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Clinical Trial Results:
A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer

Summary
EudraCT number	2014-003206-32
Trial protocol	DE BE IT FR ES
Global end of trial date	18 Jan 2021

Results information
Results version number	v3(current)
This version publication date	04 Aug 2021
First version publication date	29 Mar 2019
Other versions	v1 , v2
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GO29537

ISRCTN number

US NCT number

NCT02367781

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Jul 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Jan 2021

Was the trial ended prematurely?

Main objective of the trial

This randomized Phase III, multicenter, open-label study was designed to evaluate the safety and efficacy of atezolizumab (an engineered anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin+nab-paclitaxel compared with treatment with carboplatin+nab-paclitaxel in chemotherapy-naive subjects with Stage IV non-squamous NSCLC.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Apr 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

57 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 21

Country: Number of subjects enrolled

Germany: 132

Country: Number of subjects enrolled

Spain: 71

Country: Number of subjects enrolled

France: 45

Country: Number of subjects enrolled

Italy: 52

Country: Number of subjects enrolled

Canada: 52

Country: Number of subjects enrolled

United States: 315

Country: Number of subjects enrolled

Israel: 35

Worldwide total number of subjects

723

EEA total number of subjects

321

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

362

From 65 to 84 years

358

85 years and over

Subject disposition

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Recruitment details

At the time of study completion a few participants that were still on maintenance treatment with atezolizumab were moved to another study, Post-Trial Access Program, or commercial use. Therefore, the reason for discontinuation was entered "Study terminated by Sponsor" for these participants.

Screening details

Participants in this study included: histologically or cytologically confirmed, Stage IV non-squamous NSCLC; and no prior treatment for Stage IV non-squamous NSCLC.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Arm description

Participants received intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurred first during induction treatment phase. Participants received IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit.

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq, MPDL3280A, RO5541267

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab was administered as IV infusion at a dose of 1200 milligrams (mg) on Day 1 of each 21day cycle.

Investigational medicinal product name

Nab-Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nab-paclitaxel was administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin was administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.

Arm B (Nab-Paclitaxel+Carboplatin)

Arm description

Participants received IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurs first during induction treatment phase. Participants received best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. Participants who were consented prior to approval of protocol Version 5 were given the option to cross over to receive atezolizumab as monotherapy until disease progression.

Arm type

Active comparator

Investigational medicinal product name

Nab-Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nab-paclitaxel was administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin was administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Switch maintenance to pemetrexed can be administered within 6 weeks of Day 1 of the last induction cycle.

Number of subjects in period 1	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Started	483	240
Completed	0	0
Not completed	483	240
Adverse event, serious fatal	330	176
Physician decision	7	-
Immunotherapy Paused, Continuing Follow-Up Planned	1	-
Patient Admitted to Hospital	1	-
Patient Moving to Roll-Over Study	17	5
Study Terminated by Sponsor	3	1
Administrative-Change Facility	1	-
Death Prior First Dose	1	-
Prolonged Hospitalization	1	-
Consent withdrawn by subject	20	13
Non-Compliance	1	-
Sponsor Withdraw Patient in Survival Follow-Up	78	29
Sponsor Decision	2	-
Lost to follow-up	1	2
Patient Moved to Commercial Atezolizumab Use	14	9
Randomized in Error	5	4
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Reporting group description

Reporting group title

Arm B (Nab-Paclitaxel+Carboplatin)

Reporting group description

Reporting group values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)	Total
Number of subjects	483	240	723
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	245	117	362
From 65-84 years	236	122	358
85 years and over	2	1	3
Age Continuous
Units: Years
arithmetic mean (standard deviation)	63.8 ± 9.5	64.4 ± 8.9	-
Sex: Female, Male
Units: Participants
Female	206	102	308
Male	277	138	415
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	14	3	17
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	18	8	26
White	428	222	650
More than one race	2	0	2
Unknown or Not Reported	21	7	28
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	25	12	37
Not Hispanic or Latino	426	213	639
Unknown or Not Reported	32	15	47

End points

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Reporting group title

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Reporting group description

Reporting group title

Arm B (Nab-Paclitaxel+Carboplatin)

Reporting group description

Subject analysis set title

Arm B (Nab-Paclitaxel+Carboplatin Crossover)

Subject analysis set type

Per protocol

Subject analysis set description

Participants received IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurred first during induction treatment phase. Participants received best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. Participants who were consented prior to approval of protocol Version 5 were given the option to cross over to receive atezolizumab as monotherapy until disease progression.

Primary: Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

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End point title

Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

End point description

End point type

Primary

End point timeframe

Up to approximately 35 months after first patient enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	456	229
Units: Months
median (confidence interval 95%)	7.0 (6.3 to 7.3)	5.5 (4.4 to 5.9)

PFS in ITT WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

685

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.639

Confidence interval

level

95%

sides

2-sided

lower limit

0.536

upper limit

0.763

Notes
[1] - Stratified Analysis

Primary: Overall Survival (OS) in the ITT-WT Population

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End point title

Overall Survival (OS) in the ITT-WT Population

End point description

OS is defined as the time between the date of randomization and date of death from any cause in the ITT−WT population.

End point type

Primary

End point timeframe

Up to approximately 35 months after first patient enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	456	229
Units: Months
median (confidence interval 95%)	18.6 (15.8 to 21.2)	13.9 (12.0 to 18.7)

OS in ITT-WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

685

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.0298

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.788

Confidence interval

level

95%

sides

2-sided

lower limit

0.636

upper limit

0.977

Notes
[2] - Stratified Analysis

Secondary: PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

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End point title

PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

End point description

PFS is defined as the time between the date of randomization and the date of first documented disease progression as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurs first. The ITT population was defined as all randomized participants, regardless of receipt of the assigned treatment. The PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. The PD-L1 expression WT population is defined as the PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation.

End point type

Secondary

End point timeframe

Up to approximately 35 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	483	240
Units: Months
median (confidence interval 95%)
ITT (n=483, n=240)	7.0 (6.3 to 7.3)	5.6 (4.5 to 5.9)
TC1/2/3 or IC1/2/3 ITT (n=230, n=111)	7.5 (7.0 to 9.1)	5.7 (4.5 to 6.6)
TC1/2/3 or IC1/2/3-WT ITT (n=216, n=107)	7.5 (7.0 to 9.0)	5.9 (4.5 to 6.6)

PFS in ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.647

Confidence interval

level

95%

sides

2-sided

lower limit

0.545

upper limit

0.768

Notes
[3] - Stratified Analysis

PFS in TC1/2/3 or IC1/2/3-WT ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.561

Confidence interval

level

95%

sides

2-sided

lower limit

0.432

upper limit

0.728

Notes
[4] - Unstratified Analysis

PFS in TC1/2/3 or IC1/2/3 ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.549

Confidence interval

level

95%

sides

2-sided

lower limit

0.425

upper limit

0.708

Notes
[5] - Unstratified Analysis

Secondary: OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

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End point title

OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

End point description

OS is defined as the time between the date of randomization and date of death from any cause in the ITT population.

End point type

Secondary

End point timeframe

Up to approximately 41 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	483	240
Units: Months
median (confidence interval 95%)	17.0 (14.9 to 19.7)	13.5 (11.9 to 17.7)

OS in ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.0732

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.837

Confidence interval

level

95%

sides

2-sided

lower limit

0.689

upper limit

1.017

Notes
[6] - Stratified Analysis

Secondary: OS as Determined by the Investigator Using RECIST v1.1 in the PD-L1 Expression Population and PD-L1 Expression WT Population

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End point title

OS as Determined by the Investigator Using RECIST v1.1 in the PD-L1 Expression Population and PD-L1 Expression WT Population

End point description

OS is defined as the time between the date of randomization and date of death from any cause in the PD-L1 Expression Population and PD-L1 Expression WT Population. The PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. The PD-L1 expression WT population is defined as the PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation.

End point type

Secondary

End point timeframe

Up to approximately 35 months after first patient enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	230	111
Units: Months
median (confidence interval 95%)
TC1/2/3 or IC1/2/3 ITT (n=230, n=111)	21.2 (17.3 to 28.2)	16.9 (12.5 to 22.0)
TC1/2/3 or IC1/2/3 WT ITT (n=216, n=107)	21.2 (18.1 to 28.2)	16.9 (12.5 to 22.0)

OS in TC1/2/3 or IC1/2/3 ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

341

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.083

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.752

Confidence interval

level

95%

sides

2-sided

lower limit

0.545

upper limit

1.039

Notes
[7] - Unstratified Analysis

OS in TC1/2/3 or IC1/2/3 WT ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

341

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.0813

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.746

Confidence interval

level

95%

sides

2-sided

lower limit

0.536

upper limit

1.038

Notes
[8] - Unstratified Analysis

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

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End point title

Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

End point description

ORR (confirmation not required) is defined as the proportion of participants with an objective response, either CR or PR, with the use of RECIST v1.1, as determined by the investigator in the ITT-WT population.

End point type

Secondary

End point timeframe

Up to approximately 41 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	452	227
Units: Percentage of participants
number (not applicable)	60.2	41.0

OR in ITT WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

679

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rate

Point estimate

19.21

Confidence interval

level

95%

sides

2-sided

lower limit

11.05

upper limit

27.37

Notes
[9] - Stratified Analysis

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

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End point title

Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

End point description

ORR (confirmation not required) is defined as proportion of participants with an objective response, either CR or PR, with the use of RECIST v1.1, as determined by investigator in ITT population, PD-L1 Expression population, and PD-L1 Expression WT population. ITT population was defined as all randomized participants, regardless of receipt of the assigned treatment. PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. PD-L1 expression WT population is defined as PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation.

End point type

Secondary

End point timeframe

Up to approximately 35 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	479	237
Units: Percentage of participants
number (not applicable)
ITT (n=479, n=237)	59.1	42.2
TC1/2/3 or IC1/2/3 ITT WT (n=215, n=106)	65.6	46.2
TC1/2/3 or IC1/2/3 ITT (n=229, n=109)	64.6	45.0

OR in ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

716

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rate

Point estimate

16.89

Confidence interval

level

95%

sides

2-sided

lower limit

8.9

upper limit

24.88

Notes
[10] - Stratified Analysis

OR in TC1/2/3 or IC1/2/3 ITT WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

716

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

Method

Parameter type

Odds ratio (OR)

Point estimate

2.22

Confidence interval

level

95%

sides

2-sided

lower limit

1.38

upper limit

3.56

Notes
[11] - Stratified Analysis

OR in TC1/2/3 or IC1/2/3 ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

716

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.0007

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

2.21

Confidence interval

level

95%

sides

2-sided

lower limit

1.39

upper limit

3.51

Notes
[12] - Stratified Analysis

Secondary: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population, ITT Population, and PD-L1 Expression Population and PD-L1 Expression WT Population

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End point title

Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population, ITT Population, and PD-L1 Expression Population and PD-L1 Expression WT Population

End point description

DOR,defined for participants with objective response (OR) as time from 1st documented OR to documented disease progression as determined by investigator using RECIST v1.1,or death from any cause,whichever occurs 1st.ITT defined as all randomized participants,regardless of receipt of assigned treatment.ITT-WT defined as ITT population excluding participants with activating EGFR mutation or ALK translocation.PD-L1 expression population is defined as one of following:PD-L1 IHC TC1/2/3 or IC1/2/3 population,defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue;PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue;PD-L1 IHC TC3 or IC3 population,defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue.PD-L1 expression WT is defined as PD-L1 expression population excluding participants with activating EGFR mutation or ALK translocation.

