	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Surgical and medical procedures Spinal operation	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Vascular disorders Circulatory collapse	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Vascular disorders Haematoma	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Vascular disorders Hypertension	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Vascular disorders Orthostatic hypotension	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Vascular disorders Thrombophlebitis superficial	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Vascular disorders Vasculitis	0.19% 1/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).

Other adverse events

Other adverse events
Measure	Denosumab 120 mg Q4W (All Cohorts) n=526 participants at risk All participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.
Blood and lymphatic system disorders Anaemia	5.7% 30/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Abdominal pain	9.3% 49/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Constipation	11.4% 60/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Dental caries	6.1% 32/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Diarrhoea	11.4% 60/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Nausea	23.2% 122/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Toothache	12.9% 68/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Gastrointestinal disorders Vomiting	12.5% 66/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Asthenia	9.1% 48/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Fatigue	27.0% 142/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Influenza like illness	5.1% 27/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Oedema peripheral	8.7% 46/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
General disorders Pyrexia	8.9% 47/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Bronchitis	5.3% 28/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Influenza	8.4% 44/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Nasopharyngitis	14.4% 76/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Infections and infestations Upper respiratory tract infection	9.1% 48/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Injury, poisoning and procedural complications Procedural pain	7.4% 39/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Investigations Weight increased	5.7% 30/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Metabolism and nutrition disorders Hypercalcaemia	5.5% 29/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Metabolism and nutrition disorders Hypocalcaemia	6.8% 36/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Metabolism and nutrition disorders Hypophosphataemia	12.5% 66/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Arthralgia	36.5% 192/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Back pain	29.3% 154/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Bone pain	7.8% 41/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Joint swelling	5.3% 28/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Muscle spasms	7.0% 37/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	13.3% 70/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Myalgia	8.0% 42/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Neck pain	5.5% 29/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Pain in extremity	27.8% 146/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Musculoskeletal and connective tissue disorders Pain in jaw	7.6% 40/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Dizziness	6.5% 34/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Headache	25.5% 134/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Hypoaesthesia	7.2% 38/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Nervous system disorders Paraesthesia	9.1% 48/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Psychiatric disorders Anxiety	5.5% 29/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Psychiatric disorders Depression	5.9% 31/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Psychiatric disorders Insomnia	8.6% 45/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Cough	10.3% 54/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.8% 36/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Skin and subcutaneous tissue disorders Pruritus	6.3% 33/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Skin and subcutaneous tissue disorders Rash	8.6% 45/526 • From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7). Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER