Study of Atezolizumab as Monotherapy and in Combination With Platinum-Based Chemotherapy in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma (IMvigor130)

• ClinicalTrials.gov Identifier: NCT02807636
• Recruitment Status: Completed
• First Posted: June 21, 2016
• Results First Posted: December 13, 2023
• Last Update Posted: April 29, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Urothelial Carcinoma
• Interventions: Drug: Atezolizumab; Drug: Carboplatin; Drug: Gemcitabine; Other: Placebo; Drug: Cisplatin
• Enrollment: 1213

Participant Flow

Recruitment Details	Participants were enrolled in 221 sites in 35 countries.
Pre-assignment Details	Stage 1 included atezolizumab+gemcitabine+carboplatin arm or placebo+gemcitabine+carboplatin arm. Participants ineligible for cisplatin-based chemo were enrolled in this stage. Stage 2 included addition of atezolizumab monotherapy arm and allowed participants who were eligible for cisplatin-based chemotherapy.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Period Title: Overall Study
Started	400	451	362
Completed	0	0	0
Not Completed	400	451	362
Reason Not Completed
Lost to Follow-up	9	12	6
Protocol Deviation	2	0	0
Symptomatic Deterioration	0	1	0
Withdrawal by Subject	39	27	23
Death	298	327	266
Ongoing in Study	52	84	67

Baseline Characteristics

Arm/Group Title		Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy	Total
Arm/Group Description		Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.	Total of all reporting groups
Overall Number of Baseline Participants		400	451	362	1213
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	400 participants	451 participants	362 participants	1213 participants
		66.4 (9.5)	67.5 (9.7)	67.0 (9.1)	67.0 (9.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	400 participants	451 participants	362 participants	1213 participants
	Female	102 25.5%	113 25.1%	82 22.7%	297 24.5%
	Male	298 74.5%	338 74.9%	280 77.3%	916 75.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	400 participants	451 participants	362 participants	1213 participants
	Hispanic or Latino	44 11.0%	41 9.1%	40 11.0%	125 10.3%
	Not Hispanic or Latino	350 87.5%	402 89.1%	311 85.9%	1063 87.6%
	Unknown or Not Reported	6 1.5%	8 1.8%	11 3.0%	25 2.1%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	400 participants	451 participants	362 participants	1213 participants
	American Indian or Alaska Native	3 0.8%	4 0.9%	2 0.6%	9 0.7%
	Asian	85 21.3%	90 20.0%	94 26.0%	269 22.2%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	1 0.3%	1 0.1%
	Black or African American	0 0.0%	6 1.3%	1 0.3%	7 0.6%
	White	305 76.3%	346 76.7%	260 71.8%	911 75.1%
	More than one race	0 0.0%	0 0.0%	1 0.3%	1 0.1%
	Unknown or Not Reported	7 1.8%	5 1.1%	3 0.8%	15 1.2%

Outcome Measures

1. Primary Outcome

Title	Investigator Assessed Progression-Free Survival (PFS) in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm
Description	PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1, or death from any cause, whichever occurs first.
Time Frame	Baseline up to first documented disease progression or death, whichever occurs first (up to approximately 35 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants randomized to the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin arm or the Placebo+Gemcitabine+Carboplatin/Cisplatin arm in Stages 1 and 2, whether or not the assigned study treatment was received.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	400	451
Median (95% Confidence Interval); Unit of Measure: Months
	6.34; (6.24 to 7.00)	8.18; (6.51 to 8.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
	Comments	Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0073
	Comments	inverse normal combination
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.70 to 0.96
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Overall Survival (OS) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	OS is defined as the time from randomization to death due to any cause.
Time Frame	Baseline until death due to any cause (up to approximately 73 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants randomized to the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin arm or the Placebo+Gemcitabine+Carboplatin/Cisplatin arm in Stages 1 and 2, whether or not the assigned study treatment was received.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	400	451
Median (95% Confidence Interval); Unit of Measure: Months
	13.44; (11.99 to 15.34)	16.13; (14.19 to 18.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
	Comments	Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0230
	Comments	one-sided, inverse normal combination
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.0
	Estimation Comments	[Not Specified]

3. Primary Outcome

Title	Overall Survival (OS) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	OS is defined as the time from randomization to death due to any cause.
Time Frame	Baseline until death due to any cause (up to approximately 73 months)

Outcome Measure Data

Analysis Population Description

The ITT population includes only participants concurrently enrolled in Stage 2 and only those who had been randomized at the time of approval of Protocol WO30070 v6.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	359	360
Median (95% Confidence Interval); Unit of Measure: Months
	13.34; (11.89 to 15.61)	15.21; (13.14 to 17.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab Monotherapy
	Comments	Stratification factors: PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3968
	Comments	[Not Specified]
	Method	Log Rank
	Comments	one-sided
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.16
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Objective Response Rate (ORR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	Objective response rate (ORR) is defined as the proportion of participants with a confirmed objective response, either complete response (CR) or partial response (PR), observed on two assessments >= 28 days apart per RECIST v1.1, based on investigator assessment. The analysis population for ORR will be all randomized participants with measurable disease at baseline.
Time Frame	Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants randomized to the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin arm or the Placebo+Gemcitabine+Carboplatin/Cisplatin arm in Stages 1 and 2, whether or not the assigned study treatment was received. The measurable disease populations were defined as participants in the respective ITT populations with at least one measurable lesion according to RECIST v1.1 based on investigator assessment.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	397	447
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	44.8; (39.87 to 49.88)	48.1; (43.38 to 52.84)

5. Secondary Outcome

Title	Objective Response Rate (ORR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	Objective response rate (ORR) is defined as the proportion of participants with a confirmed objective response, either complete response (CR) or partial response (PR), observed on two assessments >= 28 days apart per RECIST v1.1, based on investigator assessment. The analysis population for ORR will be all randomized participants with measurable disease at baseline.
Time Frame	Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months)

Outcome Measure Data

Analysis Population Description

The ITT population includes only participants concurrently enrolled in Stage 2 and only those who had been randomized at the time of approval of Protocol WO30070 v6. The measurable disease populations were defined as participants in the respective ITT populations with at least one measurable lesion according to RECIST v1.1 based on investigator assessment.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	356	359
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	44.4; (39.15 to 49.71)	24.2; (19.89 to 29.01)

6. Secondary Outcome

Title	Duration of Response (DOR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	Duration of response (DOR) is defined for participants with an objective response as the time from the first documented objective response to documented disease progression per RECIST v1.1, based on investigator assessment, or death due to any cause, whichever occurs first.
Time Frame	From first documented objective response (CR or PR) to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months)

Outcome Measure Data

Analysis Population Description

The duration of response (DOR)-evaluable population is defined as participants with an objective response in the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin arm or the Placebo+Gemcitabine+Carboplatin/Cisplatin arm in Stages 1 and 2.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	178	215
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Months
	8.15; (6.34 to 8.61)	9.13; (8.02 to 10.64)

7. Secondary Outcome

Title	Duration of Response (DOR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	Duration of response (DOR) is defined for participants with an objective response as the time from the first documented objective response to documented disease progression per RECIST v1.1, based on investigator assessment, or death due to any cause, whichever occurs first.
Time Frame	From first documented objective response (CR or PR) to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months)

Outcome Measure Data

Analysis Population Description

The duration of response (DOR)-evaluable population is defined as participants with an objective response in the the ITT population which included only participants concurrently enrolled in Stage 2 and only those who had been randomized at the time of approval of Protocol WO30070 v6.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	158	87
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Months
	8.11; (6.28 to 8.54)	29.63 [1]; (15.90 to NA)

[1]

Upper CI limit is not evaluable because there were not enough events at later time to get a reliable upper CI.

8. Secondary Outcome

Title	IRF-PFS
Description	Independent review facility PFS (IRF-PFS) is defined as the time from randomization to the first documented disease progression as determined by blinded independent central review with use of RECIST v1.1, or death due to any cause, whichever occurs first.
Time Frame	Randomization to first documented disease progression or death from any cause (up to 35 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants randomized to the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin arm or the Placebo+Gemcitabine+Carboplatin/Cisplatin arm in Stages 1 and 2, whether or not the assigned study treatment was received.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	400	451
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Months
	6.34; (6.24 to 8.05)	7.10; (6.31 to 8.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
	Comments	Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0373
	Comments	inverse normal combination
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.01
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	OS Event Free Rate Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	Overall Survival (OS) Event Free Rate at 1 Year.
Time Frame	Year 1

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants randomized to the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin or the Placebo+Gemcitabine+Carboplatin/Cisplatin arm in Stages 1 and 2, whether or not the assigned study treatment was received.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	400	451
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage
	55.00; (49.98 to 60.02)	60.00; (55.39 to 64.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
	Comments	Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1509
	Comments	[Not Specified]
	Method	Z-test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Event Free Rate
	Estimated Value	5.00
	Confidence Interval	(2-Sided) 95%; -1.82 to 11.81
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	OS Event Free Rate in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	Overall Survival (OS) Event Free Rate at 1 Year.
Time Frame	Year 1

Outcome Measure Data

Analysis Population Description

The ITT population includes only participants concurrently enrolled in Stage 2 and only those who had been randomized at the time of approval of Protocol WO30070 v6.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	359	360
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage
	54.56; (49.23 to 59.88)	57.91; (52.72 to 63.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab Monotherapy
	Comments	Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3761
	Comments	[Not Specified]
	Method	Z-test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Event Free Rate
	Estimated Value	3.36
	Confidence Interval	(2-Sided) 95%; -4.08 to 10.79
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	PFS Event Free Rate
Description	Progression Free Survival (PFS) Event Free Rate at Year 1
Time Frame	Year 1

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants randomized to the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin arm or the Placebo+Gemcitabine+Carboplatin/Cisplatin arm in Stages 1 and 2, whether or not the assigned study treatment was received.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	400	451
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage
	22.17; (17.93 to 26.42)	30.47; (26.00 to 34.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
	Comments	Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0083
	Comments	[Not Specified]
	Method	Z-test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Event Free Rate
	Estimated Value	-8.29
	Confidence Interval	(2-Sided) 95%; -14.45 to -2.13
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm
Description	Time to deterioration in global health status as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm.
Time Frame	Up to approximately 73 months

Outcome Measure Data

Analysis Population Description

The patient reported outcome (PRO)-evaluable population is defined as participants in the ITT populations for comparisons of the Placebo+Chemo Arm versus Atezolizumab+Chemo Arm who have a baseline and at least one post-baseline assessment. The ITT population for the comparison of Atezo+Chemo Arm vs. Placebo+Chemo Arm included participants enrolled in Stage 1 and Stage 2, which consisted of 451 paarticipants in the Atezo+Chemo Arm and 400 participants in the Placebo+Chemo Arm.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	400	451
Median (95% Confidence Interval); Unit of Measure: Months
	12.06; (8.28 to 20.24)	32.07 [1]; (18.40 to NA)

[1]

Not evaluable due to sample size is very small and not enough events at later times to estimate the upper bound of the CI.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
	Comments	Strata are: Enrollment Stage, PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0542
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.00
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm
Description	Time to deterioration in global health status as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 in the Placebo+Chemo Arm versus Atezolizumab Monotherapy Arm.
Time Frame	Up to approximately 73 months

Outcome Measure Data

Analysis Population Description

Evaluable population defined as patients in ITT for comparisons of Placebo+Chemo vs. Atezo Mono who have a baseline and at least one post-baseline assessment. ITT for comparison of Atezo Mono vs. Placebo+Chemo consisted of 360 patients enrolled in Atezo Mono in Stage 2. Although a total of 400 patients were randomized to Placebo+Chemo throughout study, only 359 patients who were concurrently enrolled into this arm in Stage 2 and prior to Protocol v6 were included in Placebo+Chemo of this ITT.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	359	360
Median (95% Confidence Interval); Unit of Measure: Months
	12.02; (8.08 to 20.24)	23.20 [1]; (8.31 to NA)

[1]

Not evaluable due to sample size is very small and not enough events at later times to estimate the upper bound of the CI.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab Monotherapy
	Comments	Strata are: PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6139
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.19
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm
Description	Median time to deterioration in physical function as measured by the QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm.
Time Frame	Up to approximately 73 months

Outcome Measure Data

Analysis Population Description

The patient reported outcome (PRO)-evaluable population is defined as participants in the ITT populations for comparisons of the Placebo+Chemo Arm versus Atezolizumab+Chemo Arm who have a baseline and at least one post-baseline assessment. The ITT population for the comparison of Atezo+Chemo Arm vs. Placebo+Chemo Arm included participants enrolled in Stage 1 and Stage 2, which consisted of 451 paarticipants in the Atezo+Chemo Arm and 400 participants in the Placebo+Chemo Arm.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
Overall Number of Participants Analyzed	400	451
Median (95% Confidence Interval); Unit of Measure: Months
	15.74; (8.28 to 22.57)	16.39; (9.07 to 26.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
	Comments	Strata are: Enrollment Stage, PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5540
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.32
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm
Description	Median time to deterioration in physical function as measured by the QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab Monotherapy Arm.
Time Frame	Up to approximately 73 months

Outcome Measure Data

Analysis Population Description

Evaluable population defined as patients in ITT for comparisons of Placebo+Chemo vs. Atezo Mono who have a baseline and at least one post-baseline assessment. ITT for comparison of Atezo Mono vs. Placebo+Chemo consisted of 360 patients enrolled in Atezo Mono in Stage 2. Although a total of 400 patients were randomized to Placebo+Chemo throughout study, only 359 patients who were concurrently enrolled into this arm in Stage 2 and prior to Protocol v6 were included in Placebo+Chemo of this ITT.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	359	360
Median (95% Confidence Interval); Unit of Measure: Months
	16.10; (8.08 to 22.57)	9.23; (6.24 to 17.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab Monotherapy
	Comments	Strata are: Enrollment Stage, PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0241
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 1.03 to 1.62
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	Maximum Atezolizumab Serum Concentration
Description	Maximum atezolizumab serum concentration.
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK)-evaluable population is defined as all participants dosed with atezolizumab who have at least one post-baseline PK result.

Arm/Group Title	Atezolizumab+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	394	309
Mean (Standard Deviation); Unit of Measure: μg/ mL
	379 (125)	390 (129)

17. Secondary Outcome

Title	Minimum Atezolizumab Serum Concentration
Description	Minimum atezolizumab serum concentration.
Time Frame	Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 8 Day 1, Cycle 16 Day 1, Cycle 24 Day 1, Cycle 32 Day 1, Day 120 post dose of last blinded atezolizumab treatment, and study drug early discontinuation

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK)-evaluable population is defined as all participants dosed with atezolizumab who have at least one post-baseline PK result.

Arm/Group Title		Atezolizumab+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:		Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed		382	297
Mean (Standard Deviation); Unit of Measure: μg/ mL
Cycle 2 Day 1	Number Analyzed	382 participants	297 participants
		79.8 (52.5)	80.2 (46.0)
Cycle 3 Day 1	Number Analyzed	365 participants	245 participants
		122 (47.2)	129 (66.0)
Cycle 4 Day 1	Number Analyzed	321 participants	183 participants
		153 (70.4)	157 (63.4)
Cycle 8 Day 1	Number Analyzed	194 participants	104 participants
		216 (96.8)	193 (79.8)
Cycle 16 Day 1	Number Analyzed	40 participants	50 participants
		235 (103)	220 (79.8)
Cycle 24 Day 1	Number Analyzed	36 participants	29 participants
		244 (75.7)	233 (92.5)
Cycle 32 Day 1	Number Analyzed	17 participants	9 participants
		259 (97.2)	258 (60.5)
Day 120 Post Dose of Last Blinded Atezo Trt	Number Analyzed	67 participants	64 participants
		18.8 (36.9)	9.53 (12.7)
Study Drug Early Discontinuation	Number Analyzed	194 participants	148 participants
		154 (102)	124 (83.8)

18. Secondary Outcome

Title	Percentage of Participants With Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs)
Description	Percentage of participants with Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs).
Time Frame	Up to approximately 35 months

Outcome Measure Data

Analysis Population Description

The baseline ADA-evaluable population included participants who had a baseline ADA result. The post-baseline ADA-evaluable population included participants who had received at least one dose of the study treatment and who had at least one post-baseline ADA result.

Arm/Group Title		Atezolizumab+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:		Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed		434	341
Measure Type: Number; Unit of Measure: Percentage of participants
Baseline evaluable participants	Number Analyzed	434 participants	341 participants
		1.2	0.9
Post-baseline evaluable participants	Number Analyzed	421 participants	319 participants
		19.7	26.3

19. Secondary Outcome

Title	Investigator-Assessed Progression-Free Survival (INV-PFS) in Participants Treated With Atezolizumab Monotherapy Arm Compared With Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
Description	PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1, or death from any cause, whichever occurs first.
Time Frame	Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (assessed at baseline, every 9 weeks for 54 weeks and every 12 weeks thereafter up to 35 months)

Outcome Measure Data

Analysis Population Description

The ITT population includes only participants concurrently enrolled in Stage 2 and only those who had been randomized at the time of approval of Protocol WO30070 v6.

Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin	Atezolizumab Monotherapy
Arm/Group Description:	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).	Eligible participants received open-label atezolizumab as monotherapy.
Overall Number of Participants Analyzed	359	360
Median (95% Confidence Interval); Unit of Measure: Months
	6.31; (6.24 to 6.74)	2.69; (2.20 to 4.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo+Gemcitabine+Carboplatin/Cisplatin, Atezolizumab Monotherapy
	Comments	Stratification factors: PD-L1 status and Bajorin risk score/presence of liver metastases and investigator choice of chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0000
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; 1.19 to 1.69
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs) Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Description	[Not Specified]
Time Frame	Baseline up to 90 months