End point type

Secondary

End point timeframe

Up to approximately 35 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	283	100
Units: Months
median (confidence interval 95%)
ITT (n=283, n=100)	6.2 (5.6 to 7.9)	5.4 (4.1 to 5.8)
ITT-WT (n=267, n=93)	6.7 (5.6 to 8.0)	5.4 (3.9 to 5.8)
TC1/2/3 or IC1/2/3 ITT (n=148, n=49)	7.2 (5.7 to 9.0)	5.0 (3.2 to 6.1)
TC1/2/3 or IC1/2/3 ITT WT (n=141, n=49)	7.2 (5.7 to 9.0)	5.0 (3.2 to 6.1)

DOR in ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.0002

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.614

Confidence interval

level

95%

sides

2-sided

lower limit

0.473

upper limit

0.797

Notes
[13] - Unstratified Analysis

DOR in ITT-WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.0002

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.458

upper limit

0.785

Notes
[14] - Unstratified Analysis

DOR in TC1/2/3 or IC1/2/3 ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.0011

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.548

Confidence interval

level

95%

sides

2-sided

lower limit

0.379

upper limit

0.791

Notes
[15] - Unstratified Analysis

DOR in TC1/2/3 or IC1/2/3 ITT WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

= 0.0014

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.551

Confidence interval

level

95%

sides

2-sided

lower limit

0.381

upper limit

0.798

Notes
[16] - Unstratified Analysis

Secondary: Event Free Rate (%) at Year 1 and 2 in ITT-WT Population and ITT Population

Top of page

End point title

Event Free Rate (%) at Year 1 and 2 in ITT-WT Population and ITT Population

End point description

The OS rate at the 1- and 2-year landmark time points after randomization.

End point type

Secondary

End point timeframe

Up to 41 months after first patient enrolled, years 1 and 2 reported

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	483	240
Units: Percentage of participants
number (confidence interval 95%)
Alive at Year 1 ITT WT	62.02 (57.53 to 66.51)	54.56 (48.04 to 61.08)
Alive at Year 2 ITT WT	40.43 (35.64 to 45.22)	32.36 (25.80 to 38.92)
Alive at Year 1 ITT	61.65 (57.29 to 66.02)	54.47 (48.09 to 60.84)
Alive at Year 2 ITT	39.73 (35.10 to 44.37)	32.21 (25.79 to 38.63)

Alive at Year 1 ITT WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0647

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

7.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

15.37

Alive at Year 2 ITT WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0516

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

8.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

16.19

Alive at Year 1 ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0683

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

7.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

14.91

Alive at Year 2 ITT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

723

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0625

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

7.53

Confidence interval

level

95%

sides

2-sided

lower limit

-0.39

upper limit

15.44

Secondary: Event Free Rate (%) at Year 1 and 2 in PD-L1 Expression Population and PD-L1 Expression WT Population

Top of page

End point title

Event Free Rate (%) at Year 1 and 2 in PD-L1 Expression Population and PD-L1 Expression WT Population

End point description

The OS rate at the 1- and 2-year landmark time points after randomization in the PD-L1 Expression Population and PD-L1 Expression WT Population. The PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. The PD-L1 expression WT population is defined as the PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation.

End point type

Secondary

End point timeframe

Up to 35 months after first patient enrolled, years 1 and 2 reported

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	230	111
Units: Percentage of participants
number (confidence interval 95%)
Year 1 TC1/2/3 or IC1/2/3 ITT (n=230, n=111)	68.56 (62.46 to 74.66)	61.86 (52.55 to 71.17)
Year 2 TC1/2/3 or IC1/2/3 ITT(n=230, n=111)	44.63 (35.99 to 53.27)	35.98 (23.25 to 48.72)
Year 1 TC1/2/3 or IC1/2/3 ITT WT (n=216, n=107)	68.84 (62.56 to 75.13)	62.51 (53.07 to 71.94)
Year 2 TC1/2/3 or IC1/2/3 ITT WT (n=216, n=107)	44.02 (34.86 to 53.18)	35.33 (22.06 to 48.60)

Alive at Year 1 TC1/2/3 or IC1/2/3 ITT

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

341

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2385

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

6.69

Confidence interval

level

95%

sides

2-sided

lower limit

-4.44

upper limit

17.83

Alive at Year 2 TC1/2/3 or IC1/2/3 ITT

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

341

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.271

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

8.64

Confidence interval

level

95%

sides

2-sided

lower limit

-6.75

upper limit

24.03

Alive at Year 1 TC1/2/3 or IC1/2/3 ITT WT

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

341

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2733

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

6.34

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

17.67

Alive at Year 2 TC1/2/3 or IC1/2/3 ITT WT

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

341

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2909

Method

Z-test

Parameter type

Difference in Event Free Rate

Point estimate

8.69

Confidence interval

level

95%

sides

2-sided

lower limit

-7.44

upper limit

24.81

Secondary: Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

Top of page

End point title

Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

End point description

Defined as time from randomization to confirmed deterioration (10-point change) on the combined European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire−Core (EORTC QLQ-C30) and supplemental lung cancer module (EORTC QLQ-LC13) symptom subscales.

End point type

Secondary

End point timeframe

Up to approximately 35 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	451	228
Units: Months
median (confidence interval 95%)	2.2 (1.8 to 3.1)	1.9 (1.5 to 2.4)

TTD in ITT WT Population

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

679

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.3342

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.893

Confidence interval

level

95%

sides

2-sided

lower limit

0.711

upper limit

1.123

Notes
[17] - Stratified Analysis

Secondary: Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

Top of page

End point title

Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

End point description

Change from baseline per SILC scale will be analyzed for each lung cancer symptoms scores. SILC questionnaire comprises 3 individual symptoms & are scored at individual symptom level, thus have a dyspnea score, chest pain score, & cough score. There are a total of 9 questions in SILC questionnaire, each question has a minimum value of 0 & maximum value of 4. Each individual symptom score is calculated as average of responses for symptom items. 'Chest pain' score is mean of question 1 & 2, 'Cough' score is mean of question 3 & 4 and ‘Dyspnea’ score is mean of question 5 to 9 in SILC questionnaire. An increase in score is suggestive of a worsening in symptomology. A score change of ≥0.3 points for dyspnea & cough symptom scores is considered to be clinically significant; whereas a score change of≥0.5 points for chest pain score is considered to be clinically significant. Note: 999999=not available. FU=Follow-Up

