Trial Outcomes & Findings for Study of Cabozantinib in Combination With Atezolizumab Versus Second NHT in Subjects With mCRPC (NCT NCT04446117)

NCT ID: NCT04446117

Last Updated: 2025-12-18

Results Overview

Duration of PFS was defined as the time from randomization to the earlier of either the date of radiographic progression (defined as progressive disease \[PD\] per RECIST 1.1) per BIRC or the date of death due to any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions, with an absolute increase of ≥ 5 mm, unequivocal progression of non-target lesions and/or the appearance of new lesions.

• Recruitment status: ACTIVE_NOT_RECRUITING
• Study phase: PHASE3
• Target enrollment: 575 participants
• Primary outcome timeframe: Up to a maximum of approximately 30 months (Median duration of follow-up was 14.31 months)
• Results posted on: 2025-12-18

Participant Flow

The study is ongoing, so the results reported are based on a data cutoff date of 19 April 2024.

Participant milestones

Measure	Experimental Arm: Cabozantinib and Atezolizumab Participants with metastatic castration-resistant prostate cancer (mCRPC) received cabozantinib 40 milligrams (mg) as oral tablets once daily (QD) throughout the treatment period. Participants also received atezolizumab 1200 mg as an intravenous (IV) infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Control Arm: Second Novel Hormonal Therapy (NHT) Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets twice daily (BID) or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.
Overall Study STARTED	289	286
Overall Study Received at Least 1 Dose of Any Study Treatment	284	284
Overall Study Received Cabozantinib or Atezolizumab	284	0
Overall Study Received Abiraterone and Prednisone or Enzalutamide	1	283
Overall Study Discontinued Radiographic Follow-up	267	265
Overall Study Discontinued Survival Follow-up	202	202
Overall Study COMPLETED	22	20
Overall Study NOT COMPLETED	267	266

Reasons for withdrawal

Measure	Experimental Arm: Cabozantinib and Atezolizumab Participants with metastatic castration-resistant prostate cancer (mCRPC) received cabozantinib 40 milligrams (mg) as oral tablets once daily (QD) throughout the treatment period. Participants also received atezolizumab 1200 mg as an intravenous (IV) infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Control Arm: Second Novel Hormonal Therapy (NHT) Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets twice daily (BID) or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.
Overall Study No Study Treatment Given	4	3
Overall Study Radiographic Disease Progression	132	158
Overall Study Adverse Event	79	43
Overall Study Lack of Clinical Benefit	1	1
Overall Study Withdrawal by Subject	24	22
Overall Study Lost to Follow-up	0	3
Overall Study Miscellaneous	26	36
Overall Study Missing Data/Data not yet Received	1	0

Baseline Characteristics

Study of Cabozantinib in Combination With Atezolizumab Versus Second NHT in Subjects With mCRPC

Baseline characteristics by cohort

Measure	Experimental Arm: Cabozantinib and Atezolizumab n=289 Participants Participants with mCRPC received cabozantinib 40 mg as oral tablets QD throughout the treatment period. Participants also received atezolizumab 1200 mg as an IV infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Control Arm: Second NHT n=286 Participants Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets BID or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Total n=575 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=47 Participants	0 Participants n=41 Participants	0 Participants n=88 Participants
Age, Categorical Between 18 and 65 years	54 Participants n=47 Participants	67 Participants n=41 Participants	121 Participants n=88 Participants
Age, Categorical >=65 years	235 Participants n=47 Participants	219 Participants n=41 Participants	454 Participants n=88 Participants
Sex: Female, Male Female	0 Participants n=47 Participants	0 Participants n=41 Participants	0 Participants n=88 Participants
Sex: Female, Male Male	289 Participants n=47 Participants	286 Participants n=41 Participants	575 Participants n=88 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	77 Participants n=47 Participants	72 Participants n=41 Participants	149 Participants n=88 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	196 Participants n=47 Participants	196 Participants n=41 Participants	392 Participants n=88 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	16 Participants n=47 Participants	18 Participants n=41 Participants	34 Participants n=88 Participants
Race/Ethnicity, Customized American Indian/Alaska Native	3 Participants n=47 Participants	9 Participants n=41 Participants	12 Participants n=88 Participants
Race/Ethnicity, Customized Asian	39 Participants n=47 Participants	39 Participants n=41 Participants	78 Participants n=88 Participants
Race/Ethnicity, Customized Black/African American	0 Participants n=47 Participants	9 Participants n=41 Participants	9 Participants n=88 Participants
Race/Ethnicity, Customized Native Hawaiian/Pacific Islander	1 Participants n=47 Participants	0 Participants n=41 Participants	1 Participants n=88 Participants
Race/Ethnicity, Customized White	227 Participants n=47 Participants	213 Participants n=41 Participants	440 Participants n=88 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=47 Participants	0 Participants n=41 Participants	1 Participants n=88 Participants
Race/Ethnicity, Customized Other	2 Participants n=47 Participants	3 Participants n=41 Participants	5 Participants n=88 Participants
Race/Ethnicity, Customized Not Reported	16 Participants n=47 Participants	13 Participants n=41 Participants	29 Participants n=88 Participants