Outcome Measure Data Not Reported

Adverse Events

Time Frame	From the first study drug to the data cutoff date: 31 August 2022 (up to approximately 73 months)
Adverse Event Reporting Description	Serious & other adverse events reported based on safety population, which included patients who received any amount of any component of study treatment. There were 6 patients randomized to Atezo monotherapy after approval of Protocol version 6 who received open-label Atezo and chemo, and were pooled with patients in Atezo+chemo for safety analyses. All-cause mortality reported for deaths that occurred during study based on ITT, which included all randomized patients.
Arm/Group Title	Placebo+Gemcitabine+Carboplatin/Cisplatin (Arm C)		Atezolizumab+Gemcitabine+Carboplatin/Cisplatin (Arm A)		Atezolizumab Monotherapy (Arm B)
Arm/Group Description	Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).		Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).		Eligible participants received open-label atezolizumab as monotherapy.
All-Cause Mortality
	Placebo+Gemcitabine+Carboplatin/Cisplatin (Arm C)		Atezolizumab+Gemcitabine+Carboplatin/Cisplatin (Arm A)		Atezolizumab Monotherapy (Arm B)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	298/400 (74.50%)		327/451 (72.51%)		266/362 (73.48%)
Serious Adverse Events
	Placebo+Gemcitabine+Carboplatin/Cisplatin (Arm C)		Atezolizumab+Gemcitabine+Carboplatin/Cisplatin (Arm A)		Atezolizumab Monotherapy (Arm B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	196/389 (50.39%)		243/454 (53.52%)		163/354 (46.05%)
Blood and lymphatic system disorders
Anaemia † 1	19/389 (4.88%)	26	30/454 (6.61%)	34	4/354 (1.13%)	4
Febrile neutropenia † 1	9/389 (2.31%)	9	14/454 (3.08%)	15	0/354 (0.00%)	0
Haematotoxicity † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Leukopenia † 1	0/389 (0.00%)	0	2/454 (0.44%)	3	0/354 (0.00%)	0
Lymph node pain † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	2/354 (0.56%)	2
Myelosuppression † 1	3/389 (0.77%)	7	3/454 (0.66%)	6	0/354 (0.00%)	0
Neutropenia † 1	4/389 (1.03%)	5	8/454 (1.76%)	10	0/354 (0.00%)	0
Pancytopenia † 1	4/389 (1.03%)	4	6/454 (1.32%)	6	0/354 (0.00%)	0
Thrombocytopenia † 1	22/389 (5.66%)	28	21/454 (4.63%)	30	1/354 (0.28%)	1
Thrombocytosis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	1/389 (0.26%)	1	3/454 (0.66%)	3	2/354 (0.56%)	3
Acute myocardial infarction † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Angina unstable † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Arrhythmia † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Atrial fibrillation † 1	1/389 (0.26%)	1	2/454 (0.44%)	2	1/354 (0.28%)	1
Atrioventricular block complete † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Bradycardia † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	0/354 (0.00%)	0
Cardiac arrest † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	1/354 (0.28%)	1
Cardiac failure † 1	0/389 (0.00%)	0	3/454 (0.66%)	3	1/354 (0.28%)	1
Cardiac failure acute † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Cardio-respiratory arrest † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Cardiopulmonary failure † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Left ventricular dysfunction † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Myocardial infarction † 1	2/389 (0.51%)	2	2/454 (0.44%)	2	0/354 (0.00%)	0
Pericardial effusion † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Sinus arrest † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Supraventricular tachycardia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Ventricular fibrillation † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Congenital, familial and genetic disorders
Congenital cystic kidney disease † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Ear and labyrinth disorders
Deafness † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Endocrine disorders
Adrenal insufficiency † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hypophysitis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Hypopituitarism † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Hypothyroidism † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Gastrointestinal disorders
Abdominal hernia † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Abdominal incarcerated hernia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Abdominal pain † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	2/354 (0.56%)	2
Abdominal pain upper † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Autoimmune pancreatitis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Colitis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Constipation † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Diarrhoea † 1	3/389 (0.77%)	3	4/454 (0.88%)	4	3/354 (0.85%)	3
Enterocutaneous fistula † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Enterovesical fistula † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Gastritis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Haematochezia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Haemorrhoids thrombosed † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Hiatus hernia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Ileal ulcer † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Ileus † 1	3/389 (0.77%)	3	1/454 (0.22%)	1	3/354 (0.85%)	3
Intestinal obstruction † 1	3/389 (0.77%)	3	3/454 (0.66%)	3	8/354 (2.26%)	9
Large intestinal obstruction † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Lower gastrointestinal haemorrhage † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Mechanical ileus † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Obstruction gastric † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Pancreatitis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Pancreatitis acute † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Rectal obstruction † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Small intestinal obstruction † 1	1/389 (0.26%)	1	2/454 (0.44%)	2	2/354 (0.56%)	2
Stomatitis † 1	2/389 (0.51%)	2	0/454 (0.00%)	0	0/354 (0.00%)	0
Volvulus † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Vomiting † 1	3/389 (0.77%)	3	5/454 (1.10%)	6	0/354 (0.00%)	0
General disorders
Accidental death † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Asthenia † 1	2/389 (0.51%)	2	4/454 (0.88%)	4	3/354 (0.85%)	3
Chills † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Death † 1	7/389 (1.80%)	7	6/454 (1.32%)	6	2/354 (0.56%)	2
Fatigue † 1	4/389 (1.03%)	4	3/454 (0.66%)	3	2/354 (0.56%)	2
General physical health deterioration † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Malaise † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	0/354 (0.00%)	0
Mucosal inflammation † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Multiple organ dysfunction syndrome † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Oedema peripheral † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Pain † 1	2/389 (0.51%)	2	5/454 (1.10%)	6	4/354 (1.13%)	4
Pyrexia † 1	12/389 (3.08%)	13	18/454 (3.96%)	19	9/354 (2.54%)	10
Sudden cardiac death † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Suprapubic pain † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Systemic inflammatory response syndrome † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hepatobiliary disorders