End point type

Secondary

End point timeframe

Up to approximately 35 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	236	129
Units: Units on a scale
arithmetic mean (standard deviation)
Chest Pain, Week 1 (n=203,n=114)	0.19 ± 0.86	0.14 ± 0.90
Chest Pain, Week 2 (n=204,n=108)	-0.02 ± 0.89	0.03 ± 0.91
Chest Pain, Week 3 (n=197,n=106)	-0.05 ± 0.95	0.01 ± 0.92
Chest Pain, Week 4 (n=190,n=102)	-0.11 ± 0.95	0.01 ± 1.02
Chest Pain, Week 5 (n=192,n=97)	-0.12 ± 0.99	0.00 ± 1.03
Chest Pain, Week 6 (n=182,n=98)	-0.24 ± 1.07	0.03 ± 1.03
Chest Pain, Week 7 (n=176,n=87)	-0.23 ± 1.11	0.03 ± 1.08
Chest Pain, Week 8 (n=169,n=80)	-0.21 ± 0.99	-0.14 ± 1.00
Chest Pain, Week 9 (n=172,n=80)	-0.18 ± 1.07	-0.01 ± 1.07
Chest Pain, Week 10 (n=160,n=75)	-0.10 ± 1.07	-0.07 ± 1.01
Chest Pain, Week 11 (n=171,n=78)	-0.11 ± 1.14	0.01 ± 0.96
Chest Pain, Week 12 (n=160,n=72)	-0.15 ± 1.09	-0.10 ± 1.13
Chest Pain, Week 13 (n=151,n=61)	-0.26 ± 1.07	-0.03 ± 1.02
Chest Pain, Week 14 (n=144,n=62)	-0.28 ± 1.08	-0.17 ± 1.18
Chest Pain, Week 15 (n=143,n=51)	-0.26 ± 1.14	-0.19 ± 1.19
Chest Pain, Week 16 (n=139,n=52)	-0.33 ± 1.11	-0.16 ± 1.20
Chest Pain, Week 17 (n=145,n=53)	-0.33 ± 1.11	-0.14 ± 1.13
Chest Pain, Week 18 (n=136,n=49)	-0.28 ± 1.08	-0.17 ± 1.13
Chest Pain, Week 19 (n=124,n=45)	-0.28 ± 1.04	-0.16 ± 1.00
Chest Pain, Week 20 (n=123,n=43)	-0.26 ± 1.03	-0.22 ± 1.02
Chest Pain, Week 21 (n=126,n=41)	-0.25 ± 1.04	-0.32 ± 1.08
Chest Pain, Week 22 (n=116,n=37)	-0.28 ± 1.01	-0.11 ± 1.03
Chest Pain, Week 23 (n=122,n=35)	-0.24 ± 1.03	-0.19 ± 1.04
Chest Pain, Week 24 (n=110,n=34)	-0.21 ± 1.01	-0.43 ± 1.03
Chest Pain, Week 25 (n=104,n=31)	-0.20 ± 0.98	-0.24 ± 1.07
Chest Pain, Week 26 (n=109,n=31)	-0.17 ± 1.01	-0.13 ± 0.91
Chest Pain, Week 27 (n=102,n=27)	-0.22 ± 1.01	-0.15 ± 1.17
Chest Pain, Week 28 (n=96,n=28)	-0.20 ± 0.98	-0.07 ± 0.91
Chest Pain, Week 29 (n=104,n=27)	-0.27 ± 1.09	-0.04 ± 0.92
Chest Pain, Week 30 (n=100,n=23)	-0.15 ± 1.06	-0.28 ± 1.12
Chest Pain, Week 31 (n=93,n=25)	-0.16 ± 0.95	-0.12 ± 1.05
Chest Pain, Week 32 (n=88,n=25)	-0.19 ± 0.89	-0.30 ± 1.10
Chest Pain, Week 33 (n=88,n=25)	-0.18 ± 1.00	-0.18 ± 1.11
Chest Pain, Week 34 (n=85,n=24)	-0.18 ± 1.07	-0.17 ± 1.18
Chest Pain, Week 35 (n=87,n=20)	-0.10 ± 1.09	0.05 ± 1.06
Chest Pain, Week 36 (n=85,n=20)	-0.21 ± 1.08	-0.35 ± 1.01
Chest Pain, Week 37 (n=82,n=21)	-0.18 ± 1.18	-0.10 ± 1.04
Chest Pain, Week 38 (n=83,n=19)	-0.32 ± 1.02	-0.05 ± 1.01
Chest Pain, Week 39 (n=78,n=18)	-0.28 ± 0.90	-0.22 ± 1.06
Chest Pain, Week 40 (n=76,n=14)	-0.19 ± 0.87	-0.39 ± 0.81
Chest Pain, Week 41 (n=77,n=16)	-0.25 ± 0.93	-0.19 ± 0.89
Chest Pain, Week 42 (n=70,n=16)	-0.16 ± 1.02	-0.41 ± 0.74
Chest Pain, Week 43 (n=68,n=16)	-0.24 ± 0.90	-0.22 ± 0.95
Chest Pain, Week 44 (n=76,n=16)	-0.24 ± 0.95	0.00 ± 0.98
Chest Pain, Week 45 (n=69,n=14)	-0.14 ± 0.95	-0.07 ± 0.78
Chest Pain, Week 46 (n=71,n=15)	-0.15 ± 0.94	-0.07 ± 1.03
Chest Pain, Week 47 (n=70,n=13)	-0.22 ± 0.98	-0.15 ± 0.90
Chest Pain, Week 48 (n=66,n=11)	-0.14 ± 0.91	-0.18 ± 0.98
Chest Pain, Week 49 (n=65,n=9)	-0.22 ± 0.91	-0.72 ± 0.75
Chest Pain, Week 50 (n=70,n=8)	-0.18 ± 0.91	-0.19 ± 0.70
Chest Pain, Week 51 (n=65,n=10)	-0.13 ± 0.71	-0.50 ± 0.78
Chest Pain, Week 52 (n=72,n=7)	-0.15 ± 0.83	-0.36 ± 0.63
Chest Pain, Week 53 (n=64,n=6)	-0.20 ± 0.82	-0.33 ± 0.61
Chest Pain, Week 54 (n=65,n=7)	-0.22 ± 0.87	-0.21 ± 0.70
Chest Pain, Week 55 (n=62,n=5)	-0.34 ± 0.80	-0.30 ± 0.76
Chest Pain, Week 56 (n=62,n=6)	-0.19 ± 0.95	-0.33 ± 0.68
Chest Pain, Week 57 (n=62,n=5)	-0.19 ± 0.76	-0.40 ± 0.65
Chest Pain, Week 58 (n=56,n=4)	-0.32 ± 0.92	-0.50 ± 1.15
Chest Pain, Week 59 (n=52,n=4)	-0.25 ± 0.93	-0.63 ± 0.75
Chest Pain, Week 60 (n=48,n=4)	-0.27 ± 1.03	-0.50 ± 1.08
Chest Pain, Week 61 (n=49,n=5)	-0.28 ± 1.02	-0.20 ± 1.15
Chest Pain, Week 62 (n=41,n=5)	-0.16 ± 1.06	-0.40 ± 1.47
Chest Pain, Week 63 (n=43,n=5)	-0.12 ± 0.82	-0.10 ± 1.34
Chest Pain, Week 64 (n=42,n=4)	-0.15 ± 0.83	0.38 ± 1.44
Chest Pain, Week 65 (n=40,n=3)	-0.31 ± 0.84	0.17 ± 1.76
Chest Pain, Week 66 (n=38,n=4)	-0.25 ± 0.92	0.25 ± 1.19
Chest Pain, Week 67 (n=33,n=4)	-0.18 ± 0.86	0.13 ± 1.44
Chest Pain, Week 68 (n=34,n=4)	-0.15 ± 0.93	-0.25 ± 1.55
Chest Pain, Week 69 (n=35,n=3)	-0.13 ± 0.83	-0.17 ± 1.89
Chest Pain, Week 70 (n=36,n=3)	-0.14 ± 0.93	0.00 ± 1.80
Chest Pain, Week 71 (n=31,n=3)	-0.10 ± 0.88	0.00 ± 0.87
Chest Pain, Week 72 (n=29,n=2)	-0.24 ± 0.85	-1.00 ± 0.71
Chest Pain, Week 73 (n=28,n=1)	-0.25 ± 1.02	-1.50 ± 999999
Chest Pain, Week 74 (n=31,n=1)	-0.08 ± 0.93	-1.50 ± 999999
Chest Pain, Week 75 (n=31,n=1)	-0.21 ± 0.98	-1.50 ± 999999
Chest Pain, Week 76 (n=29,n=1)	0.03 ± 1.00	-1.50 ± 999999
Chest Pain, Week 77 (n=26,n=2)	-0.06 ± 0.89	-1.50 ± 0.00
Chest Pain, Week 78 (n=23,n=1)	-0.04 ± 0.84	-1.50 ± 999999
Chest Pain, Week 79 (n=19,n=1)	-0.11 ± 1.09	-0.50 ± 999999
Chest Pain, Week 80 (n=20,n=1)	-0.18 ± 1.05	-1.50 ± 999999
Chest Pain, Week 81 (n=17,n=1)	-0.59 ± 0.96	-1.50 ± 999999
Chest Pain, Week 82 (n=18,n=1)	-0.39 ± 0.96	-1.50 ± 999999
Chest Pain, Week 83 (n=22,n=1)	-0.34 ± 0.90	-1.50 ± 999999
Chest Pain, Week 84 (n=20,n=1)	-0.20 ± 0.75	-1.50 ± 999999
Chest Pain, Week 85 (n=17,n=1)	-0.44 ± 0.97	-1.50 ± 999999
Chest Pain, Week 86 (n=12,n=1)	-0.38 ± 0.64	-1.50 ± 999999
Chest Pain, Week 87 (n=15,n=1)	-0.53 ± 1.01	-1.50 ± 999999
Chest Pain, Week 88 (n=14,n=1)	-0.46 ± 1.06	-1.50 ± 999999
Chest Pain, Week 89 (n=11,n=1)	-0.55 ± 0.96	-1.50 ± 999999
Chest Pain, Week 90 (n=14,n=1)	-0.18 ± 0.85	-1.50 ± 999999
Chest Pain, Week 91 (n=11,n=1)	-0.32 ± 1.08	-1.50 ± 999999
Chest Pain, Week 92 (n=10,n=1)	-0.40 ± 0.66	-1.50 ± 999999
Chest Pain, Week 93 (n=11,n=1)	-0.18 ± 1.08	-1.50 ± 999999
Chest Pain, Week 94 (n=10,n=1)	-0.30 ± 1.09	999999 ± 999999
Chest Pain, Week 95 (n=10,n=0)	-0.05 ± 1.26	999999 ± 999999
Chest Pain, Week 96 (n=9,n=0)	-0.17 ± 1.25	999999 ± 999999
Chest Pain, Week 97 (n=8,n=0)	-0.19 ± 1.31	999999 ± 999999
Chest Pain, Week 98 (n=10,n=0)	-0.25 ± 1.16	999999 ± 999999
Chest Pain, Week 99 (n=7,n=0)	-0.21 ± 1.47	999999 ± 999999
Chest Pain, Week 100 (n=6,n=0)	-0.50 ± 1.38	999999 ± 999999
Chest Pain, Week 101 (n=7,n=0)	-0.36 ± 1.38	999999 ± 999999
Chest Pain, Week 102 (n=4,n=0)	-0.75 ± 1.71	999999 ± 999999
Chest Pain, Week 103 (n=6,n=0)	-0.33 ± 1.54	999999 ± 999999
Chest Pain, Week 104 (n=5,n=0)	-0.60 ± 1.39	999999 ± 999999
Chest Pain, Week 105 (n=4,n=0)	-1.00 ± 1.41	999999 ± 999999
Chest Pain, Week 106 (n=4,n=0)	-1.00 ± 1.41	999999 ± 999999
Chest Pain, Week 107 (n=4,n=0)	-1.00 ± 1.41	999999 ± 999999
Chest Pain, Week 108 (n=4,n=0)	-0.75 ± 1.50	999999 ± 999999
Chest Pain, Week 109 (n=5,n=0)	-0.60 ± 1.52	999999 ± 999999
Chest Pain, Week 110 (n=6,n=0)	-0.42 ± 1.43	999999 ± 999999
Chest Pain, Week 111 (n=5,n=0)	-0.50 ± 1.50	999999 ± 999999
Chest Pain, Week 112 (n=4,n=0)	-0.13 ± 0.63	999999 ± 999999
Chest Pain, Week 113 (n=4,n=0)	0.13 ± 0.63	999999 ± 999999
Chest Pain, Week 114 (n=3,n=0)	0.00 ± 1.00	999999 ± 999999
Chest Pain, Week 115 (n=2,n=0)	0.25 ± 0.35	999999 ± 999999
Chest Pain, Week 116 (n=2,n=0)	0.50 ± 0.71	999999 ± 999999
Chest Pain, Week 117 (n=2,n=0)	0.25 ± 1.06	999999 ± 999999
Chest Pain, Week 118 (n=2,n=0)	-0.25 ± 1.06	999999 ± 999999
Chest Pain, Week 119 (n=2,n=0)	-0.25 ± 0.35	999999 ± 999999
Chest Pain, Week 120 (n=2,n=0)	0.00 ± 0.71	999999 ± 999999
Chest Pain, Week 121 (n=2,n=0)	0.00 ± 1.41	999999 ± 999999
Chest Pain, Week 122 (n=2,n=0)	0.00 ± 1.41	999999 ± 999999
Chest Pain, Week 123 (n=2,n=0)	-0.75 ± 1.77	999999 ± 999999
Chest Pain, Week 124 (n=1,n=0)	0.50 ± 999999	999999 ± 999999
Chest Pain, Week 125 (n=1,n=0)	0.50 ± 999999	999999 ± 999999
Chest Pain, Survival FU Month 1 (n=158, n=58)	0.01 ± 1.13	0.22 ± 0.87