PRIMARY outcome

Timeframe: Up to a maximum of approximately 30 months (Median duration of follow-up was 14.31 months)

Population: PFS ITT (PITT) analysis population: Included the first 400 participants who were randomized to the Experimental Arm or Control Arm.

Duration of PFS was defined as the time from randomization to the earlier of either the date of radiographic progression (defined as progressive disease [PD] per RECIST 1.1) per BIRC or the date of death due to any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions, with an absolute increase of ≥ 5 mm, unequivocal progression of non-target lesions and/or the appearance of new lesions.

Outcome measures

Measure	Experimental Arm: Cabozantinib and Atezolizumab n=200 Participants Participants with mCRPC received cabozantinib 40 mg as oral tablets QD throughout the treatment period. Participants also received atezolizumab 1200 mg as an IV infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Control Arm: Second NHT n=200 Participants Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets BID or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.
Duration of Progression Free Survival (PFS) Per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Radiology Committee (BIRC)	6.34 months Interval 6.18 to 8.8	4.17 months Interval 3.71 to 5.65

PRIMARY outcome

Timeframe: Up to a maximum of approximately 45 months (Median duration of follow-up was 24.05 months)

Population: ITT population: Included all participants who were randomized regardless of whether any study treatment or the correct study treatment was received.

Duration of OS was defined as the time from randomization to death due to any cause. For participants, who were not known to have died at the time of data cutoff and were permanently lost to follow-up, duration of OS was censored at the earlier of the following dates: date the participant was last known to be alive or date of full withdrawal of consent (including survival follow-up), or date of data cutoff.

OS was calculated as earlier of date of death or censoring - date of randomization + 1)/30.4375

Outcome measures

Measure	Experimental Arm: Cabozantinib and Atezolizumab n=289 Participants Participants with mCRPC received cabozantinib 40 mg as oral tablets QD throughout the treatment period. Participants also received atezolizumab 1200 mg as an IV infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Control Arm: Second NHT n=286 Participants Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets BID or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.
Duration of Overall Survival (OS)	14.78 months Interval 13.37 to 16.66	14.98 months Interval 13.01 to 18.5