Autoimmune hepatitis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	2/354 (0.56%)	2
Cholecystitis † 1	1/389 (0.26%)	1	2/454 (0.44%)	2	0/354 (0.00%)	0
Cholecystitis acute † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Cholelithiasis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hepatic failure † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Hepatic function abnormal † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Hepatitis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Hepatitis toxic † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Hyperbilirubinaemia † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Hypertransaminasaemia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Jaundice cholestatic † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Immune system disorders
Anaphylactic reaction † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Anaphylactic shock † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hypersensitivity † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Infections and infestations
Abdominal infection † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Appendicitis † 1	2/389 (0.51%)	2	1/454 (0.22%)	1	0/354 (0.00%)	0
Bacteraemia † 1	1/389 (0.26%)	2	0/454 (0.00%)	0	1/354 (0.28%)	1
Bacterial infection † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	0/354 (0.00%)	0
Bacterial sepsis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Bronchitis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
COVID-19 † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Campylobacter infection † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Cellulitis † 1	0/389 (0.00%)	0	2/454 (0.44%)	3	0/354 (0.00%)	0
Cystitis † 1	1/389 (0.26%)	1	2/454 (0.44%)	2	0/354 (0.00%)	0
Diverticulitis † 1	0/389 (0.00%)	0	1/454 (0.22%)	2	0/354 (0.00%)	0
Emphysematous pyelonephritis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Encephalitis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Endocarditis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Escherichia sepsis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Escherichia urinary tract infection † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Fungal infection † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Gastroenteritis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	2
Gastrointestinal infection † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Infected skin ulcer † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Infection † 1	2/389 (0.51%)	2	2/454 (0.44%)	2	3/354 (0.85%)	3
Influenza † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Kidney infection † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Klebsiella sepsis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Muscle abscess † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Nasopharyngitis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Norovirus infection † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Orchitis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Peritonitis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Pharyngitis streptococcal † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Pneumonia † 1	8/389 (2.06%)	8	21/454 (4.63%)	23	8/354 (2.26%)	8
Pneumonia aspiration † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Pneumonia pneumococcal † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	2/354 (0.56%)	2
Pseudomonal bacteraemia † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Pulmonary sepsis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Pyelonephritis † 1	3/389 (0.77%)	3	1/454 (0.22%)	1	3/354 (0.85%)	3
Pyelonephritis acute † 1	1/389 (0.26%)	1	4/454 (0.88%)	9	1/354 (0.28%)	1
Respiratory tract infection † 1	1/389 (0.26%)	1	3/454 (0.66%)	3	2/354 (0.56%)	2
Sepsis † 1	7/389 (1.80%)	8	7/454 (1.54%)	8	1/354 (0.28%)	1
Septic shock † 1	2/389 (0.51%)	2	2/454 (0.44%)	2	3/354 (0.85%)	3
Skin infection † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Subcutaneous abscess † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Tracheobronchitis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Tuberculosis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Upper respiratory tract infection † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Urinary tract infection † 1	30/389 (7.71%)	42	41/454 (9.03%)	57	22/354 (6.21%)	23
Urinary tract infection bacterial † 1	2/389 (0.51%)	2	1/454 (0.22%)	1	0/354 (0.00%)	0
Urinary tract infection fungal † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Urinary tract infection staphylococcal † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Urosepsis † 1	4/389 (1.03%)	4	3/454 (0.66%)	3	5/354 (1.41%)	5
Vascular device infection † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Viral upper respiratory tract infection † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Injury, poisoning and procedural complications
Fall † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	1/354 (0.28%)	1
Femoral neck fracture † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Femur fracture † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	1/354 (0.28%)	1
Head injury † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hip fracture † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Incisional hernia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Infusion related reaction † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Injury † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Lumbar vertebral fracture † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Multiple fractures † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Postoperative adhesion † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Procedural intestinal perforation † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Road traffic accident † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Stoma prolapse † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Stoma site haemorrhage † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Stoma site pain † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Subdural haematoma † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Tibia fracture † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Toxicity to various agents † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	1/354 (0.28%)	1
Transfusion reaction † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Unintentional medical device removal † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Urinary tract stoma complication † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Urostomy complication † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	1/389 (0.26%)	2	1/454 (0.22%)	1	0/354 (0.00%)	0
Aspartate aminotransferase increased † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Blood alkaline phosphatase increased † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Blood bilirubin increased † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Blood creatinine increased † 1	6/389 (1.54%)	7	3/454 (0.66%)	4	0/354 (0.00%)	0
Liver function test abnormal † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Neutrophil count decreased † 1	7/389 (1.80%)	8	3/454 (0.66%)	3	0/354 (0.00%)	0
Platelet count decreased † 1	12/389 (3.08%)	18	14/454 (3.08%)	23	0/354 (0.00%)	0
Transaminases increased † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Weight decreased † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