Chest Pain, Survival FU Month 2 (n=42, n=47)	-0.07 ± 1.18	-0.16 ± 0.96
Chest Pain, Survival FU Month 3 (n=36, n=26)	0.15 ± 1.33	-0.08 ± 0.87
Chest Pain, Survival FU Month 4 (n=23, n=28)	-0.28 ± 1.40	-0.07 ± 0.79
Chest Pain, Survival FU Month 5 (n=22, n=22)	-0.11 ± 1.49	-0.02 ± 0.65
Chest Pain, Survival FU Month 6 (n=15, n=21)	-0.37 ± 1.67	0.02 ± 0.78
Cough, Week 1 (n=203, n=114)	0.08 ± 0.69	0.04 ± 0.73
Cough, Week 2 (n=204, n=108)	0.02 ± 0.78	0.04 ± 0.84
Cough, Week 3 (n=197, n=106)	0.02 ± 0.86	-0.09 ± 0.93
Cough, Week 4 (n=190, n=102)	-0.06 ± 0.86	-0.10 ± 0.93
Cough, Week 5 (n=192, n=97)	-0.09 ± 0.84	-0.09 ± 0.99
Cough, Week 6 (n=182, n=98)	-0.15 ± 0.86	-0.08 ± 0.98
Cough, Week 7 (n=176, n=87)	-0.11 ± 0.86	-0.06 ± 1.01
Cough, Week 8 (n=169, n=80)	-0.13 ± 0.95	-0.21 ± 1.04
Cough, Week 9 (n=172, n=80)	-0.15 ± 0.99	-0.13 ± 1.23
Cough, Week 10 (n=166, n=75)	-0.20 ± 1.05	-0.07 ± 1.17
Cough, Week 11 (n=171, n=78)	-0.15 ± 1.03	-0.15 ± 1.17
Cough, Week 12 (n=160, n=72)	-0.17 ± 1.03	-0.11 ± 1.09
Cough, Week 13 (n=151, n=61)	-0.24 ± 1.08	-0.04 ± 1.11
Cough, Week 14 (n=144, n=62)	-0.23 ± 1.06	-0.18 ± 1.08
Cough, Week 15 (n=143, n=51)	-0.27 ± 1.06	-0.05 ± 1.10
Cough, Week 16 (n=139, n=52)	-0.37 ± 1.07	-0.25 ± 1.09
Cough, Week 17 (n=145, n=53)	-0.32 ± 1.09	-0.21 ± 1.01
Cough, Week 18 (n=136, n=49)	-0.33 ± 1.07	-0.33 ± 1.09
Cough, Week 19 (n=124, n=45)	-0.33 ± 1.06	-0.40 ± 0.89
Cough, Week 20 (n=123, n=43)	-0.37 ± 1.10	-0.31 ± 0.90
Cough, Week 21 (n=126, n=41)	-0.37 ± 1.08	-0.33 ± 0.96
Cough, Week 22 (n=116, n=37)	-0.37 ± 1.15	-0.24 ± 0.97
Cough, Week 23 (n=122, n=35)	-0.30 ± 1.10	-0.41 ± 1.03
Cough, Week 24 (n=110, n=34)	-0.38 ± 1.09	-0.54 ± 1.04
Cough, Week 25 (n=104, n=31)	-0.49 ± 0.91	-0.47 ± 1.05
Cough, Week 26 (n=109, n=31)	-0.43 ± 0.99	-0.34 ± 1.02
Cough, Week 27 (n=102, n=27)	-0.41 ± 0.97	-0.48 ± 0.98
Cough, Week 28 (n=96, n=28)	-0.52 ± 0.96	-0.43 ± 0.84
Cough, Week 29 (n=104, n=27)	-0.43 ± 0.98	-0.46 ± 0.91
Cough, Week 30 (n=100, n=23)	-0.43 ± 0.95	-0.46 ± 1.07
Cough, Week 31 (n=93, n=25)	-0.32 ± 1.07	-0.38 ± 0.77
Cough, Week 32 (n=88, n=25)	-0.30 ± 0.94	-0.12 ± 0.99
Cough, Week 33 (n=88, n=25)	-0.19 ± 1.12	-0.52 ± 1.03
Cough, Week 34 (n=85, n=24)	-0.35 ± 1.12	-0.33 ± 1.03
Cough, Week 35 (n=87, n=20)	-0.46 ± 1.01	0.00 ± 1.22
Cough, Week 36 (n=85, n=20)	-0.35 ± 1.08	-0.20 ± 1.01
Cough, Week 37 (n=82, n=21)	-0.46 ± 1.03	-0.45 ± 1.11
Cough, Week 38 (n=83, n=19)	-0.38 ± 1.06	-0.03 ± 0.89
Cough, Week 39 (n=78, n=18)	-0.27 ± 0.99	-0.17 ± 1.00
Cough, Week 40 (n=76, n=14)	-0.38 ± 0.95	-0.50 ± 0.90
Cough, Week 41 (n=77, n=16)	-0.44 ± 0.92	-0.22 ± 0.77
Cough, Week 42 (n=70, n=16)	-0.44 ± 0.92	-0.41 ± 0.97
Cough, Week 43 (n=68, n=16)	-0.39 ± 0.98	-0.13 ± 0.92
Cough, Week 44 (n=76, n=16)	-0.38 ± 0.94	-0.16 ± 0.89
Cough, Week 45 (n=69, n=14)	-0.30 ± 1.10	-0.14 ± 1.03
Cough, Week 46 (n=71, n=15)	-0.25 ± 0.99	-0.03 ± 1.23
Cough, Week 47 (n=70, n=13)	-0.44 ± 0.88	-0.12 ± 1.23
Cough, Week 48 (n=66, n=11)	-0.29 ± 0.99	0.14 ± 1.21
Cough, Week 49 (n=65, n=9)	-0.38 ± 1.00	-0.56 ± 1.36
Cough, Week 50 (n=70, n=8)	-0.39 ± 0.96	-0.19 ± 1.16
Cough, Week 51 (n=65, n=10)	-0.30 ± 1.00	-0.40 ± 1.20
Cough, Week 52 (n=72, n=7)	-0.32 ± 1.03	-0.21 ± 1.07
Cough, Week 53 (n=64, n=6)	-0.37 ± 1.03	-0.17 ± 1.33
Cough, Week 54 (n=65, n=7)	-0.41 ± 0.93	-0.07 ± 1.21
Cough, Week 55 (n=62, n=5)	-0.40 ± 0.93	0.10 ± 1.34
Cough, Week 56 (n=62, n=6)	-0.26 ± 0.94	0.17 ± 1.13
Cough, Week 57 (n=62, n=5)	-0.35 ± 0.98	0.00 ± 1.27
Cough, Week 58 (n=56, n=4)	-0.33 ± 1.06	0.13 ± 1.31
Cough, Week 59 (n=52, n=4)	-0.31 ± 0.97	0.13 ± 1.60
Cough, Week 60 (n=48, n=4)	-0.42 ± 0.89	0.38 ± 1.18
Cough, Week 61 (n=49, n=5)	-0.35 ± 0.95	0.80 ± 1.20
Cough, Week 62 (n=41, n=5)	-0.23 ± 1.03	0.50 ± 1.62
Cough, Week 63 (n=43, n=5)	-0.22 ± 1.04	0.50 ± 1.27
Cough, Week 64 (n=42, n=4)	-0.19 ± 1.07	0.00 ± 1.87
Cough, Week 65 (n=40, n=3)	-0.23 ± 1.04	0.83 ± 1.04
Cough, Week 66 (n=38, n=4)	-0.29 ± 0.90	0.63 ± 1.03
Cough, Week 67 (n=33, n=4)	-0.48 ± 0.91	0.38 ± 1.38
Cough, Week 68 (n=34, n=4)	-0.34 ± 0.82	0.13 ± 1.49
Cough, Week 69 (n=35, n=3)	-0.34 ± 1.03	0.17 ± 1.61
Cough, Week 70 (n=36, n=3)	-0.26 ± 0.94	0.17 ± 1.61
Cough, Week 71 (n=31, n=3)	-0.23 ± 0.91	0.33 ± 1.04
Cough, Week 72 (n=29, n=2)	-0.48 ± 0.87	-1.50 ± 1.41
Cough, Week 73 (n=28, n=1)	-0.43 ± 0.91	-0.50 ± 999999
Cough, Week 74 (n=31, n=1)	-0.42 ± 0.93	-0.50 ± 999999
Cough, Week 75 (n=31, n=1)	-0.32 ± 1.00	-0.50 ± 999999
Cough, Week 76 (n=29, n=1)	-0.31 ± 0.91	-0.50 ± 999999
Cough, Week 77 (n=26, n=2)	-0.40 ± 0.92	-0.50 ± 2.83
Cough, Week 78 (n=23, n=1)	-0.52 ± 0.94	0.00 ± 999999
Cough, Week 79 (n=19, n=1)	-0.08 ± 0.93	1.00 ± 999999
Cough, Week 80 (n=20, n=1)	-0.48 ± 0.87	1.00 ± 999999
Cough, Week 81 (n=17, n=1)	-0.44 ± 1.01	-0.50 ± 999999
Cough, Week 82 (n=18, n=1)	-0.39 ± 0.90	1.00 ± 999999
Cough, Week 83 (n=22, n=1)	-0.25 ± 1.09	0.50 ± 999999
Cough, Week 84 (n=20, n=1)	-0.30 ± 0.91	1.00 ± 999999
Cough, Week 85 (n=17, n=1)	-0.32 ± 1.25	1.50 ± 999999
Cough, Week 86 (n=12, n=1)	-0.54 ± 1.27	0.00 ± 999999
Cough, Week 87 (n=15, n=1)	-0.33 ± 1.18	0.00 ± 999999
Cough, Week 88 (n=14, n=1)	-0.46 ± 1.26	0.00 ± 999999
Cough, Week 89 (n=11, n=1)	-0.36 ± 1.07	0.00 ± 999999
Cough, Week 90 (n=14, n=1)	-0.29 ± 1.05	0.00 ± 999999
Cough, Week 91 (n=11, n=1)	-0.27 ± 1.17	0.00 ± 999999
Cough, Week 92 (n=10, n=1)	-0.35 ± 1.27	1.00 ± 999999
Cough, Week 93 (n=11, n=1)	-0.55 ± 0.96	0.00 ± 999999
Cough, Week 94 (n=10, n=0)	-0.40 ± 0.81	999999 ± 999999
Cough, Week 95 (n=10, n=0)	0.05 ± 1.23	999999 ± 999999
Cough, Week 96 (n=9, n=0)	-0.28 ± 1.28	999999 ± 999999
Cough, Week 97 (n=8, n=0)	-0.31 ± 1.19	999999 ± 999999
Cough, Week 98 (n=10, n=0)	-0.10 ± 0.99	999999 ± 999999
Cough, Week 99 (n=7, n=0)	-0.43 ± 0.98	999999 ± 999999
Cough, Week 100 (n=6, n=0)	-0.58 ± 0.86	999999 ± 999999
Cough, Week 101 (n=7, n=0)	-0.50 ± 0.96	999999 ± 999999
Cough, Week 102 (n=4, n=0)	-0.50 ± 0.41	999999 ± 999999
Cough, Week 103 (n=6, n=0)	-0.75 ± 0.42	999999 ± 999999
Cough, Week 104 (n=5, n=0)	-0.80 ± 0.27	999999 ± 999999
Cough, Week 105 (n=4, n=0)	-0.63 ± 0.48	999999 ± 999999
Cough, Week 106 (n=4, n=0)	-0.63 ± 0.48	999999 ± 999999
Cough, Week 107 (n=4, n=0)	-0.63 ± 0.48	999999 ± 999999
Cough, Week 108 (n=4, n=0)	-0.50 ± 0.71	999999 ± 999999
Cough, Week 109 (n=5, n=0)	-0.50 ± 0.50	999999 ± 999999
Cough, Week 110 (n=6, n=0)	-0.50 ± 0.45	999999 ± 999999
Cough, Week 111 (n=5, n=0)	-0.30 ± 0.84	999999 ± 999999
Cough, Week 112 (n=4, n=0)	-0.63 ± 0.48	999999 ± 999999
Cough, Week 113 (n=4, n=0)	-0.25 ± 0.65	999999 ± 999999
Cough, Week 114 (n=3, n=0)	-0.33 ± 0.29	999999 ± 999999
Cough, Week 115 (n=2, n=0)	0.25 ± 0.35	999999 ± 999999
Cough, Week 116 (n=2, n=0)	-0.25 ± 1.06	999999 ± 999999
Cough, Week 117 (n=2, n=0)	-0.50 ± 0.71	999999 ± 999999
Cough, Week 118 (n=2, n=0)	-0.25 ± 0.35	999999 ± 999999
Cough, Week 119 (n=2, n=0)	0.00 ± 0.00	999999 ± 999999
Cough, Week 120 (n=2, n=0)	-0.25 ± 0.35	999999 ± 999999
Cough, Week 121 (n=2, n=0)	-0.50 ± 0.71	999999 ± 999999
Cough, Week 122 (n=2, n=0)	-0.50 ± 0.71	999999 ± 999999
Cough, Week 123 (n=2, n=0)	-0.75 ± 1.06	999999 ± 999999
Cough, Week 124 (n=1, n=0)	0.50 ± 999999	999999 ± 999999
Cough, Week 125 (n=1, n=0)	0.50 ± 999999	999999 ± 999999
Cough, Survival Follow-Up Month 1 (n=158, n=58)	-0.21 ± 1.05	-0.01 ± 0.96
Cough, Survival Follow-Up Month 2 (n=42, n=47)	-0.07 ± 1.16	-0.31 ± 1.18
Cough, Survival Follow-Up Month 3 (n=36, n=26)	-0.14 ± 1.12	-0.13 ± 1.32
Cough, Survival Follow-Up Month 4 (n=23, n=28)	-0.39 ± 1.15	-0.45 ± 1.17
Cough, Survival Follow-Up Month 5 (n=22, n=22)	-0.25 ± 1.44	-0.27 ± 1.32