Adverse Events

Experimental Arm: Cabozantinib and Atezolizumab

Serious events: 135 serious events

Other events: 281 other events

Deaths: 173 deaths

Control Arm: Second NHT

Serious events: 89 serious events

Other events: 254 other events

Deaths: 179 deaths

Serious adverse events

Measure	Experimental Arm: Cabozantinib and Atezolizumab n=284 participants at risk Participants with mCRPC received cabozantinib 40 mg as oral tablets QD throughout the treatment period. Participants also received atezolizumab 1200 mg as an IV infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Control Arm: Second NHT n=284 participants at risk Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets BID or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.
Infections and infestations Pneumonia	2.8% 8/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Urinary tract infection	2.5% 7/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.4% 4/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Anal abscess	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Sepsis	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Urosepsis	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Appendicitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Appendicitis perforated	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Bronchopulmonary aspergillosis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations COVID-19	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations COVID-19 pneumonia	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Cellulitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Diabetic foot infection	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Emphysematous cystitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Encephalitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Endocarditis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Herpes simplex	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Pneumonia aspiration	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Pyelonephritis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Respiratory tract infection bacterial	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Septic shock	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Soft tissue infection	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Systemic candida	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Urinary tract abscess	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Urinary tract candidiasis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Abdominal sepsis	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Biliary sepsis	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Diarrhoea infectious	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Pneumonia bacterial	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Pulmonary sepsis	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Respiratory tract infection	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	7.7% 22/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	7.0% 20/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant pleural effusion	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour hyperprogression	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Acute kidney injury	3.2% 9/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Urinary retention	2.8% 8/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Haematuria	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.4% 4/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Hydronephrosis	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Urinary tract obstruction	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Nephrolithiasis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Renal failure	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Bladder perforation	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Diarrhoea	2.5% 7/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Vomiting	1.8% 5/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Abdominal pain	1.4% 4/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Abdominal pain upper	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Anal fistula	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Colitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Enteritis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Enterocutaneous fistula	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Haematochezia	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Immune-mediated enterocolitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Inguinal hernia	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Melaena	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Nausea	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Pancreatitis acute	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Stomatitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Large intestinal obstruction	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Asthenia	1.8% 5/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Pyrexia	1.4% 4/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders General physical health deterioration	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.1% 6/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Oedema peripheral	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Chest pain	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Death	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Fatigue	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Prosthetic cardiac valve thrombosis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Systemic inflammatory response syndrome	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Pain	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.5% 10/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Immune-mediated lung disease	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Laryngeal oedema	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Pulmonary venous thrombosis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Syncope	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Ischaemic stroke	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Transient ischaemic attack	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Aphasia	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Cerebral haemorrhage	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Cerebrovascular accident	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Embolic cerebral infarction	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Embolic stroke	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Immune-mediated encephalitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Peroneal nerve palsy	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Somnolence	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Vascular encephalopathy	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Cognitive disorder	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Haemorrhage intracranial	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Hypoaesthesia	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Spinal cord compression	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Hyponatraemia	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Decreased appetite	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Dehydration	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Electrolyte imbalance	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Gout	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Hypophosphataemia	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Back pain	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Bone pain	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Arthralgia	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Muscular weakness	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Osteoporotic fracture	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Spinal pain	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Cardiac failure	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Acute myocardial infarction	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Anomalous atrioventricular excitation	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Atrial fibrillation	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Cardiac failure congestive	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Myocardial infarction	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Atrioventricular block second degree	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Cardiac disorders Left ventricular failure	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Deep vein thrombosis	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Arteritis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Embolism	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Hypertension	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Hypertensive crisis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Orthostatic hypotension	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Hypotension	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Hypovolaemic shock	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Blood and lymphatic system disorders Anaemia	1.8% 5/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.8% 8/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Blood and lymphatic system disorders Febrile neutropenia	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Cholangitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Cholecystitis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Drug-induced liver injury	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Hepatic failure	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Jaundice	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Cholangitis acute	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Hepatobiliary disorders Hepatitis acute	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Psychiatric disorders Confusional state	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Psychiatric disorders Delirium	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Psychiatric disorders Completed suicide	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Psychiatric disorders Depression	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Injury, poisoning and procedural complications Craniocerebral injury	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Injury, poisoning and procedural complications Fall	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Injury, poisoning and procedural complications Hip fracture	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Injury, poisoning and procedural complications Periprosthetic fracture	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Injury, poisoning and procedural complications Skin laceration	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Alanine aminotransferase increased	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Aspartate aminotransferase increased	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Electrocardiogram QT prolonged	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Lymphocyte count decreased	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Skin and subcutaneous tissue disorders Diabetic foot	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Skin and subcutaneous tissue disorders Drug eruption	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Skin and subcutaneous tissue disorders Rash	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Endocrine disorders Adrenal insufficiency	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Endocrine disorders Autoimmune thyroid disorder	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Endocrine disorders Immune-mediated adrenal insufficiency	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Endocrine disorders Primary adrenal insufficiency	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Reproductive system and breast disorders Prostatic obstruction	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Reproductive system and breast disorders Scrotal oedema	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Eye disorders Diplopia	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Immune system disorders Haemophagocytic lymphohistiocytosis	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.

Other adverse events

Measure	Experimental Arm: Cabozantinib and Atezolizumab n=284 participants at risk Participants with mCRPC received cabozantinib 40 mg as oral tablets QD throughout the treatment period. Participants also received atezolizumab 1200 mg as an IV infusion once every 3 weeks, administered on Day 1 of each 21-day cycle throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.	Control Arm: Second NHT n=284 participants at risk Participants with mCRPC received either abiraterone 1000 mg as oral tablets QD and prednisone 5 mg as oral tablets BID or enzalutamide 160 mg as oral tablets QD throughout the treatment period. Participants received study treatment as long as they continued to experience clinical benefit in the opinion of the Investigator or until there was unacceptable toxicity, the need for subsequent systemic anticancer treatment, or any other reasons for the treatment discontinuation.
Gastrointestinal disorders Constipation	16.9% 48/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	9.5% 27/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Vomiting	12.3% 35/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	6.0% 17/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Dry mouth	5.6% 16/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Diarrhoea	46.8% 133/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	6.7% 19/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Stomatitis	19.7% 56/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.1% 3/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Nausea	28.2% 80/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	12.7% 36/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Abdominal pain	12.3% 35/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	3.5% 10/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Gastrointestinal disorders Dyspepsia	5.6% 16/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Alanine aminotransferase increased	24.3% 69/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	3.2% 9/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Aspartate aminotransferase increased	24.6% 70/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	5.3% 15/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Weight decreased	19.4% 55/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	4.9% 14/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Blood thyroid stimulating hormone increased	7.4% 21/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Blood lactate dehydrogenase increased	7.4% 21/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.1% 6/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Lipase increased	7.4% 21/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.5% 7/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Gamma-glutamyltransferase increased	6.7% 19/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.5% 7/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Amylase increased	5.6% 16/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.8% 5/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Blood alkaline phosphatase increased	5.6% 16/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	4.9% 14/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Investigations Blood creatinine increased	5.3% 15/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	6.0% 17/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	16.5% 47/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.00% 0/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Skin and subcutaneous tissue disorders Dry skin	5.3% 15/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Skin and subcutaneous tissue disorders Pruritus	6.0% 17/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.8% 5/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Skin and subcutaneous tissue disorders Rash	6.0% 17/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.5% 7/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Endocrine disorders Hypothyroidism	22.9% 65/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.4% 4/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Dysphonia	13.7% 39/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	6.0% 17/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.35% 1/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.3% 15/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.6% 16/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	3.2% 9/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Respiratory, thoracic and mediastinal disorders Cough	7.7% 22/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	6.0% 17/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Asthenia	27.1% 77/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	13.0% 37/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Fatigue	29.9% 85/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	20.1% 57/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Pyrexia	12.0% 34/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	3.2% 9/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
General disorders Oedema peripheral	8.1% 23/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	7.4% 21/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Decreased appetite	39.8% 113/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	15.1% 43/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Hypomagnesaemia	6.7% 19/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.8% 5/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Hypocalcaemia	5.6% 16/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.5% 7/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Metabolism and nutrition disorders Hypokalaemia	6.0% 17/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	4.2% 12/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Vascular disorders Hypertension	21.1% 60/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	7.0% 20/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Dysgeusia	12.0% 34/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	1.8% 5/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Nervous system disorders Headache	6.7% 19/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	3.9% 11/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Blood and lymphatic system disorders Anaemia	27.1% 77/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	18.3% 52/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Blood and lymphatic system disorders Neutropenia	5.6% 16/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	0.70% 2/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations Urinary tract infection	12.3% 35/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	7.4% 21/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Infections and infestations COVID-19	8.1% 23/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	7.0% 20/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Arthralgia	15.5% 44/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	11.6% 33/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Muscle spasms	6.3% 18/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	2.5% 7/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Pain in extremity	8.5% 24/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	5.3% 15/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Back pain	10.2% 29/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	9.5% 27/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Musculoskeletal and connective tissue disorders Bone pain	7.7% 22/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	7.7% 22/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Proteinuria	13.0% 37/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	4.6% 13/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.
Renal and urinary disorders Haematuria	6.3% 18/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.	6.7% 19/284 • Up to a maximum of approximately 45 months Safety Population: Consisted of all participants who received any amount of study treatment. Participants were analyzed according to the actual treatment received.

Additional Information

Exelixis Medical Information

Exelixis, Inc.

Phone: 855-292-3935

Email: druginfo@exelixis.com

Results disclosure agreements

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