White blood cell count decreased † 1	3/389 (0.77%)	4	1/454 (0.22%)	1	0/354 (0.00%)	0
Metabolism and nutrition disorders
Acidosis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Cachexia † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Decreased appetite † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	2/354 (0.56%)	2
Dehydration † 1	2/389 (0.51%)	2	2/454 (0.44%)	2	1/354 (0.28%)	1
Diabetes mellitus † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Diabetic metabolic decompensation † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Hypercalcaemia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	2/354 (0.56%)	3
Hypercreatininaemia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hyperglycaemia † 1	1/389 (0.26%)	1	2/454 (0.44%)	2	1/354 (0.28%)	1
Hyperkalaemia † 1	2/389 (0.51%)	2	0/454 (0.00%)	0	1/354 (0.28%)	1
Hypoglycaemia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Hypokalaemia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hypomagnesaemia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hyponatraemia † 1	2/389 (0.51%)	2	0/454 (0.00%)	0	1/354 (0.28%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Arthritis † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Back pain † 1	3/389 (0.77%)	3	3/454 (0.66%)	3	0/354 (0.00%)	0
Bone pain † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Fistula † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Flank pain † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Groin pain † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Lumbar spinal stenosis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Myositis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Osteoporotic fracture † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Pain in extremity † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Pathological fracture † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	1/354 (0.28%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Lung neoplasm malignant † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Malignant pleural effusion † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Oesophageal carcinoma † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Tumour associated fever † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	2/354 (0.56%)	2
Tumour pain † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Nervous system disorders
Ataxia † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Autoimmune encephalopathy † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Central nervous system haemorrhage † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Cerebral artery embolism † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Cerebral haemorrhage † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Cerebral ischaemia † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Cerebrovascular accident † 1	1/389 (0.26%)	1	2/454 (0.44%)	2	0/354 (0.00%)	0
Demyelination † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Dysaesthesia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Embolic stroke † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Encephalopathy † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	0/354 (0.00%)	0
Haemorrhage intracranial † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Haemorrhagic stroke † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Headache † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Hemianopia † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Intraventricular haemorrhage † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Ischaemic cerebral infarction † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Ischaemic stroke † 1	1/389 (0.26%)	1	3/454 (0.66%)	3	0/354 (0.00%)	0
Lumbosacral radiculopathy † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Migraine † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Miller Fisher syndrome † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Myasthenia gravis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Myasthenic syndrome † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Neuralgia † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Paraparesis † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Presyncope † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	1/354 (0.28%)	1
Seizure † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Spinal cord compression † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Syncope † 1	0/389 (0.00%)	0	3/454 (0.66%)	3	2/354 (0.56%)	2
Transient ischaemic attack † 1	0/389 (0.00%)	0	2/454 (0.44%)	2	0/354 (0.00%)	0
Tremor † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Product Issues
Device dislocation † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Device occlusion † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Psychiatric disorders
Anxiety † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Completed suicide † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Confusional state † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Delirium † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	12/389 (3.08%)	12	15/454 (3.30%)	16	8/354 (2.26%)	8
Anuria † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Autoimmune nephritis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Bladder pain † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Bladder tamponade † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Calculus urinary † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Chronic kidney disease † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Haematuria † 1	10/389 (2.57%)	11	10/454 (2.20%)	11	13/354 (3.67%)	13
Hydronephrosis † 1	3/389 (0.77%)	3	1/454 (0.22%)	1	3/354 (0.85%)	3
Pollakiuria † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Proteinuria † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Renal artery stenosis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Renal disorder † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Renal failure † 1	2/389 (0.51%)	2	3/454 (0.66%)	3	8/354 (2.26%)	8
Renal impairment † 1	1/389 (0.26%)	1	5/454 (1.10%)	5	2/354 (0.56%)	2
Renal injury † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Renal tubular injury † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Tubulointerstitial nephritis † 1	0/389 (0.00%)	0	3/454 (0.66%)	5	1/354 (0.28%)	1
Ureteric obstruction † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Ureterolithiasis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Urinary fistula † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Urinary retention † 1	2/389 (0.51%)	2	5/454 (1.10%)	5	4/354 (1.13%)	5
Urinary tract obstruction † 1	3/389 (0.77%)	3	7/454 (1.54%)	7	2/354 (0.56%)	2
Reproductive system and breast disorders
Prostatitis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Vaginal haemorrhage † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Chronic obstructive pulmonary disease † 1	2/389 (0.51%)	2	2/454 (0.44%)	2	1/354 (0.28%)	1
Dyspnoea † 1	1/389 (0.26%)	1	7/454 (1.54%)	8	5/354 (1.41%)	5
Dyspnoea exertional † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Interstitial lung disease † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	3/354 (0.85%)	3
Oropharyngeal pain † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Pleural effusion † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	2/354 (0.56%)	2