Cough, Survival Follow-Up Month 6 (n=15, n=21)	-0.23 ± 1.53	-0.29 ± 1.26
Dyspnoea, Week 1 (n=203, n=114)	0.13 ± 0.76	0.23 ± 0.79
Dyspnoea, Week 2 (n=204, n=108)	0.10 ± 0.68	0.31 ± 0.84
Dyspnoea, Week 3 (n=197, n=106)	0.22 ± 0.78	0.32 ± 0.76
Dyspnoea, Week 4 (n=190, n=102)	0.23 ± 0.80	0.45 ± 0.84
Dyspnoea, Week 5 (n=192, n=97)	0.26 ± 0.84	0.42 ± 0.92
Dyspnoea, Week 6 (n=182, n=96)	0.27 ± 0.92	0.51 ± 0.95
Dyspnoea, Week 7 (n=176, n=87)	0.29 ± 0.88	0.60 ± 1.00
Dyspnoea, Week 8 (n=169, n=80)	0.32 ± 0.97	0.53 ± 1.02
Dyspnoea, Week 9 (n=172, n=80)	0.38 ± 0.95	0.62 ± 1.07
Dyspnoea, Week 10 (n=166, n=75)	0.41 ± 1.04	0.75 ± 1.13
Dyspnoea, Week 11 (n=171, n=78)	0.50 ± 1.05	0.60 ± 1.06
Dyspnoea, Week 12 (n=160, n=72)	0.47 ± 1.07	0.74 ± 1.08
Dyspnoea, Week 13 (n=151, n=61)	0.32 ± 1.00	0.76 ± 1.00
Dyspnoea, Week 14 (n=144, n=62)	0.34 ± 0.99	0.61 ± 1.10
Dyspnoea, Week 15 (n=143, n=51)	0.29 ± 1.06	0.71 ± 1.02
Dyspnoea, Week 16 (n=139, n=52)	0.22 ± 0.99	0.67 ± 1.11
Dyspnoea, Week 17 (n=145, n=53)	0.28 ± 1.10	0.68 ± 1.03
Dyspnoea, Week 18 (n=136, n=49)	0.23 ± 1.02	0.62 ± 1.03
Dyspnoea, Week 19 (n=124, n=45)	0.26 ± 1.06	0.54 ± 0.95
Dyspnoea, Week 20 (n=123, n=43)	0.24 ± 1.02	0.54 ± 1.08
Dyspnoea, Week 21 (n=126, n=41)	0.26 ± 1.04	0.39 ± 1.05
Dyspnoea, Week 22 (n=116, n=37)	0.21 ± 0.94	0.41 ± 1.05
Dyspnoea, Week 23 (n=122, n=35)	0.18 ± 0.97	0.41 ± 1.06
Dyspnoea, Week 24 (n=110, n=34)	0.22 ± 0.93	0.31 ± 1.01
Dyspnoea, Week 25 (n=104, n=31)	0.21 ± 0.88	0.20 ± 0.91
Dyspnoea, Week 26 (n=109, n=31)	0.17 ± 0.89	0.30 ± 1.00
Dyspnoea, Week 27 (n=102, n=27)	0.20 ± 1.04	0.30 ± 0.92
Dyspnoea, Week 28 (n=96, n=28)	0.16 ± 0.94	0.22 ± 1.01
Dyspnoea, Week 29 (n=104, n=27)	0.16 ± 0.92	0.33 ± 0.98
Dyspnoea, Week 30 (n=100, n=23)	0.24 ± 1.04	0.27 ± 1.02
Dyspnoea, Week 31 (n=93, n=25)	0.12 ± 0.99	0.26 ± 1.04
Dyspnoea, Week 32 (n=88, n=25)	0.20 ± 0.95	0.38 ± 1.06
Dyspnoea, Week 33 (n=88, n=25)	0.18 ± 0.98	0.19 ± 1.14
Dyspnoea, Week 34 (n=85, n=24)	0.21 ± 1.06	0.30 ± 1.02
Dyspnoea, Week 35 (n=87, n=20)	0.22 ± 1.03	0.46 ± 0.96
Dyspnoea, Week 36 (n=85, n=20)	0.21 ± 1.09	0.34 ± 1.14
Dyspnoea, Week 37 (n=82, n=21)	0.16 ± 1.13	0.10 ± 1.07
Dyspnoea, Week 38 (n=83, n=19)	0.18 ± 1.07	0.51 ± 0.99
Dyspnoea, Week 39 (n=78, n=18)	0.31 ± 1.04	0.26 ± 0.83
Dyspnoea, Week 40 (n=76, n=14)	0.31 ± 0.99	0.04 ± 0.79
Dyspnoea, Week 41 (n=77, n=16)	0.24 ± 0.99	0.18 ± 0.85
Dyspnoea, Week 42 (n=70, n=16)	0.26 ± 1.03	0.08 ± 0.70
Dyspnoea, Week 43 (n=68, n=16)	0.17 ± 1.13	0.41 ± 0.91
Dyspnoea, Week 44 (n=76, n=16)	0.22 ± 1.06	0.29 ± 0.86
Dyspnoea, Week 45 (n=69, n=14)	0.26 ± 1.09	0.31 ± 0.90
Dyspnoea, Week 46 (n=71, n=15)	0.29 ± 0.99	0.47 ± 1.03
Dyspnoea, Week 47 (n=70, n=13)	0.20 ± 1.02	0.45 ± 0.85
Dyspnoea, Week 48 (n=66, n=11)	0.32 ± 1.00	0.29 ± 0.91
Dyspnoea, Week 49 (n=65, n=9)	0.24 ± 1.04	0.00 ± 1.30
Dyspnoea, Week 50 (n=70, n=8)	0.32 ± 0.98	0.43 ± 0.88
Dyspnoea, Week 51 (n=65, n=10)	0.24 ± 0.92	0.06 ± 1.04
Dyspnoea, Week 52 (n=72, n=7)	0.27 ± 0.95	0.29 ± 0.90
Dyspnoea, Week 53 (n=64, n=6)	0.24 ± 1.00	0.30 ± 0.85
Dyspnoea, Week 54 (n=65, n=7)	0.28 ± 0.89	0.40 ± 0.95
Dyspnoea, Week 55 (n=62, n=5)	0.26 ± 0.98	0.44 ± 1.02
Dyspnoea, Week 56 (n=62, n=6)	0.26 ± 0.97	0.53 ± 1.10
Dyspnoea, Week 57 (n=62, n=5)	0.37 ± 0.95	0.24 ± 1.08
Dyspnoea, Week 58 (n=56, n=4)	0.19 ± 1.01	0.35 ± 1.40
Dyspnoea, Week 59 (n=52, n=4)	0.32 ± 0.84	0.35 ± 1.40
Dyspnoea, Week 60 (n=48, n=4)	0.35 ± 0.99	0.50 ± 1.51
Dyspnoea, Week 61 (n=49, n=5)	0.33 ± 1.03	0.60 ± 1.40
Dyspnoea, Week 62 (n=41, n=5)	0.45 ± 0.99	0.72 ± 1.36
Dyspnoea, Week 63 (n=43, n=5)	0.44 ± 1.05	0.56 ± 1.35
Dyspnoea, Week 64 (n=42, n=4)	0.36 ± 0.98	-0.50 ± 1.91
Dyspnoea, Week 65 (n=40, n=3)	0.27 ± 0.97	0.07 ± 1.68
Dyspnoea, Week 66 (n=38, n=4)	0.32 ± 1.11	0.50 ± 1.23
Dyspnoea, Week 67 (n=33, n=4)	0.28 ± 0.91	0.40 ± 1.36
Dyspnoea, Week 68 (n=34, n=4)	0.35 ± 0.96	0.40 ± 1.43
Dyspnoea, Week 69 (n=35, n=3)	0.44 ± 1.02	0.73 ± 1.55
Dyspnoea, Week 70 (n=36, n=3)	0.33 ± 0.97	0.73 ± 1.55
Dyspnoea, Week 71 (n=31, n=3)	0.50 ± 0.95	0.60 ± 1.51
Dyspnoea, Week 72 (n=29, n=3)	0.17 ± 0.95	0.60 ± 1.44
Dyspnoea, Week 73 (n=28, n=2)	0.41 ± 0.96	-1.80 ± 1.13
Dyspnoea, Week 74 (n=31, n=1)	0.30 ± 1.00	-1.00 ± 999999
Dyspnoea, Week 75 (n=31, n=1)	0.26 ± 0.89	-1.00 ± 999999
Dyspnoea, Week 76 (n=29, n=1)	0.23 ± 0.89	-1.00 ± 999999
Dyspnoea, Week 77 (n=26, n=2)	0.20 ± 0.97	-1.50 ± 1.56
Dyspnoea, Week 78 (n=23, n=1)	0.31 ± 0.94	-1.00 ± 999999
Dyspnoea, Week 79 (n=19, n=1)	0.32 ± 0.95	-1.00 ± 999999
Dyspnoea, Week 80 (n=20, n=1)	0.30 ± 0.92	-1.00 ± 999999
Dyspnoea, Week 81 (n=17, n=1)	-0.12 ± 1.00	-0.80 ± 999999
Dyspnoea, Week 82 (n=18, n=1)	0.02 ± 1.06	-0.80 ± 999999
Dyspnoea, Week 83 (n=22, n=1)	0.13 ± 1.01	-1.00 ± 999999
Dyspnoea, Week 84 (n=20, n=1)	0.19 ± 1.00	-1.00 ± 999999
Dyspnoea, Week 85 (n=17, n=1)	0.05 ± 1.17	-0.80 ± 999999
Dyspnoea, Week 86 (n=12, n=1)	-0.07 ± 1.05	-1.00 ± 999999
Dyspnoea, Week 87 (n=15, n=1)	-0.11 ± 0.96	-1.00 ± 999999
Dyspnoea, Week 88 (n=14, n=1)	0.06 ± 1.12	-1.00 ± 999999
Dyspnoea, Week 89 (n=11, n=1)	0.09 ± 0.91	-1.00 ± 999999
Dyspnoea, Week 90 (n=14, n=1)	0.37 ± 0.83	-1.00 ± 999999
Dyspnoea, Week 91 (n=11, n=1)	0.33 ± 1.11	-1.00 ± 999999
Dyspnoea, Week 92 (n=10, n=1)	0.20 ± 1.05	-0.80 ± 999999
Dyspnoea, Week 93 (n=93, n=1)	0.35 ± 0.96	-0.80 ± 999999
Dyspnoea, Week 94 (n=10, n=0)	0.50 ± 0.93	999999 ± 999999
Dyspnoea, Week 95 (n=10, n=0)	0.48 ± 0.98	999999 ± 999999
Dyspnoea, Week 96 (n=9, n=0)	0.51 ± 1.09	999999 ± 999999
Dyspnoea, Week 97 (n=8, n=0)	0.33 ± 1.18	999999 ± 999999
Dyspnoea, Week 98 (n=10, n=0)	0.38 ± 1.05	999999 ± 999999
Dyspnoea, Week 99 (n=7, n=0)	0.11 ± 0.99	999999 ± 999999
Dyspnoea, Week 100 (n=6, n=0)	0.27 ± 1.11	999999 ± 999999
Dyspnoea, Week 101 (n=7, n=0)	0.20 ± 1.11	999999 ± 999999
Dyspnoea, Week 102 (n=4, n=0)	0.35 ± 1.06	999999 ± 999999
Dyspnoea, Week 103 (n=6, n=0)	0.47 ± 1.29	999999 ± 999999
Dyspnoea, Week 104 (n=5, n=0)	0.48 ± 1.22	999999 ± 999999
Dyspnoea, Week 105 (n=4, n=0)	-0.20 ± 0.71	999999 ± 999999
Dyspnoea, Week 106 (n=4, n=0)	-0.20 ± 0.99	999999 ± 999999
Dyspnoea, Week 107 (n=4, n=0)	-0.30 ± 0.62	999999 ± 999999
Dyspnoea, Week 108 (n=4, n=0)	-0.15 ± 0.98	999999 ± 999999
Dyspnoea, Week 109 (n=5, n=0)	0.16 ± 1.17	999999 ± 999999
Dyspnoea, Week 110 (n=6, n=0)	0.33 ± 1.00	999999 ± 999999
Dyspnoea, Week 111 (n=5, n=0)	-0.04 ± 0.86	999999 ± 999999
Dyspnoea, Week 112 (n=4, n=0)	0.20 ± 0.43	999999 ± 999999
Dyspnoea, Week 113 (n=4, n=0)	0.20 ± 0.67	999999 ± 999999
Dyspnoea, Week 114 (n=3, n=0)	0.40 ± 0.72	999999999999 ± 999999
Dyspnoea, Week 115 (n=2, n=0)	0.80 ± 0.85	999999 ± 999999
Dyspnoea, Week 116 (n=2, n=0)	0.60 ± 0.57	999999 ± 999999
Dyspnoea, Week 117 (n=2, n=0)	0.30 ± 0.14	999999 ± 999999
Dyspnoea, Week 118 (n=2, n=0)	0.30 ± 0.42	999999 ± 999999
Dyspnoea, Week 119 (n=2, n=0)	0.50 ± 0.42	999999 ± 999999
Dyspnoea, Week 120 (n=2, n=0)	0.30 ± 0.42	999999 ± 999999
Dyspnoea, Week 121 (n=2, n=0)	0.60 ± 0.57	999999 ± 999999
Dyspnoea, Week 122 (n=2, n=0)	0.60 ± 0.00	999999 ± 999999
Dyspnoea, Week 123 (n=2, n=0)	-0.20 ± 0.57	999999 ± 999999
Dyspnoea, Week 124 (n=1, n=0)	-0.20 ± 999999	999999 ± 999999
Dyspnoea, Week 125 (n=1, n=0)	0.20 ± 999999	999999 ± 999999
Dyspnoea, Survival Follow-Up Month 1 (n=158, n=58)	0.41 ± 1.11	0.60 ± 1.14
Dyspnoea, Survival Follow-Up Month 2 (n=42, n=47)	0.36 ± 1.20	0.46 ± 1.22
Dyspnoea, Survival Follow-Up Month 3 (n=36, n=26)	0.27 ± 0.96	0.61 ± 1.19
Dyspnoea, Survival Follow-Up Month 4 (n=23, n=28)	0.02 ± 1.11	0.45 ± 0.88
Dyspnoea, Survival Follow-Up Month 5 (n=22, n=22)	0.13 ± 1.24	0.48 ± 1.00
Dyspnoea, Survival Follow-Up Month 6 (n=15, n=21)	-0.09 ± 1.29	0.54 ± 0.97

