Trial Outcomes & Findings for Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer (NCT NCT03451331)

Last Updated: 2024-05-16

Results Overview

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the percentage of patients who achieve a response (confirmed PR or CR) according to RECIST 1.1.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

49 participants

Primary outcome timeframe

Up to a maximum of 50 months

Results posted on

2024-05-16

Participant Flow

Participant milestones

Participant milestones
Measure	Arm A Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Overall Study STARTED	25	24
Overall Study COMPLETED	23	23
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Overall Study Withdrawal by Subject	1	0
Overall Study Unable to start treatment.	1	1

Baseline Characteristics

Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A n=23 Participants Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B n=23 Participants Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2	Total n=46 Participants Total of all reporting groups
Age, Continuous	72 years n=5 Participants	72 years n=7 Participants	72 years n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	16 Participants n=7 Participants	34 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	22 Participants n=5 Participants	21 Participants n=7 Participants	43 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) White	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment United States	23 participants n=5 Participants	23 participants n=7 Participants	46 participants n=5 Participants
Tobacco use history Never	6 Participants n=5 Participants	10 Participants n=7 Participants	16 Participants n=5 Participants
Tobacco use history Current	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Tobacco use history Former	16 Participants n=5 Participants	11 Participants n=7 Participants	27 Participants n=5 Participants
Primary tumor site Bladder	17 Participants n=5 Participants	18 Participants n=7 Participants	35 Participants n=5 Participants
Primary tumor site Urethra	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Primary tumor site Renal pelvis	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Primary tumor site Ureters	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
ECOG performance status ECOG = 0	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
ECOG performance status ECOG = 1	11 Participants n=5 Participants	8 Participants n=7 Participants	19 Participants n=5 Participants
ECOG performance status ECOG = 2	4 Participants n=5 Participants	8 Participants n=7 Participants	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to a maximum of 50 months

Population: Out of 23 subjects in Arm B, two subjects were not evaluable for best response.

Outcome measures

Outcome measures
Measure	Arm A n=23 Participants Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B n=21 Participants Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Objective Response Rate (ORR)	69.6 Percentage of participants Interval 47.0 to 87.0	33.3 Percentage of participants Interval 15.0 to 57.0

SECONDARY outcome

Timeframe: AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 19 months.

The frequency and severity of grade 3+ treatment emergent adverse events are reported by CTCAEv4 term and grade.

Outcome measures

Outcome measures
Measure	Arm A n=23 Participants Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B n=23 Participants Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Adverse Events Anemia	8 Number of Participants	3 Number of Participants
Adverse Events Febrile neutropenia	2 Number of Participants	0 Number of Participants
Adverse Events Hepatitis viral	1 Number of Participants	0 Number of Participants
Adverse Events Kidney infection	2 Number of Participants	0 Number of Participants
Adverse Events Lung infection	1 Number of Participants	0 Number of Participants
Adverse Events Pancreatitis	1 Number of Participants	0 Number of Participants
Adverse Events Upper gastrointestinal hemorrhage	1 Number of Participants	0 Number of Participants
Adverse Events Other infections and infestations	1 Number of Participants	0 Number of Participants
Adverse Events Skin infection	1 Number of Participants	2 Number of Participants
Adverse Events Urinary tract infection	4 Number of Participants	1 Number of Participants
Adverse Events Alanine aminotransferase increased	1 Number of Participants	1 Number of Participants
Adverse Events Alkaline phosphatase increased	0 Number of Participants	2 Number of Participants
Adverse Events Aspartate aminotransferase increased	1 Number of Participants	4 Number of Participants
Adverse Events Lipase increased	3 Number of Participants	7 Number of Participants
Adverse Events Lymphocyte count decreased	3 Number of Participants	1 Number of Participants
Adverse Events Neutrophil count decreased	12 Number of Participants	6 Number of Participants
Adverse Events Other investigations	1 Number of Participants	0 Number of Participants
Adverse Events Platelet count decreased	1 Number of Participants	5 Number of Participants
Adverse Events Serum amylase increased	1 Number of Participants	4 Number of Participants
Adverse Events White blood cell decreased	4 Number of Participants	2 Number of Participants
Adverse Events Hyperglycemia	0 Number of Participants	1 Number of Participants
Adverse Events Hyponatremia	1 Number of Participants	0 Number of Participants
Adverse Events Hypophosphatemia	1 Number of Participants	0 Number of Participants
Adverse Events Muscle weakness left-sided	1 Number of Participants	0 Number of Participants
Adverse Events Peripheral sensory neuropathy	1 Number of Participants	0 Number of Participants
Adverse Events Atrial fibrillation	1 Number of Participants	0 Number of Participants
Adverse Events Bladder spasm	1 Number of Participants	0 Number of Participants
Adverse Events Dyspnea	2 Number of Participants	1 Number of Participants
Adverse Events Other respiratory, thoracic and mediastinal disorders	1 Number of Participants	2 Number of Participants
Adverse Events Other skin and subcutaneous tissue disorders	2 Number of Participants	0 Number of Participants
Adverse Events Rash maculo-papular	2 Number of Participants	0 Number of Participants
Adverse Events Other surgical and medical procedures	0 Number of Participants	1 Number of Participants
Adverse Events Hypertension	1 Number of Participants	2 Number of Participants
Adverse Events Hypotension	1 Number of Participants	0 Number of Participants
Adverse Events Thromboembolic event	2 Number of Participants	1 Number of Participants
Adverse Events Hearing impaired	1 Number of Participants	1 Number of Participants
Adverse Events Diarrhea	0 Number of Participants	1 Number of Participants
Adverse Events Nausea	0 Number of Participants	1 Number of Participants
Adverse Events Other gastrointestinal disorders	0 Number of Participants	1 Number of Participants
Adverse Events Vomiting	0 Number of Participants	1 Number of Participants
Adverse Events Fatigue	1 Number of Participants	0 Number of Participants
Adverse Events Pain	2 Number of Participants	1 Number of Participants

SECONDARY outcome

Timeframe: Up to a maximum of 50 months

Population: Out of 23 subjects in Arm B, two subjects were not evaluable for efficacy analysis.

DOR was defined as the period measured from the date that evaluation criteria were met for CR or PR (whichever status was recorded first) until the date that recurrence or PD was objectively documented.

Outcome measures

Outcome measures
Measure	Arm A n=23 Participants Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B n=21 Participants Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Duration of Response (DOR)	8.64 Months Interval 4.37 to 19.29	6.51 Months Interval 1.2 to Not enough participants achieved response to calculate upper 95% confidence interval.

SECONDARY outcome

Timeframe: Up to maximum of 50 months

Population: Out of 23 subjects in Arm B, two subjects were not evaluable for efficacy analysis.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause.

Outcome measures

Outcome measures
Measure	Arm A n=23 Participants Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B n=21 Participants Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Progression-Free Survival (PFS)	9.4 Months Interval 5.62 to 12.88	8.57 Months Interval 2.56 to 10.38

SECONDARY outcome

Timeframe: Up to a maximum of 53 months

Overall survival is defined as the time from randomization until death or date of last contact.

Outcome measures

Outcome measures
Measure	Arm A n=23 Participants Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B n=23 Participants Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Overall Survival (OS)	24.74 Months Interval 17.45 to Not enough events occur to calculate the upper 95% Confidence Interval.	16.43 Months Interval 7.66 to 28.68

Adverse Events

Arm A

Serious events: 15 serious events

Other events: 22 other events

Deaths: 12 deaths

Arm B

Serious events: 17 serious events

Other events: 23 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Additional Information

Fauzia Sharmin

Hoosier Cancer Research Network

Phone: 317-921-2050

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm A n=23 participants at risk Gemcitabine plus carboplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Carboplatin: AUC 4.5 (based on the Calvert formula)	Arm B n=23 participants at risk Gemcitabine plus oxaliplatin plus nivolumab Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) Gemcitabine: 1000 mg/m\^2 Oxaliplatin: 130 mg/m\^2
Renal and urinary disorders ACUTE KIDNEY INJURY	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Musculoskeletal and connective tissue disorders ARTHRITIS	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Cardiac disorders ATRIAL FIBRILLATION	4.3% 1/23 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Infections and infestations DEVICE RELATED INFECTION	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
General disorders FATIGUE	4.3% 1/23 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Blood and lymphatic system disorders FEBRILE NEUTROPENIA	8.7% 2/23 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Nervous system disorders HEADACHE	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Infections and infestations HEPATITIS VIRAL	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Vascular disorders HYPOTENSION	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Infections and infestations INFECTIONS AND INFESTATIONS - OTHER, SPECIFY	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Infections and infestations KIDNEY INFECTION	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Musculoskeletal and connective tissue disorders MUSCLE WEAKNESS LEFT-SIDED	4.3% 1/23 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Investigations NEUTROPHIL COUNT DECREASED	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Gastrointestinal disorders PANCREATITIS	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Respiratory, thoracic and mediastinal disorders RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	8.7% 2/23 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Skin and subcutaneous tissue disorders SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY	8.7% 2/23 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Infections and infestations SKIN INFECTION	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	8.7% 2/23 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Nervous system disorders STROKE	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Vascular disorders THROMBOEMBOLIC EVENT	8.7% 2/23 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Gastrointestinal disorders UPPER GASTROINTESTINAL HEMORRHAGE	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Infections and infestations URINARY TRACT INFECTION	21.7% 5/23 • Number of events 8 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Investigations ALANINE AMINOTRANSFERASE INCREASED	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Blood and lymphatic system disorders ANEMIA	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Investigations ASPARTATE AMINOTRANSFERASE INCREASED	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Renal and urinary disorders BLADDER PERFORATION	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Blood and lymphatic system disorders BLOOD AND LYMPHATIC SYSTEM DISORDERS - OTHER, SPECIFY	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Investigations BLOOD BILIRUBIN INCREASED	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Hepatobiliary disorders CHOLECYSTITIS	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Investigations CPK INCREASED	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	8.7% 2/23 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Gastrointestinal disorders DIARRHEA	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Respiratory, thoracic and mediastinal disorders DYSPNEA	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Respiratory, thoracic and mediastinal disorders EPISTAXIS	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
General disorders FEVER	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Metabolism and nutrition disorders HYPERGLYCEMIA	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Nervous system disorders INTRACRANIAL HEMORRHAGE	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Investigations LIPASE INCREASED	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
General disorders PAIN	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Investigations PLATELET COUNT DECREASED	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	13.0% 3/23 • Number of events 4 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Nervous system disorders SYNCOPE	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Renal and urinary disorders URINARY TRACT OBSTRUCTION	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.
Gastrointestinal disorders VOMITING	0.00% 0/23 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.	4.3% 1/23 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 19 months.