Pleurisy † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Pneumonitis † 1	3/389 (0.77%)	3	7/454 (1.54%)	7	4/354 (1.13%)	5
Pneumothorax † 1	1/389 (0.26%)	1	1/454 (0.22%)	1	0/354 (0.00%)	0
Pulmonary embolism † 1	4/389 (1.03%)	4	7/454 (1.54%)	8	1/354 (0.28%)	1
Pulmonary oedema † 1	2/389 (0.51%)	2	0/454 (0.00%)	0	0/354 (0.00%)	0
Respiratory failure † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Skin and subcutaneous tissue disorders
Dermal cyst † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Dermatomyositis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Pruritus † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Skin necrosis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Surgical and medical procedures
Euthanasia † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Nephrostomy † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Nephrostomy tube removal † 1	2/389 (0.51%)	2	0/454 (0.00%)	0	1/354 (0.28%)	1
Vascular disorders
Deep vein thrombosis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Embolism † 1	2/389 (0.51%)	2	1/454 (0.22%)	1	0/354 (0.00%)	0
Embolism venous † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Hypertension † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Hypovolaemic shock † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	1/354 (0.28%)	1
Jugular vein thrombosis † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
Leriche syndrome † 1	0/389 (0.00%)	0	0/454 (0.00%)	0	1/354 (0.28%)	1
Peripheral venous disease † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Thrombosis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	1/354 (0.28%)	1
Venous thrombosis † 1	1/389 (0.26%)	1	0/454 (0.00%)	0	0/354 (0.00%)	0
Venous thrombosis limb † 1	0/389 (0.00%)	0	1/454 (0.22%)	1	0/354 (0.00%)	0
1 Term from vocabulary, MedDRA version 25.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo+Gemcitabine+Carboplatin/Cisplatin (Arm C)		Atezolizumab+Gemcitabine+Carboplatin/Cisplatin (Arm A)		Atezolizumab Monotherapy (Arm B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	379/389 (97.43%)		441/454 (97.14%)		300/354 (84.75%)
Blood and lymphatic system disorders
Anaemia † 1	257/389 (66.07%)	481	308/454 (67.84%)	488	67/354 (18.93%)	81
Leukopenia † 1	64/389 (16.45%)	192	63/454 (13.88%)	131	0/354 (0.00%)	0
Neutropenia † 1	148/389 (38.05%)	421	215/454 (47.36%)	509	2/354 (0.56%)	2
Thrombocytopenia † 1	117/389 (30.08%)	297	183/454 (40.31%)	378	12/354 (3.39%)	13
Endocrine disorders
Hyperthyroidism † 1	6/389 (1.54%)	6	35/454 (7.71%)	39	18/354 (5.08%)	20
Hypothyroidism † 1	12/389 (3.08%)	12	44/454 (9.69%)	47	30/354 (8.47%)	31
Gastrointestinal disorders
Abdominal pain † 1	37/389 (9.51%)	54	44/454 (9.69%)	54	22/354 (6.21%)	27
Constipation † 1	111/389 (28.53%)	149	140/454 (30.84%)	186	67/354 (18.93%)	74
Diarrhoea † 1	73/389 (18.77%)	96	94/454 (20.70%)	142	42/354 (11.86%)	57
Dyspepsia † 1	22/389 (5.66%)	28	20/454 (4.41%)	21	5/354 (1.41%)	10
Nausea † 1	181/389 (46.53%)	317	202/454 (44.49%)	329	43/354 (12.15%)	53
Vomiting † 1	106/389 (27.25%)	175	122/454 (26.87%)	178	33/354 (9.32%)	41
General disorders
Asthenia † 1	98/389 (25.19%)	156	133/454 (29.30%)	207	51/354 (14.41%)	76
Fatigue † 1	122/389 (31.36%)	182	134/454 (29.52%)	185	64/354 (18.08%)	83
Malaise † 1	24/389 (6.17%)	35	18/454 (3.96%)	34	6/354 (1.69%)	6
Oedema peripheral † 1	56/389 (14.40%)	67	53/454 (11.67%)	68	41/354 (11.58%)	56
Pyrexia † 1	68/389 (17.48%)	113	122/454 (26.87%)	172	43/354 (12.15%)	57
Infections and infestations
Nasopharyngitis † 1	20/389 (5.14%)	25	33/454 (7.27%)	44	18/354 (5.08%)	26
Upper respiratory tract infection † 1	19/389 (4.88%)	26	30/454 (6.61%)	36	18/354 (5.08%)	22
Urinary tract infection † 1	61/389 (15.68%)	91	89/454 (19.60%)	134	58/354 (16.38%)	101
Investigations
Alanine aminotransferase increased † 1	26/389 (6.68%)	32	47/454 (10.35%)	57	24/354 (6.78%)	27
Aspartate aminotransferase increased † 1	17/389 (4.37%)	28	46/454 (10.13%)	61	22/354 (6.21%)	25
Blood alkaline phosphatase increased † 1	10/389 (2.57%)	15	26/454 (5.73%)	33	22/354 (6.21%)	27
Blood creatinine increased † 1	45/389 (11.57%)	64	66/454 (14.54%)	89	28/354 (7.91%)	33
Neutrophil count decreased † 1	129/389 (33.16%)	344	119/454 (26.21%)	331	0/354 (0.00%)	0
Platelet count decreased † 1	138/389 (35.48%)	331	132/454 (29.07%)	350	5/354 (1.41%)	7
Weight decreased † 1	25/389 (6.43%)	25	30/454 (6.61%)	35	23/354 (6.50%)	23
White blood cell count decreased † 1	59/389 (15.17%)	166	62/454 (13.66%)	144	1/354 (0.28%)	1
Metabolism and nutrition disorders
Decreased appetite † 1	119/389 (30.59%)	165	143/454 (31.50%)	212	69/354 (19.49%)	72
Hyperglycaemia † 1	12/389 (3.08%)	21	26/454 (5.73%)	30	14/354 (3.95%)	33
Hyperkalaemia † 1	29/389 (7.46%)	39	24/454 (5.29%)	39	13/354 (3.67%)	17
Hypoalbuminaemia † 1	15/389 (3.86%)	24	21/454 (4.63%)	27	19/354 (5.37%)	20
Hypomagnesaemia † 1	22/389 (5.66%)	27	26/454 (5.73%)	31	8/354 (2.26%)	11
Hyponatraemia † 1	16/389 (4.11%)	21	30/454 (6.61%)	37	9/354 (2.54%)	10
Musculoskeletal and connective tissue disorders
Arthralgia † 1	44/389 (11.31%)	56	57/454 (12.56%)	79	39/354 (11.02%)	55
Back pain † 1	45/389 (11.57%)	56	56/454 (12.33%)	66	33/354 (9.32%)	39
Myalgia † 1	23/389 (5.91%)	35	27/454 (5.95%)	29	23/354 (6.50%)	30
Pain in extremity † 1	30/389 (7.71%)	37	35/454 (7.71%)	43	21/354 (5.93%)	24
Nervous system disorders
Dizziness † 1	39/389 (10.03%)	51	45/454 (9.91%)	59	18/354 (5.08%)	19
Headache † 1	34/389 (8.74%)	43	42/454 (9.25%)	65	24/354 (6.78%)	35
Neuropathy peripheral † 1	23/389 (5.91%)	25	17/454 (3.74%)	19	6/354 (1.69%)	8
Psychiatric disorders
Insomnia † 1	34/389 (8.74%)	37	36/454 (7.93%)	39	19/354 (5.37%)	20
Renal and urinary disorders
Dysuria † 1	20/389 (5.14%)	26	29/454 (6.39%)	41	20/354 (5.65%)	23
Haematuria † 1	51/389 (13.11%)	65	73/454 (16.08%)	102	47/354 (13.28%)	55
Respiratory, thoracic and mediastinal disorders
Cough † 1	38/389 (9.77%)	46	58/454 (12.78%)	67	30/354 (8.47%)	49
Dyspnoea † 1	33/389 (8.48%)	43	43/454 (9.47%)	54	25/354 (7.06%)	28
Skin and subcutaneous tissue disorders
Alopecia † 1	49/389 (12.60%)	50	33/454 (7.27%)	35	2/354 (0.56%)	2
Pruritus † 1	33/389 (8.48%)	38	84/454 (18.50%)	122	41/354 (11.58%)	65
Rash † 1	43/389 (11.05%)	52	91/454 (20.04%)	117	27/354 (7.63%)	32
Vascular disorders
Hypertension † 1	31/389 (7.97%)	41	45/454 (9.91%)	62	21/354 (5.93%)	26
1 Term from vocabulary, MedDRA version 25.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800-821-8590
• EMail: genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Galsky MD, Arija JAA, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Ozguroglu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thastrom A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. doi: 10.1016/S0140-6736(20)30230-0.

Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Duran I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thastrom A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. doi: 10.1016/S0140-6736(16)32455-2. Epub 2016 Dec 8. Erratum In: Lancet. 2017 Aug 26;390(10097):848.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02807636
• Other Study ID Numbers: WO30070; 2016-000250-35 ( EudraCT Number )
• First Submitted: June 17, 2016
• First Posted: June 21, 2016
• Results First Submitted: August 22, 2023
• Results First Posted: December 13, 2023
• Last Update Posted: April 29, 2024