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events

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End point title

Percentage of Participants With Adverse Events

End point description

Percentage of participants with at least one adverse event. Adverse event onset date before cross over.

End point type

Secondary

End point timeframe

Up to approximately 69 months after first patient enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	473	232
Units: Percentage of participants
number (not applicable)	99.6	98.7

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

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End point title

Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

End point description

Baseline prevalence and post-baseline incidence of anti-drug antibodies (ADA) to Atezolizumab in the Arm A (Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) and Arm B Carboplatin+nab-paclitaxel Crossover Participants

End point type

Secondary

End point timeframe

Up to approximately 35 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	451	85
Units: Perecentage of participants
number (not applicable)
Baseline (n=451, n=84)	3.1	4.8
Post-baseline (n=446, n=85)	22.4	23.5

No statistical analyses for this end point

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab for Patients in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

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End point title

Maximum Observed Serum Concentration (Cmax) of Atezolizumab for Patients in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm ^[18]

End point description

Predose samples will be collected on the same day of treatment administration. The infusion duration of atezolizumab will be of 30-60 minutes.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 and Cycle 3 Day 1 (Cycle length = 21 days)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There is no statistical analysis for the end point.

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	465
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=446)	392 ± 114
Cycle 3 Day 1 (n=356)	454 ± 170

No statistical analyses for this end point

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplain+Nab-Paclitaxel

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End point title

Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplain+Nab-Paclitaxel ^[19]

End point description

Predose samples will be collected on the same day of treatment administration.

End point type

Secondary

End point timeframe

Cycle 1 Day 21, Cycle 2 Day 21, Cycle 3 Day 21, and Cycle 7 Day 21 (Cycle length = 21 days)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There is no statistical analysis for the end point.

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	465
Units: mcg/mL
geometric mean (standard deviation)
Cycle 1 Day 21 (n=416)	70.9 ± 35.1
Cycle 2 Day 21 (n=384)	111 ± 52.2
Cycle 3 Day 21 (n=352)	134 ± 57.8
Cycle 7 Day 21 (n=257)	218 ± 93.7

No statistical analyses for this end point

Secondary: Plasma Concentrations of Carboplatin for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

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End point title

Plasma Concentrations of Carboplatin for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) ^[20]

End point description

Note: 999999=below the level of detection.

End point type

Secondary

End point timeframe

Predose (same day of treatment administration), 5-10 minutes before end of carboplatin infusion, 1 hour after carboplatin infusion (infusion duration=15 to 30 minutes) on Day 1 of Cycle 1 and 3 (1 Cycle=21 days) (up to approximately 35 months)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There is no statistical analysis for the end point.

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	29
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 Pre-dose (n=29)	999999 ± 999999
Cycle 1 Day 1 Before End of Infusion (n=23)	20500 ± 7500
Cycle 1 Day 1 Post Infusion(n=29)	11900 ± 3100
Cycle 3 Day 1 Pre-dose (n=23)	169 ± 63.8
Cycle 3 Day 1 Before End of Infusion (n=16)	15300 ± 6600
Cycle 3 Day 1 Post Infusion (n=18)	11400 ± 3060

No statistical analyses for this end point

Secondary: Plasma Concentrations of Carboplatin for Arm B (Nab-Paclitaxel+Carboplatin CrossOver)

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End point title

Plasma Concentrations of Carboplatin for Arm B (Nab-Paclitaxel+Carboplatin CrossOver)

End point description

Note: 999999=below the level of deteccion.

End point type

Secondary

End point timeframe

End point values	Arm B (Nab-Paclitaxel+Carboplatin Crossover)
Number of subjects analysed	19
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 (Pre-dose) (n=19)	999999 ± 999999
Cycle 1 Day 1 Before End of Infusion (n=18)	17000 ± 5200
Cycle 1 Day 1 Post Infusion (n=18)	12400 ± 3800
Cycle 3 Day 1 Pre-dose (n=16)	160 ± 48.8
Cycle 3 Day 1 Before End of Infusion (n=14)	17800 ± 7550
Cycle 3 Day 1 Post Infusion (n=15)	13400 ± 6650

No statistical analyses for this end point

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

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End point title

Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) ^[21]

End point description

Note: 999999=non-reportable. 888888=below the level of detection.

End point type

Secondary

End point timeframe

Predose (same day of treatment administration), 5-10 minutes before end of nab-paclitaxel infusion, 1 hour after nab-paclitaxel infusion (infusion duration=30 minutes) on Day 1 of Cycle 1 and 3 (1 Cycle=21 days) (up to approximately 35 months)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There is no statistical analysis for the end point.

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	30
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 Pre-dose (n=29)	888888 ± 888888
Cycle 1 Day 1 Before End of Infusion (n=27)	3520 ± 2210
Cycle 1 Day 1 Post Infusion (n=25)	307 ± 153
Cycle 3 Day 1 Pre-dose (n=23)	999999 ± 999999
Cycle 3 Day 1 Before End of Infusion (n=17)	4480 ± 3520
Cycle 3 Day 1 Post Infusion (n=18)	357 ± 253

No statistical analyses for this end point

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm B (Nab-Paclitaxel+Carboplatin Crossover)

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End point title

Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm B (Nab-Paclitaxel+Carboplatin Crossover)

End point description

Note: 999999=non-reportable. 888888=below the level of detection.

End point type

Secondary

End point timeframe

End point values	Arm B (Nab-Paclitaxel+Carboplatin Crossover)
Number of subjects analysed	20
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 Pre-dose (n=19)	888888 ± 888888
Cycle 1 Day 1 Before End of Infusion (n=15)	2530 ± 1420
Cycle 1 Day 1 Post Infusion (n=17)	417 ± 217
Cycle 3 Day 1 Pre-dose (n=16)	999999 ± 999999
Cycle 3 Day 1 Before End of Infusion (n=10)	2030 ± 1690
Cycle 3 Day 1 Post Infusion (n=15)	447 ± 322

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first study drug to the data cutoff date: 18 January 2021 (approximately 69 months)

Adverse event reporting additional description

Safety-evaluable population included all treated participants, defined as randomized participants who received any protocol treatment. For safety analyses, participants were grouped according to whether any full or partial dose of atezolizumab was received, including when atezolizumab was received in error.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Arm A

Reporting group description

Participants received intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first during induction treatment phase. Participants received IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit.

Reporting group title

Arm B With Crossover

Reporting group description

Reporting group title

Arm B Without Crossover Participants

Reporting group description

Serious adverse events	Arm A	Arm B With Crossover	Arm B Without Crossover Participants
Total subjects affected by serious adverse events
subjects affected / exposed	252 / 473 (53.28%)	24 / 101 (23.76%)	63 / 131 (48.09%)
number of deaths (all causes)	338	70	108
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR PAIN
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ADENOCARCINOMA OF COLON
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NON-SMALL CELL LUNG CANCER
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
SARCOMA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Vascular disorders
ARTERIAL OCCLUSIVE DISEASE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EMBOLISM
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEMORAL ARTERY ANEURYSM
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
JUGULAR VEIN THROMBOSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PHLEBITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VASCULAR STENOSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
ABORTION INDUCED
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	5 / 473 (1.06%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEATH
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	3 / 131 (2.29%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 3
DRUG INTERACTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FATIGUE
subjects affected / exposed	2 / 473 (0.42%)	1 / 101 (0.99%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 2	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	4 / 473 (0.85%)	1 / 101 (0.99%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 4	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENERALISED OEDEMA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUCOSAL INFLAMMATION
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PAIN
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERFORMANCE STATUS DECREASED
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	8 / 473 (1.69%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	5 / 9	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUDDEN DEATH
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
NON-CARDIAC CHEST PAIN
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
ANAPHYLACTIC REACTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
VAGINAL HAEMORRHAGE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ASPIRATION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
ASTHMA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	13 / 473 (2.75%)	0 / 101 (0.00%)	5 / 131 (3.82%)
occurrences causally related to treatment / all	0 / 22	0 / 0	1 / 8
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 2
COUGH
subjects affected / exposed	2 / 473 (0.42%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	12 / 473 (2.54%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 12	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPISTAXIS
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	6 / 473 (1.27%)	0 / 101 (0.00%)	3 / 131 (2.29%)
occurrences causally related to treatment / all	0 / 8	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
LUNG DISORDER
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORGANISING PNEUMONIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OROPHARYNGEAL DISCOMFORT
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	8 / 473 (1.69%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	9 / 473 (1.90%)	1 / 101 (0.99%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	9 / 9	0 / 1	1 / 2
deaths causally related to treatment / all	2 / 2	0 / 0	0 / 1
PNEUMOTHORAX
subjects affected / exposed	1 / 473 (0.21%)	2 / 101 (1.98%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOTHORAX SPONTANEOUS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	17 / 473 (3.59%)	2 / 101 (1.98%)	3 / 131 (2.29%)
occurrences causally related to treatment / all	0 / 18	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 6	0 / 0	0 / 1
PULMONARY HAEMORRHAGE
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY DISTRESS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 3	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOXIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Psychiatric disorders
CONFUSIONAL STATE
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DISORIENTATION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENTAL STATUS CHANGES
subjects affected / exposed	4 / 473 (0.85%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLOOD CREATININE INCREASED
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLOOD GLUCOSE INCREASED
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LYMPHOCYTE COUNT DECREASED
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	6 / 473 (1.27%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	6 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLATELET COUNT DECREASED
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	4 / 473 (0.85%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LIPASE INCREASED
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEMORAL NECK FRACTURE
subjects affected / exposed	0 / 473 (0.00%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFUSION RELATED REACTION
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL FRACTURE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UPPER LIMB FRACTURE
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUMBAR VERTEBRAL FRACTURE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PELVIC FRACTURE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANGINA UNSTABLE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	4 / 473 (0.85%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIAL FLUTTER
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRADYCARDIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC ANEURYSM
subjects affected / exposed	0 / 473 (0.00%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE CHRONIC
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC TAMPONADE
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 0
PALPITATIONS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERICARDIAL EFFUSION
subjects affected / exposed	6 / 473 (1.27%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
ACUTE CORONARY SYNDROME
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIO-RESPIRATORY ARREST
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Nervous system disorders
ATAXIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CAROTID ARTERY STENOSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	4 / 473 (0.85%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EMBOLIC STROKE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPILEPSY
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEADACHE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEMIPARESIS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ISCHAEMIC STROKE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LETHARGY
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARAESTHESIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SEIZURE
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TOXIC NEUROPATHY
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VASOGENIC CEREBRAL OEDEMA
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
AGRANULOCYTOSIS
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	14 / 473 (2.96%)	4 / 101 (3.96%)	4 / 131 (3.05%)
occurrences causally related to treatment / all	12 / 16	3 / 4	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	9 / 473 (1.90%)	2 / 101 (1.98%)	3 / 131 (2.29%)
occurrences causally related to treatment / all	10 / 10	2 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOLYTIC URAEMIC SYNDROME
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	14 / 473 (2.96%)	1 / 101 (0.99%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	16 / 16	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	6 / 473 (1.27%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	6 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN LOWER
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLITIS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	14 / 473 (2.96%)	1 / 101 (0.99%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	12 / 14	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DUODENAL ULCER
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	1 / 473 (0.21%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL VASCULAR MALFORMATION HAEMORRHAGIC
subjects affected / exposed	0 / 473 (0.00%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ILEUS PARALYTIC
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LARGE INTESTINAL OBSTRUCTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LARGE INTESTINAL STENOSIS
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MELAENA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	5 / 473 (1.06%)	1 / 101 (0.99%)	3 / 131 (2.29%)
occurrences causally related to treatment / all	4 / 5	1 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL FOOD IMPACTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STOMATITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	6 / 473 (1.27%)	1 / 101 (0.99%)	3 / 131 (2.29%)
occurrences causally related to treatment / all	4 / 7	1 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IMMUNE-MEDIATED ENTEROCOLITIS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
AUTOIMMUNE HEPATITIS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BILE DUCT STONE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS ACUTE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLESTASIS
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATIC CIRRHOSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
HEPATITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATOCELLULAR INJURY
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IMMUNE-MEDIATED HEPATITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
DRUG ERUPTION
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RASH
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SKIN ULCER
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	4 / 473 (0.85%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEPHRITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEPHROLITHIASIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEPHROPATHY TOXIC
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POSTRENAL FAILURE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	5 / 473 (1.06%)	1 / 101 (0.99%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	3 / 5	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUBULOINTERSTITIAL NEPHRITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
AUTOIMMUNE NEPHRITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY RETENTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
HYPOTHYROIDISM
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ADDISON'S DISEASE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GLUCOCORTICOID DEFICIENCY
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BONE PAIN
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCULAR WEAKNESS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MYALGIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL PAIN
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUMBAR SPINAL STENOSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
APPENDICITIS PERFORATED
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACTERIAL COLITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACTERIAL SEPSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	6 / 473 (1.27%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CAMPYLOBACTER INFECTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONJUNCTIVITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	0 / 473 (0.00%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENCEPHALITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE INFECTION
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GANGRENE
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTION
subjects affected / exposed	2 / 473 (0.42%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTIOUS PLEURAL EFFUSION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	5 / 473 (1.06%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NASOPHARYNGITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIC INFECTION
subjects affected / exposed	0 / 473 (0.00%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	45 / 473 (9.51%)	2 / 101 (1.98%)	13 / 131 (9.92%)
occurrences causally related to treatment / all	12 / 55	0 / 2	3 / 15
deaths causally related to treatment / all	0 / 5	0 / 0	0 / 2
PULMONARY SEPSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	3 / 473 (0.63%)	1 / 101 (0.99%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	7 / 473 (1.48%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	1 / 7	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	1 / 2
SEPTIC SHOCK
subjects affected / exposed	5 / 473 (1.06%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	3 / 5	0 / 0	0 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 1
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
TRACHEOBRONCHITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	4 / 473 (0.85%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 4	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
APPENDICITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE COLITIS
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CYTOMEGALOVIRUS COLITIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FURUNCLE
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARAPHARYNGEAL SPACE INFECTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TOOTH INFECTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VASCULAR DEVICE INFECTION
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	0 / 473 (0.00%)	1 / 101 (0.99%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIABETIC KETOACIDOSIS
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
HYPERGLYCAEMIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOALBUMINAEMIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOCALCAEMIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	2 / 5	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOMAGNESAEMIA
subjects affected / exposed	1 / 473 (0.21%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	3 / 473 (0.63%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TYPE 2 DIABETES MELLITUS
subjects affected / exposed	0 / 473 (0.00%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Arm A	Arm B With Crossover	Arm B Without Crossover Participants
Total subjects affected by non serious adverse events
subjects affected / exposed	467 / 473 (98.73%)	100 / 101 (99.01%)	127 / 131 (96.95%)
Vascular disorders
HYPOTENSION
subjects affected / exposed	34 / 473 (7.19%)	7 / 101 (6.93%)	6 / 131 (4.58%)
occurrences all number	43	7	8
HYPERTENSION
subjects affected / exposed	26 / 473 (5.50%)	5 / 101 (4.95%)	3 / 131 (2.29%)
occurrences all number	33	6	4
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	89 / 473 (18.82%)	21 / 101 (20.79%)	19 / 131 (14.50%)
occurrences all number	133	29	26
CHEST PAIN
subjects affected / exposed	33 / 473 (6.98%)	2 / 101 (1.98%)	10 / 131 (7.63%)
occurrences all number	43	2	10
FATIGUE
subjects affected / exposed	228 / 473 (48.20%)	52 / 101 (51.49%)	57 / 131 (43.51%)
occurrences all number	297	61	73
OEDEMA PERIPHERAL
subjects affected / exposed	71 / 473 (15.01%)	11 / 101 (10.89%)	14 / 131 (10.69%)
occurrences all number	81	13	17
PAIN
subjects affected / exposed	30 / 473 (6.34%)	2 / 101 (1.98%)	6 / 131 (4.58%)
occurrences all number	33	3	7
PYREXIA
subjects affected / exposed	80 / 473 (16.91%)	10 / 101 (9.90%)	12 / 131 (9.16%)
occurrences all number	104	15	16
CHILLS
subjects affected / exposed	25 / 473 (5.29%)	3 / 101 (2.97%)	4 / 131 (3.05%)
occurrences all number	32	4	4
MUCOSAL INFLAMMATION
subjects affected / exposed	24 / 473 (5.07%)	4 / 101 (3.96%)	4 / 131 (3.05%)
occurrences all number	26	4	5
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	135 / 473 (28.54%)	18 / 101 (17.82%)	21 / 131 (16.03%)
occurrences all number	162	21	21
DYSPNOEA
subjects affected / exposed	134 / 473 (28.33%)	23 / 101 (22.77%)	28 / 131 (21.37%)
occurrences all number	181	29	30
EPISTAXIS
subjects affected / exposed	69 / 473 (14.59%)	10 / 101 (9.90%)	17 / 131 (12.98%)
occurrences all number	84	12	18
HAEMOPTYSIS
subjects affected / exposed	30 / 473 (6.34%)	2 / 101 (1.98%)	6 / 131 (4.58%)
occurrences all number	42	2	6
PRODUCTIVE COUGH
subjects affected / exposed	35 / 473 (7.40%)	4 / 101 (3.96%)	4 / 131 (3.05%)
occurrences all number	44	4	4
PNEUMONITIS
subjects affected / exposed	24 / 473 (5.07%)	0 / 101 (0.00%)	0 / 131 (0.00%)
occurrences all number	26	0	0
Psychiatric disorders
ANXIETY
subjects affected / exposed	32 / 473 (6.77%)	3 / 101 (2.97%)	4 / 131 (3.05%)
occurrences all number	32	3	4
DEPRESSION
subjects affected / exposed	29 / 473 (6.13%)	0 / 101 (0.00%)	5 / 131 (3.82%)
occurrences all number	29	0	5
INSOMNIA
subjects affected / exposed	70 / 473 (14.80%)	16 / 101 (15.84%)	15 / 131 (11.45%)
occurrences all number	76	16	17
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	26 / 473 (5.50%)	5 / 101 (4.95%)	9 / 131 (6.87%)
occurrences all number	42	5	13
BLOOD CREATININE INCREASED
subjects affected / exposed	27 / 473 (5.71%)	1 / 101 (0.99%)	7 / 131 (5.34%)
occurrences all number	32	2	11
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	93 / 473 (19.66%)	17 / 101 (16.83%)	18 / 131 (13.74%)
occurrences all number	188	29	33
PLATELET COUNT DECREASED
subjects affected / exposed	108 / 473 (22.83%)	16 / 101 (15.84%)	22 / 131 (16.79%)
occurrences all number	179	32	29
WEIGHT DECREASED
subjects affected / exposed	63 / 473 (13.32%)	13 / 101 (12.87%)	15 / 131 (11.45%)
occurrences all number	71	13	16
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	49 / 473 (10.36%)	9 / 101 (8.91%)	9 / 131 (6.87%)
occurrences all number	80	12	16
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	20 / 473 (4.23%)	1 / 101 (0.99%)	8 / 131 (6.11%)
occurrences all number	30	1	10
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	24 / 473 (5.07%)	0 / 101 (0.00%)	4 / 131 (3.05%)
occurrences all number	33	0	4
Nervous system disorders
DIZZINESS
subjects affected / exposed	78 / 473 (16.49%)	11 / 101 (10.89%)	14 / 131 (10.69%)
occurrences all number	90	15	21
DYSGEUSIA
subjects affected / exposed	43 / 473 (9.09%)	7 / 101 (6.93%)	5 / 131 (3.82%)
occurrences all number	46	7	5
HEADACHE
subjects affected / exposed	85 / 473 (17.97%)	11 / 101 (10.89%)	12 / 131 (9.16%)
occurrences all number	106	13	13
NEUROPATHY PERIPHERAL
subjects affected / exposed	56 / 473 (11.84%)	9 / 101 (8.91%)	13 / 131 (9.92%)
occurrences all number	58	10	16
PARAESTHESIA
subjects affected / exposed	43 / 473 (9.09%)	5 / 101 (4.95%)	7 / 131 (5.34%)
occurrences all number	51	6	7
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	60 / 473 (12.68%)	13 / 101 (12.87%)	10 / 131 (7.63%)
occurrences all number	71	15	14
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	259 / 473 (54.76%)	50 / 101 (49.50%)	67 / 131 (51.15%)
occurrences all number	357	55	79
LEUKOPENIA
subjects affected / exposed	51 / 473 (10.78%)	6 / 101 (5.94%)	13 / 131 (9.92%)
occurrences all number	92	7	22
NEUTROPENIA
subjects affected / exposed	213 / 473 (45.03%)	53 / 101 (52.48%)	52 / 131 (39.69%)
occurrences all number	424	99	95
THROMBOCYTOPENIA
subjects affected / exposed	132 / 473 (27.91%)	31 / 101 (30.69%)	29 / 131 (22.14%)
occurrences all number	210	47	49
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	17 / 473 (3.59%)	7 / 101 (6.93%)	2 / 131 (1.53%)
occurrences all number	21	7	2
Eye disorders
VISION BLURRED
subjects affected / exposed	25 / 473 (5.29%)	4 / 101 (3.96%)	2 / 131 (1.53%)
occurrences all number	28	4	2
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	54 / 473 (11.42%)	8 / 101 (7.92%)	9 / 131 (6.87%)
occurrences all number	67	9	11
CONSTIPATION
subjects affected / exposed	176 / 473 (37.21%)	33 / 101 (32.67%)	38 / 131 (29.01%)
occurrences all number	224	42	47
DIARRHOEA
subjects affected / exposed	196 / 473 (41.44%)	35 / 101 (34.65%)	37 / 131 (28.24%)
occurrences all number	321	41	61
DYSPEPSIA
subjects affected / exposed	33 / 473 (6.98%)	5 / 101 (4.95%)	2 / 131 (1.53%)
occurrences all number	34	6	2
NAUSEA
subjects affected / exposed	236 / 473 (49.89%)	44 / 101 (43.56%)	61 / 131 (46.56%)
occurrences all number	354	65	85
STOMATITIS
subjects affected / exposed	40 / 473 (8.46%)	4 / 101 (3.96%)	8 / 131 (6.11%)
occurrences all number	45	5	9
VOMITING
subjects affected / exposed	130 / 473 (27.48%)	18 / 101 (17.82%)	25 / 131 (19.08%)
occurrences all number	228	30	38
ABDOMINAL PAIN UPPER
subjects affected / exposed	25 / 473 (5.29%)	6 / 101 (5.94%)	5 / 131 (3.82%)
occurrences all number	33	7	7
DRY MOUTH
subjects affected / exposed	24 / 473 (5.07%)	2 / 101 (1.98%)	3 / 131 (2.29%)
occurrences all number	24	2	3
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	24 / 473 (5.07%)	4 / 101 (3.96%)	2 / 131 (1.53%)
occurrences all number	25	4	3
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	152 / 473 (32.14%)	30 / 101 (29.70%)	33 / 131 (25.19%)
occurrences all number	155	30	33
DRY SKIN
subjects affected / exposed	28 / 473 (5.92%)	6 / 101 (5.94%)	6 / 131 (4.58%)
occurrences all number	31	6	6
PRURITUS
subjects affected / exposed	61 / 473 (12.90%)	5 / 101 (4.95%)	7 / 131 (5.34%)
occurrences all number	81	5	7
RASH
subjects affected / exposed	73 / 473 (15.43%)	11 / 101 (10.89%)	6 / 131 (4.58%)
occurrences all number	86	12	7
RASH MACULO-PAPULAR
subjects affected / exposed	20 / 473 (4.23%)	1 / 101 (0.99%)	7 / 131 (5.34%)
occurrences all number	21	2	8
Endocrine disorders
HYPOTHYROIDISM
subjects affected / exposed	51 / 473 (10.78%)	0 / 101 (0.00%)	1 / 131 (0.76%)
occurrences all number	55	0	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	113 / 473 (23.89%)	17 / 101 (16.83%)	19 / 131 (14.50%)
occurrences all number	161	20	20
BACK PAIN
subjects affected / exposed	89 / 473 (18.82%)	7 / 101 (6.93%)	9 / 131 (6.87%)
occurrences all number	105	7	9
MUSCULAR WEAKNESS
subjects affected / exposed	25 / 473 (5.29%)	6 / 101 (5.94%)	8 / 131 (6.11%)
occurrences all number	27	6	10
MYALGIA
subjects affected / exposed	50 / 473 (10.57%)	5 / 101 (4.95%)	5 / 131 (3.82%)
occurrences all number	60	7	5
PAIN IN EXTREMITY
subjects affected / exposed	61 / 473 (12.90%)	8 / 101 (7.92%)	7 / 131 (5.34%)
occurrences all number	72	8	7
Infections and infestations
BRONCHITIS
subjects affected / exposed	29 / 473 (6.13%)	4 / 101 (3.96%)	2 / 131 (1.53%)
occurrences all number	30	5	2
NASOPHARYNGITIS
subjects affected / exposed	38 / 473 (8.03%)	6 / 101 (5.94%)	4 / 131 (3.05%)
occurrences all number	61	7	4
PNEUMONIA
subjects affected / exposed	37 / 473 (7.82%)	2 / 101 (1.98%)	6 / 131 (4.58%)
occurrences all number	41	2	6
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	35 / 473 (7.40%)	4 / 101 (3.96%)	8 / 131 (6.11%)
occurrences all number	55	6	9
URINARY TRACT INFECTION
subjects affected / exposed	63 / 473 (13.32%)	10 / 101 (9.90%)	9 / 131 (6.87%)
occurrences all number	91	11	9
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	144 / 473 (30.44%)	30 / 101 (29.70%)	34 / 131 (25.95%)
occurrences all number	169	34	36
DEHYDRATION
subjects affected / exposed	52 / 473 (10.99%)	8 / 101 (7.92%)	17 / 131 (12.98%)
occurrences all number	73	8	27
HYPOKALAEMIA
subjects affected / exposed	77 / 473 (16.28%)	12 / 101 (11.88%)	12 / 131 (9.16%)
occurrences all number	98	16	13
HYPOMAGNESAEMIA
subjects affected / exposed	94 / 473 (19.87%)	17 / 101 (16.83%)	23 / 131 (17.56%)
occurrences all number	130	23	27
HYPONATRAEMIA
subjects affected / exposed	31 / 473 (6.55%)	0 / 101 (0.00%)	8 / 131 (6.11%)
occurrences all number	54	0	10
HYPOPHOSPHATAEMIA
subjects affected / exposed	20 / 473 (4.23%)	1 / 101 (0.99%)	7 / 131 (5.34%)
occurrences all number	32	1	8

More information

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Were there any global substantial amendments to the protocol? Yes

24 Aug 2015

Protocol was amended to include change to the name of the test product from MPDL3280A to atezolizumab. The evaluations of progression-free survival at 6 months and at 1 year and overall survival at 3 years have been added as exploratory objectives to further evaluate the clinical benefit of atezolizumab at these time points. The contraception requirements in the inclusion and exclusion criteria and the pregnancy-reporting information have been updated to be consistent with safety information for nab-paclitaxel. The study inclusion criteria have been modified, on the basis of data from an expanding safety database, to allow for patients with treated, asymptomatic cerebellar metastases to be enrolled provided specific criteria are met. The exclusion criteria for history of autoimmune disease has been broadened, on the basis of data from an expanding safety database, to allow for patients with eczema, psoriasis, or lichen simplex chronicus of vitiligo with dermatologic manifestations only to be permitted provided that they meet the specific conditions. The study exclusion criterion regarding treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug (whichever is shorter) prior to randomization has been modified to 4 weeks prior to randomization for consistency with more recent atezolizumab protocols. The exclusion criterion specifying that patients with a history of allergic reaction to intravenous contrast that requires steroid pretreatment should have baseline and subsequent tumor assessments performed via magnetic resonance imaging (MRI) has been removed because this is in conflict with Section 4.5.5. Patients with contraindications to contrast may have assessments done with non-contrast computed tomography or MRI.

11 Nov 2015

Protocol was amended to clarify that a wash-out period of at least 4 weeks or five half-lives, whichever is longer, of any systemic immunomodulatory agent is required prior to enrollment.

15 Jun 2016

Protocol was amended to add a co-primary endpoint of overall survival (OS) to the progression-free survival (PFS) primary endpoint. For patients consented and randomized to Arm B after Ethics Committee or Institutional Review Board approval of Protocol GO29537, Version 5 at each respective site, the option for crossover to atezolizumab maintenance therapy has been removed to enable the comparative analyses of the two treatment arms. Patients randomized to Arm B who were consented under previous versions of this protocol prior to the approval of Version 5 will continue to have the option for crossover to atezolizumab maintenance therapy. The total number of patients to be randomized in the study has increased from 550 patients to 650 patients to ensure that the study is adequately powered for the comparative analyses. Erlotinib switch maintenance therapy has been removed from the protocol. A secondary efficacy objective and outcome measure has been added to evaluate the efficacy of atezolizumab + carboplatin + nab-paclitaxel compared with carboplatin + nab-paclitaxel as measured by investigator-assessed time to response (TTR) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for both the intent-to-treat (ITT) and programmed death−ligand 1(PD-L1)−selected populations.

01 Mar 2017

Protocol was amended to include change to the primary analysis populations for the co-primary endpoints of progression-free survival (PFS) and overall survival (OS). OS will be analyzed in the intent-to-treat (ITT) population. PFS will be analyzed in the ITT population and a population with a defined level of expression of a PD-L1 and T-effector gene signature in tumor tissue as determined by an RNA-based assay. Patients with known sensitizing EGFR mutations or ALK translocations will be excluded from the primary analysis populations. The analyses of PFS and OS in all randomized patients will be conducted as secondary analyses. Additional censoring rule for the primary endpoint of PFS for U.S. registration purposes has been removed. The statistical testing procedures have been amended to reflect the change in analysis populations. All endpoints (secondary and exploratory) based on the review by an Independent Review Facility (IRF) have been removed.

24 Oct 2018

Protocol was amended to correct the end of study definition corrected. This correction ensures that the study continues until last patient, last visit or until the Sponsor terminates the study. The inclusion criterion that addresses female contraception has been modified to specify when women must refrain from donating eggs.

29 Mar 2019

Protocol was amended to clarify the inclusion criterion on contraception. In addition, reporting for serious adverse events and adverse events of special interest has been extended to 90 days after last dose of study treatment or until initiation of a new anticancer therapy, whichever occurs first.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

Primary: Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

Primary: Overall Survival (OS) in the ITT-WT Population

Primary: Overall Survival (OS) in the ITT-WT Population

Secondary: PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

Secondary: PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

Secondary: OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

Secondary: OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

Secondary: OS as Determined by the Investigator Using RECIST v1.1 in the PD-L1 Expression Population and PD-L1 Expression WT Population

Secondary: OS as Determined by the Investigator Using RECIST v1.1 in the PD-L1 Expression Population and PD-L1 Expression WT Population

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population

Secondary: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population, ITT Population, and PD-L1 Expression Population and PD-L1 Expression WT Population

Secondary: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population, ITT Population, and PD-L1 Expression Population and PD-L1 Expression WT Population

Secondary: Event Free Rate (%) at Year 1 and 2 in ITT-WT Population and ITT Population

Secondary: Event Free Rate (%) at Year 1 and 2 in ITT-WT Population and ITT Population

Secondary: Event Free Rate (%) at Year 1 and 2 in PD-L1 Expression Population and PD-L1 Expression WT Population

Secondary: Event Free Rate (%) at Year 1 and 2 in PD-L1 Expression Population and PD-L1 Expression WT Population

Secondary: Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

Secondary: Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

Secondary: Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

Secondary: Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

Secondary: Percentage of Participants With Adverse Events

Secondary: Percentage of Participants With Adverse Events

Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab for Patients in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab for Patients in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplain+Nab-Paclitaxel

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplain+Nab-Paclitaxel

Secondary: Plasma Concentrations of Carboplatin for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Secondary: Plasma Concentrations of Carboplatin for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Secondary: Plasma Concentrations of Carboplatin for Arm B (Nab-Paclitaxel+Carboplatin CrossOver)

Secondary: Plasma Concentrations of Carboplatin for Arm B (Nab-Paclitaxel+Carboplatin CrossOver)

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm B (Nab-Paclitaxel+Carboplatin Crossover)

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel for Arm B (Nab-Paclitaxel+Carboplatin Crossover)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer