Download PDF

Clinical Trial Results:
A Multistage, Phase II Study Evaluating the Safety and Efficacy of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as First-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer

Summary
EudraCT number	2014-002230-32
Trial protocol	ES GB CZ BE FR LT LV IT
Global end of trial date	17 Sep 2021

Results information
Results version number	v6(current)
This version publication date	01 Apr 2023
First version publication date	08 Sep 2022
Other versions	v1 , v2 , v3 , v4 , v5
Version creation reason

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

WO29479

ISRCTN number

US NCT number

NCT02322814

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

17 Sep 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Sep 2021

Was the trial ended prematurely?

Main objective of the trial

The objective of this trial was to evaluate the safety and tolerability and estimate the efficacy of cobimetinib plus paclitaxel versus placebo plus paclitaxel in Cohort I, of cobimetinib plus atezolizumab plus paclitaxel in Cohort II, and of cobimetinib plus atezolizumab plus nab-paclitaxel in Cohort III in participants with metastatic or locally advanced, triple-negative adenocarcinoma of the breast who have not received prior systemic therapy for metastatic breast cancer (MBC).

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Mar 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

3 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 14

Country: Number of subjects enrolled

Belgium: 21

Country: Number of subjects enrolled

Czechia: 2

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Israel: 2

Country: Number of subjects enrolled

Italy: 12

Country: Number of subjects enrolled

Korea, Republic of: 20

Country: Number of subjects enrolled

Latvia: 18

Country: Number of subjects enrolled

Romania: 10

Country: Number of subjects enrolled

Spain: 24

Country: Number of subjects enrolled

Taiwan: 8

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

United States: 22

Worldwide total number of subjects

169

EEA total number of subjects

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)

137

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

The study recruited participants with metastatic or locally advanced, triple-negative adenocarcinoma of the breast who had not received prior systemic therapy for metastatic breast cancer. Locally advanced disease must not have been amenable to resection with curative intent.

Screening details

One participant from Cohort III never started any treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

The run-in stage of Cohort I and all of Cohorts II and III were open label. The expansion (randomized) stage of Cohort I was double-blind.

Are arms mutually exclusive

Yes

Cohort I: Safety Run-In

Arm description

Participants received cobimetinib plus paclitaxel until 12 participants completed one cycle of study treatment (28 days).

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered at a dose of 80 milligrams per square meter (mg/m^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Cohort I: Cobimetinib, Paclitaxel

Arm description

Participants received a combination of cobimetinib plus paclitaxel in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered at a dose of 80 milligrams per square meter (mg/m^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Cohort I: Placebo, Paclitaxel

Arm description

Participants received a combination of cobimetinib placebo plus paclitaxel in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matching to cobimetinib was administered orally, once a day, on Day 3 through Day 23 of each 28 day treatment cycle.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered at a dose of 80 milligrams per square meter (mg/m^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Cohort II:Cobimetinib,Paclitaxel,Atezolizumab

Arm description

Participants received cobimetinib plus paclitaxel plus atezolizumab in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab was administered to Cohorts II and III at a dose of 840 mg IV every 2 weeks on Days 1 and 15 of each 28-day treatment cycle.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered at a dose of 80 milligrams per square meter (mg/m^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab

Arm description

Participants received cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Arm type

Experimental

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 to Cohort III according to the local prescribing information at a starting dose of 100 mg/m^2 by IV infusion on Days 1, 8, and 15 of each 28 day cycle.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab was administered to Cohorts II and III at a dose of 840 mg IV every 2 weeks on Days 1 and 15 of each 28-day treatment cycle.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Number of subjects in period 1	Cohort I: Safety Run-In	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Started	16	47	43	32	31
Completed	0	0	0	0	0
Not completed	16	47	43	32	31
Death	7	32	29	23	14
Progressive Disease	-	-	-	1	1
Withdrawal by Subject	5	2	4	1	3
Study Terminated by Sponsor	-	9	7	5	13
Lost to follow-up	1	3	3	1	-
Various Reasons	2	1	-	1	-
Protocol deviation	1	-	-	-	-

Baseline characteristics

Top of page

Reporting group title

Cohort I: Safety Run-In

Reporting group description

Participants received cobimetinib plus paclitaxel until 12 participants completed one cycle of study treatment (28 days).

Reporting group title

Cohort I: Cobimetinib, Paclitaxel

Reporting group description

Reporting group title

Cohort I: Placebo, Paclitaxel

Reporting group description

Reporting group title

Cohort II:Cobimetinib,Paclitaxel,Atezolizumab

Reporting group description

Reporting group title

Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab

Reporting group description

Participants received cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Reporting group values	Cohort I: Safety Run-In	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab	Total
Number of subjects	16	47	43	32	31	169
Age Categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	13	40	34	24	26	137
From 65-84 years	3	7	9	8	5	32
85 years and over	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	53.6 ( 12.7 )	54.2 ( 10.3 )	52.9 ( 13.7 )	53.7 ( 13.1 )	52.2 ( 11.8 )	-
Gender Categorical
Units: Subjects
Female	16	47	43	32	31	169
Male	0	0	0	0	0	0
Race (NIH/OMB)
Units: Subjects
Asian	3	11	9	2	5	30
Black or African American	2	2	0	1	0	5
White	10	32	34	28	25	129
Other	1	0	0	1	1	3
Unknown	0	2	0	0	0	2
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	3	7	2	3	16
Not Hispanic or Latino	13	41	35	30	28	147
Not Stated	2	2	1	0	0	5
Unknown	0	1	0	0	0	1

End points

Top of page

Reporting group title

Cohort I: Safety Run-In

Reporting group description

Participants received cobimetinib plus paclitaxel until 12 participants completed one cycle of study treatment (28 days).

Reporting group title

Cohort I: Cobimetinib, Paclitaxel

Reporting group description

Reporting group title

Cohort I: Placebo, Paclitaxel

Reporting group description

Reporting group title

Cohort II:Cobimetinib,Paclitaxel,Atezolizumab

Reporting group description

Reporting group title

Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab

Reporting group description

Participants received cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Primary: Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

Top of page

End point title

Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) ^[1]

End point description

PFS was defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by the investigator, using RECIST v1.1. As per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions is also considered progression. Data were only collected from participants in the Cohort I Expansion Stage (Cohort I: Cobimetinib, Paclitaxel, Cohort I: Placebo, Paclitaxel) for this outcome measure. ITT population was defined as all enrolled participants, whether or not the assigned study treatment was received.

End point type

Primary

End point timeframe

Randomization up to disease progression or relapse, whichever occurs first (up to approximately 2 years)

Notes
[1] - 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: The primary objective was to estimate the clinical benefit of cobimetinib plus paclitaxel relative to placebo plus paclitaxel, as measured by investigator-assessed PFS, so only these two arms have data related to primary endpoint.

End point values	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel
Number of subjects analysed	47	43
Units: Weeks
median (confidence interval 95%)	23.71 (18.14 to 32.14)	16.43 (8.14 to 31.14)

Cobimetinib vs. Placebo

Comparison groups

Cohort I: Placebo, Paclitaxel v Cohort I: Cobimetinib, Paclitaxel

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.247

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.24

Primary: Cohort II, III: Percentage of Participants With Confirmed Overall Response (OR) (Partial Response [PR] or Complete Response [CR]), as Determined by the Investigator Using RECIST v1.1

Top of page

End point title

Cohort II, III: Percentage of Participants With Confirmed Overall Response (OR) (Partial Response [PR] or Complete Response [CR]), as Determined by the Investigator Using RECIST v1.1 ^[2] ^[3]

End point description

OR was defined as the rate of a PR or CR occurring after randomization and confirmed >=28 days later as determined by the investigator using RECIST v1.1. As per RECIST v1.1, CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target and new measurable lesions. ITT population was defined as all enrolled participants, whether or not the assigned study treatment was received.

End point type

Primary

End point timeframe

Randomization up to disease progression or relapse, whichever occurs first (up to approximately 5.25 years)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses for this end point.
[3] - 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: This analysis was only performed on Cohorts II and III and hence why not all arms are presented.

End point values	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	32	31
Units: Percentage of participants
number (not applicable)
Responders	37.5	32.3
Non-Responders	62.5	67.7

No statistical analyses for this end point

Secondary: Cohort I, II, III: Overall Survival (OS)

Top of page

End point title

Cohort I, II, III: Overall Survival (OS) ^[4]

End point description

OS was defined as the time from randomization to death from any cause. Data were only collected from participants in the Cohort I Expansion Stage (Cohort I: Cobimetinib, Paclitaxel, Cohort I: Placebo, Paclitaxel) along with the Cohort II and III for this outcome measure. ITT population was defined as all enrolled participants, whether or not the assigned study treatment was received. 9999999 = The upper limit of 95% CI was not evaluable due to insufficient events observed.

End point type

Secondary

End point timeframe

Randomization up to death from any cause (up to approximately 6.5 years)

Notes
[4] - 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: The analysis excludes the Safety Run-In cohort.

End point values	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	47	43	32	31
Units: Months
median (confidence interval 95%)	16.72 (13.50 to 20.24)	19.58 (14.75 to 29.37)	11.04 (9.53 to 22.51)	15.57 (14.26 to 9999999)

Cohort I: Cobimetinib vs. Placebo

Comparison groups

Cohort I: Cobimetinib, Paclitaxel v Cohort I: Placebo, Paclitaxel

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5912

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

2.13

Secondary: Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1

Top of page

End point title

Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1 ^[5]

End point description

OR was defined as the rate of a PR or CR occurring after randomization and confirmed >=28 days later as determined by the investigator using RECIST v1.1. As per RECIST v1.1, CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target and new measurable lesions. Data were only collected from participants in the Cohort I Expansion Stage (Cohort I: Cobimetinib, Paclitaxel, Cohort I: Placebo, Paclitaxel) for this outcome measure. ITT population was defined as all enrolled participants, whether or not the assigned study treatment was received.

End point type

Secondary

End point timeframe

Randomization up to disease progression or relapse, whichever occurs first (up to approximately 2 years)

Notes
[5] - 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: This analysis was only performed on Cohort I and hence why not all arms are presented.

End point values	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel
Number of subjects analysed	47	43
Units: Percentage of participants
number (not applicable)
Responders	38.3	20.9
Non-Responders	61.7	79.1

No statistical analyses for this end point

Secondary: Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1

Top of page

End point title

Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1

End point description

DOR was defined as the time from the first occurrence of a documented objective response to the time of relapse, as determined by the investigator using RECIST v1.1 or death from any cause during the study, whichever occurred first. ITT population was defined as all enrolled participants, whether or not the assigned study treatment was received. 9999999 = The upper limit of 95% CI was not evaluable due to insufficient events observed.

End point type

Secondary

End point timeframe

Time from the first occurrence of documented objective response to time of relapse or death, whichever occurs first (up to approximately 6.5 years)

End point values	Cohort I: Safety Run-In	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	16	47	43	32	31
Units: Months
median (confidence interval 95%)	39.29 (23.14 to 56.29)	23.14 (16.14 to 26.57)	24.14 (17.14 to 9999999)	5.78 (4.44 to 16.33)	11.42 (5.78 to 17.94)

No statistical analyses for this end point

Secondary: Cohort I, II, III: Percentage of Participants With Unconfirmed Overall Response (OR_uc) (Unconfirmed PR or CR), as Determined by the Investigator Using RECIST v1.1

Top of page

End point title

Cohort I, II, III: Percentage of Participants With Unconfirmed Overall Response (OR_uc) (Unconfirmed PR or CR), as Determined by the Investigator Using RECIST v1.1 ^[6]

End point description

ORR_uc (ORR confirmation not required) was defined as the rate of a PR or CR occurring after randomization as determined by the investigator using RECIST v1.1, confirmation not required. As per RECIST v1.1, CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target and new measurable lesions. Data were only collected from participants in the Cohort I Expansion Stage (Cohort I: Cobimetinib, Paclitaxel, Cohort I: Placebo, Paclitaxel) along with the Cohort II and III for this outcome measure. ITT population was defined as all enrolled participants, whether or not the assigned study treatment was received.

End point type

Secondary

End point timeframe

Randomization up to disease progression or relapse, whichever occurs fist (up to approximately 6.5 years)

Notes
[6] - 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: The analysis excludes the Safety Run-In cohort.

End point values	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	47	43	32	31
Units: Percentage of participants
number (not applicable)
Responders	42.6	25.6	46.9	45.2
Non-Responders	57.4	74.4	53.1	54.8

No statistical analyses for this end point

Secondary: Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1

Top of page

End point title

Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1 ^[7]

End point description

PFS was defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by the investigator, using RECIST v1.1. As per RECIST v1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. ITT population was defined as all enrolled participants, whether or not the assigned study treatment was received.

End point type

Secondary

End point timeframe

Randomization up to disease progression or relapse, whichever occurs first (up to approximately 6.5 years)

Notes
[7] - 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: This analysis was only performed on Cohorts II and III and hence why not all arms are presented.

End point values	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	32	31
Units: Months
median (confidence interval 95%)	3.75 (3.02 to 7.29)	7.66 (3.65 to 11.04)

No statistical analyses for this end point

Secondary: Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)

Top of page

End point title

Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)

End point description

The safety-evaluable population was defined as participants who received any amount of any study drug.

End point type

Secondary

End point timeframe

Randomization up to end of study (up to approximately 6.5 years)

End point values	Cohort I: Safety Run-In	Cohort I: Cobimetinib, Paclitaxel	Cohort I: Placebo, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	16	47	43	32	31
Units: Percentage of participants
number (not applicable)	93.8	97.9	100.0	100.0	100.0

No statistical analyses for this end point

Secondary: Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib

Top of page

End point title

Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib ^[8]

End point description

The pharmacokinetic (PK) population included all participants with evaluable PK data who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hour [Hr] 0) on Cycle (Cy) 1 Day (D) 8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose (2, 4 Hr postdose for Cohorts II, III) on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15; predose (Hr 0) on Cy2 D15 (Cy=28 days)

Notes
[8] - 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: This analysis was only performed on the arms with Cobimetinib and hence why not all arms are presented.

End point values	Cohort I: Safety Run-In	Cohort I: Cobimetinib, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	11	8	17	15
Units: Nanograms per millilitre (ng/mL)
geometric mean (geometric coefficient of variation)	285 ( 62.2 )	266 ( 82.0 )	213 ( 68.0 )	407 ( 90.7 )

No statistical analyses for this end point

Secondary: Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib

Top of page

End point title

Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib ^[9]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy 1 D8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose (2, 4 Hr postdose for Cohorts II, III) on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15; predose (Hr 0) on Cy2 D15 (Cy=28 days)

Notes
[9] - 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: This analysis was only performed on the arms with Cobimetinib and hence why not all arms are presented.

End point values	Cohort I: Safety Run-In	Cohort I: Cobimetinib, Paclitaxel	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	13	38	14	13
Units: ng/mL
geometric mean (geometric coefficient of variation)	65.6 ( 1279.5 )	130 ( 190.7 )	138 ( 79.0 )	136 ( 67.2 )

No statistical analyses for this end point

Secondary: Cohort I: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib

Top of page

End point title

Cohort I: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib ^[10]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug. Data were only collected from participants in the Cohort I: Safety Run-In stage for this outcome measure.

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy 1 D8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15 (Cy=28 days)

Notes
[10] - 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: This analysis was only performed on the arms with Cobimetinib and hence why not all arms are presented.

End point values	Cohort I: Safety Run-In
Number of subjects analysed	11
Units: Nanograms/milliliter/hour (hr*ng/mL)
geometric mean (geometric coefficient of variation)	1620 ( 80.0 )

No statistical analyses for this end point

Secondary: Cohort I, II: Cmax of Paclitaxel

Top of page

End point title

Cohort I, II: Cmax of Paclitaxel ^[11]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug. Data were only collected from Cohort I: Safety Run-In and Cohort II participants for this outcome measure.

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (2, 4 Hr postdose for Cohort II) (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)

Notes
[11] - 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: This analysis was only performed on the arms with Paclitaxel and hence why not all arms are presented.

End point values	Cohort I: Safety Run-In	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab
Number of subjects analysed	11	14
Units: ng/mL
geometric mean (geometric coefficient of variation)	1770 ( 553.4 )	283 ( 490.9 )

No statistical analyses for this end point

Secondary: Cohort I, II: Cmin of Paclitaxel

Top of page

End point title

Cohort I, II: Cmin of Paclitaxel ^[12]

End point description

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (2, 4 Hr postdose for Cohort II) (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)

Notes
[12] - 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: This analysis was only performed on the arms with Paclitaxel and hence why not all arms are presented.

End point values	Cohort I: Safety Run-In	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab
Number of subjects analysed	13	15
Units: ng/mL
geometric mean (geometric coefficient of variation)	1.40 ( 89.9 )	1.26 ( 53.3 )

No statistical analyses for this end point

Secondary: Cohort I: AUC0-tau of Paclitaxel

Top of page

End point title

Cohort I: AUC0-tau of Paclitaxel ^[13]

End point description

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)

Notes
[13] - 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: This analysis was only performed on the arms with Paclitaxel and hence why not all arms are presented.

End point values	Cohort I: Safety Run-In
Number of subjects analysed	10
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	4220 ( 310.4 )

No statistical analyses for this end point

Secondary: Cohort III: Cmax of Nab-Paclitaxel

Top of page

End point title

Cohort III: Cmax of Nab-Paclitaxel ^[14]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)

Notes
[14] - 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: This analysis was only performed on the arms with Nab-Paclitaxel and hence why not all arms are presented.

End point values	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	13
Units: ng/mL
geometric mean (geometric coefficient of variation)	277 ( 658.5 )

No statistical analyses for this end point

Secondary: Cohort III: Cmin of Nab-Paclitaxel

Top of page

End point title

Cohort III: Cmin of Nab-Paclitaxel ^[15]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)

Notes
[15] - 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: This analysis was only performed on the arms with Nab-Paclitaxel and hence why not all arms are presented.

End point values	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	12
Units: ng/mL
geometric mean (geometric coefficient of variation)	2.05 ( 173.9 )

No statistical analyses for this end point

Secondary: Cohort III: AUC0-tau of Nab-Paclitaxel

Top of page

End point title

Cohort III: AUC0-tau of Nab-Paclitaxel ^[16]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug. Due to the sparse nature of PK sampling, the estimation of this PK parameter requires the use of population PK analysis. This would have enabled the exposure-response analysis with this OM. Given the outcome of the study, the Sponsors did not proceed with popPK analysis, which was planned, only if data warranted. AUC0-tau was not estimated and analyzed using the sparse PK samples.

End point type

Secondary

End point timeframe

Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)

Notes
[16] - 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: This analysis was only performed on the arms with Nab-Paclitaxel and hence why not all arms are presented.

End point values	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	0 ^[17]
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	( )

Notes
[17] - Insufficient data was collected which precludes the calculation of this outcome measure.

No statistical analyses for this end point

Secondary: Cohort II, III: Cmax (in Serum) of Atezolizumab

Top of page

End point title

Cohort II, III: Cmax (in Serum) of Atezolizumab ^[18]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug

End point type

Secondary

End point timeframe

Safety Run-In, Expansion:Predose (Hr0), 0.5Hr postdose (infusion duration:1Hr) on D1 of Cy1, 3; predose (Hr0) on D1 of Cy2, 4, 8, every 8 Cy up to end of treatment (EOT); 120 days after EOT (approximately 5.25 years) (Cy=28 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: This analysis was only performed on the arms with Atezolizumab and hence why not all arms are presented.

End point values	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	10	10
Units: ng/mL
geometric mean (geometric coefficient of variation)	346 ( 48.3 )	374 ( 38.8 )

No statistical analyses for this end point

Secondary: Cohort II, III: Cmin (in Serum) of Atezolizumab

Top of page

End point title

Cohort II, III: Cmin (in Serum) of Atezolizumab ^[19]

End point description

The PK population included all participants with evaluable PK data who received at least one dose of study drug

End point type

Secondary

End point timeframe

Safety Run-In, Expansion: Predose (Hr 0), 0.5 Hr postdose (infusion duration: 1 Hr) on D1 of Cy1, 3; predose (Hr 0) on D1 of Cy2, 4, 8, every 8 Cy up to EOT; 120 days after EOT (approximately 5.5 years) (Cy=28 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: This analysis was only performed on the arms with Atezolizumab and hence why not all arms are presented.

End point values	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	10	10
Units: ng/mL
geometric mean (geometric coefficient of variation)	144 ( 34.6 )	109 ( 89.9 )

No statistical analyses for this end point

Secondary: Cohort II, III: AUC0-tau (in Serum) of Atezolizumab

Top of page

End point title

Cohort II, III: AUC0-tau (in Serum) of Atezolizumab ^[20]

End point description

End point type

Secondary

End point timeframe

Safety Run-In, Expansion: Predose (Hr 0), 0.5 Hr postdose (infusion duration: 1 Hr) on D1 of Cy1, 3; predose (Hr 0) on D1 of Cy2, 4, 8, every 8 Cy up to EOT (approximately 5.5 years); 120 days after EOT (approximately 5.5 years) (Cy=28 days)

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: This analysis was only performed on the arms with Atezolizumab and hence why not all arms are presented.

End point values	Cohort II:Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Number of subjects analysed	0 ^[21]	0 ^[22]
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	( )	( )

Notes
[21] - Insufficient data was collected which precludes the calculation of this outcome measure.
[22] - Insufficient data was collected which precludes the calculation of this outcome measure.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From randomization up until 6.5 years

Adverse event reporting additional description

The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Cohort I: Safety Run-In

Reporting group description

Participants received cobimetinib plus paclitaxel until 12 participants completed one cycle of study treatment (28 days).

Reporting group title

Cohort I: Placebo, Paclitaxel

Reporting group description

Reporting group title

Cohort I: Cobimetinib, Paclitaxel

Reporting group description

Reporting group title

Cohort II: Cobimetinib,Paclitaxel,Atezolizumab

Reporting group description

Reporting group title

Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab

Reporting group description

Participants received cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Serious adverse events	Cohort I: Safety Run-In	Cohort I: Placebo, Paclitaxel	Cohort I: Cobimetinib, Paclitaxel	Cohort II: Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 16 (37.50%)	8 / 43 (18.60%)	17 / 47 (36.17%)	16 / 32 (50.00%)	15 / 31 (48.39%)
number of deaths (all causes)	7	29	32	23	14
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR HAEMORRHAGE
subjects affected / exposed ^[1]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
EMBOLISM
subjects affected / exposed ^[2]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EMBOLISM VENOUS
subjects affected / exposed ^[3]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORTHOSTATIC HYPOTENSION
subjects affected / exposed ^[4]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
PYREXIA
subjects affected / exposed ^[5]	2 / 16 (12.50%)	0 / 43 (0.00%)	6 / 47 (12.77%)	4 / 32 (12.50%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	1 / 2	0 / 0	2 / 6	2 / 4	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUCOSAL INFLAMMATION
subjects affected / exposed ^[6]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASTHENIA
subjects affected / exposed ^[7]	1 / 16 (6.25%)	1 / 43 (2.33%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FATIGUE
subjects affected / exposed ^[8]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
EPISTAXIS
subjects affected / exposed ^[9]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed ^[10]	0 / 16 (0.00%)	1 / 43 (2.33%)	2 / 47 (4.26%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	3 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUNG INFILTRATION
subjects affected / exposed ^[11]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
PLEURITIC PAIN
subjects affected / exposed ^[12]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed ^[13]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed ^[14]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed ^[15]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
BLOOD CREATININE INCREASED
subjects affected / exposed ^[16]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
MITRAL VALVE INCOMPETENCE
subjects affected / exposed ^[17]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed ^[18]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed ^[19]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
BRAIN OEDEMA
subjects affected / exposed ^[20]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed ^[21]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENCEPHALOPATHY
subjects affected / exposed ^[22]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed ^[23]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PARTIAL SEIZURES
subjects affected / exposed ^[24]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OPTIC NEURITIS
subjects affected / exposed ^[25]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
FEBRILE NEUTROPENIA
subjects affected / exposed ^[26]	0 / 16 (0.00%)	1 / 43 (2.33%)	1 / 47 (2.13%)	1 / 32 (3.13%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed ^[27]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
PAPILLOEDEMA
subjects affected / exposed ^[28]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
DIARRHOEA
subjects affected / exposed ^[29]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	2 / 32 (6.25%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed ^[30]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed ^[31]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
subjects affected / exposed ^[32]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed ^[33]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC PERFORATION
subjects affected / exposed ^[34]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed ^[35]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RASH ERYTHEMATOUS
subjects affected / exposed ^[36]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed ^[37]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
PERIORBITAL CELLULITIS
subjects affected / exposed ^[38]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed ^[39]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed ^[40]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed ^[41]	0 / 16 (0.00%)	0 / 43 (0.00%)	2 / 47 (4.26%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed ^[42]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed ^[43]	0 / 16 (0.00%)	0 / 43 (0.00%)	4 / 47 (8.51%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
KIDNEY INFECTION
subjects affected / exposed ^[44]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed ^[45]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS ACUTE
subjects affected / exposed ^[46]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STREPTOCOCCAL SEPSIS
subjects affected / exposed ^[47]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed ^[48]	0 / 16 (0.00%)	1 / 43 (2.33%)	3 / 47 (6.38%)	0 / 32 (0.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 5	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MASTITIS
subjects affected / exposed ^[49]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed ^[50]	1 / 16 (6.25%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
HYPOKALAEMIA
subjects affected / exposed ^[51]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DECREASED APPETITE
subjects affected / exposed ^[52]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[22] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[23] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[24] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[25] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[26] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[27] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[28] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[29] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[30] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[31] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[32] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[33] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[34] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[35] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[36] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[37] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[38] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[39] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[40] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[41] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[42] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[43] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[44] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[45] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[46] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[47] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[48] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[49] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[50] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[51] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[52] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.

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

Non-serious adverse events	Cohort I: Safety Run-In	Cohort I: Placebo, Paclitaxel	Cohort I: Cobimetinib, Paclitaxel	Cohort II: Cobimetinib,Paclitaxel,Atezolizumab	Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab
Total subjects affected by non serious adverse events
subjects affected / exposed	15 / 16 (93.75%)	43 / 43 (100.00%)	46 / 47 (97.87%)	32 / 32 (100.00%)	29 / 31 (93.55%)
Vascular disorders
HOT FLUSH
subjects affected / exposed ^[53]	0 / 16 (0.00%)	2 / 43 (4.65%)	1 / 47 (2.13%)	3 / 32 (9.38%)	1 / 30 (3.33%)
occurrences all number	0	2	1	3	1
FLUSHING
subjects affected / exposed ^[54]	1 / 16 (6.25%)	2 / 43 (4.65%)	1 / 47 (2.13%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	1	2	1	1	0
HYPOTENSION
subjects affected / exposed ^[55]	1 / 16 (6.25%)	1 / 43 (2.33%)	0 / 47 (0.00%)	2 / 32 (6.25%)	1 / 30 (3.33%)
occurrences all number	1	1	0	2	1
HYPERTENSION
subjects affected / exposed ^[56]	0 / 16 (0.00%)	3 / 43 (6.98%)	4 / 47 (8.51%)	1 / 32 (3.13%)	1 / 30 (3.33%)
occurrences all number	0	5	7	1	1
LYMPHOEDEMA
subjects affected / exposed ^[57]	0 / 16 (0.00%)	1 / 43 (2.33%)	4 / 47 (8.51%)	3 / 32 (9.38%)	2 / 30 (6.67%)
occurrences all number	0	3	4	5	2
General disorders and administration site conditions
CHILLS
subjects affected / exposed ^[58]	1 / 16 (6.25%)	0 / 43 (0.00%)	3 / 47 (6.38%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	3	0	0
PYREXIA
subjects affected / exposed ^[59]	4 / 16 (25.00%)	8 / 43 (18.60%)	9 / 47 (19.15%)	1 / 32 (3.13%)	9 / 30 (30.00%)
occurrences all number	7	13	15	1	12
GENERALISED OEDEMA
subjects affected / exposed ^[60]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	2
OEDEMA
subjects affected / exposed ^[61]	1 / 16 (6.25%)	2 / 43 (4.65%)	5 / 47 (10.64%)	0 / 32 (0.00%)	3 / 30 (10.00%)
occurrences all number	1	2	7	0	4
GAIT DISTURBANCE
subjects affected / exposed ^[62]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
MUCOSAL INFLAMMATION
subjects affected / exposed ^[63]	1 / 16 (6.25%)	2 / 43 (4.65%)	4 / 47 (8.51%)	5 / 32 (15.63%)	5 / 30 (16.67%)
occurrences all number	3	3	9	6	9
FATIGUE
subjects affected / exposed ^[64]	3 / 16 (18.75%)	15 / 43 (34.88%)	13 / 47 (27.66%)	11 / 32 (34.38%)	10 / 30 (33.33%)
occurrences all number	3	19	15	16	10
PERIPHERAL SWELLING
subjects affected / exposed ^[65]	1 / 16 (6.25%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	1	0	0
OEDEMA PERIPHERAL
subjects affected / exposed ^[66]	4 / 16 (25.00%)	9 / 43 (20.93%)	9 / 47 (19.15%)	7 / 32 (21.88%)	5 / 30 (16.67%)
occurrences all number	4	9	12	12	6
CHEST PAIN
subjects affected / exposed ^[67]	0 / 16 (0.00%)	7 / 43 (16.28%)	5 / 47 (10.64%)	2 / 32 (6.25%)	1 / 30 (3.33%)
occurrences all number	0	9	5	4	1
ASTHENIA
subjects affected / exposed ^[68]	3 / 16 (18.75%)	11 / 43 (25.58%)	13 / 47 (27.66%)	6 / 32 (18.75%)	6 / 30 (20.00%)
occurrences all number	3	18	15	11	8
INFLUENZA LIKE ILLNESS
subjects affected / exposed ^[69]	0 / 16 (0.00%)	0 / 43 (0.00%)	3 / 47 (6.38%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	0	3	1	2
PAIN
subjects affected / exposed ^[70]	1 / 16 (6.25%)	3 / 43 (6.98%)	3 / 47 (6.38%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	3	3	0	1
Reproductive system and breast disorders
CYSTOCELE
subjects affected / exposed ^[71]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
BREAST PAIN
subjects affected / exposed ^[72]	0 / 16 (0.00%)	3 / 43 (6.98%)	1 / 47 (2.13%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	5	1	1	3
Respiratory, thoracic and mediastinal disorders
PRODUCTIVE COUGH
subjects affected / exposed ^[73]	1 / 16 (6.25%)	3 / 43 (6.98%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	3	1	0	0
NASAL DRYNESS
subjects affected / exposed ^[74]	2 / 16 (12.50%)	0 / 43 (0.00%)	2 / 47 (4.26%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	2	0	0
PLEURAL EFFUSION
subjects affected / exposed ^[75]	0 / 16 (0.00%)	1 / 43 (2.33%)	3 / 47 (6.38%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	1	3	2	0
DYSPHONIA
subjects affected / exposed ^[76]	2 / 16 (12.50%)	3 / 43 (6.98%)	2 / 47 (4.26%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	2	3	3	1	2
PULMONARY EMBOLISM
subjects affected / exposed ^[77]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1	1
PNEUMONITIS
subjects affected / exposed ^[78]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	2 / 32 (6.25%)	1 / 30 (3.33%)
occurrences all number	0	1	0	2	1
OROPHARYNGEAL PAIN
subjects affected / exposed ^[79]	0 / 16 (0.00%)	1 / 43 (2.33%)	4 / 47 (8.51%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	1	4	2	2
EPISTAXIS
subjects affected / exposed ^[80]	2 / 16 (12.50%)	4 / 43 (9.30%)	4 / 47 (8.51%)	7 / 32 (21.88%)	7 / 30 (23.33%)
occurrences all number	2	5	5	8	8
DYSPNOEA
subjects affected / exposed ^[81]	4 / 16 (25.00%)	3 / 43 (6.98%)	7 / 47 (14.89%)	3 / 32 (9.38%)	1 / 30 (3.33%)
occurrences all number	5	6	12	3	1
COUGH
subjects affected / exposed ^[82]	2 / 16 (12.50%)	12 / 43 (27.91%)	7 / 47 (14.89%)	6 / 32 (18.75%)	5 / 30 (16.67%)
occurrences all number	2	14	8	7	6
Psychiatric disorders
INSOMNIA
subjects affected / exposed ^[83]	2 / 16 (12.50%)	7 / 43 (16.28%)	3 / 47 (6.38%)	3 / 32 (9.38%)	4 / 30 (13.33%)
occurrences all number	2	8	3	3	5
ANXIETY
subjects affected / exposed ^[84]	0 / 16 (0.00%)	1 / 43 (2.33%)	2 / 47 (4.26%)	1 / 32 (3.13%)	3 / 30 (10.00%)
occurrences all number	0	1	3	1	3
Investigations
TRANSFERRIN SATURATION DECREASED
subjects affected / exposed ^[85]	1 / 16 (6.25%)	0 / 43 (0.00%)	1 / 47 (2.13%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	1	0	1	1	0
BLOOD POTASSIUM DECREASED
subjects affected / exposed ^[86]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0
NEUTROPHIL COUNT DECREASED
subjects affected / exposed ^[87]	0 / 16 (0.00%)	1 / 43 (2.33%)	2 / 47 (4.26%)	4 / 32 (12.50%)	4 / 30 (13.33%)
occurrences all number	0	1	2	9	7
WEIGHT DECREASED
subjects affected / exposed ^[88]	0 / 16 (0.00%)	3 / 43 (6.98%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	4	0	2	0
EJECTION FRACTION DECREASED
subjects affected / exposed ^[89]	0 / 16 (0.00%)	0 / 43 (0.00%)	3 / 47 (6.38%)	1 / 32 (3.13%)	1 / 30 (3.33%)
occurrences all number	0	0	3	1	1
CARBOHYDRATE ANTIGEN 15-3 INCREASED
subjects affected / exposed ^[90]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
BLOOD CREATINE PHOSPHOKINASE INCREASED
subjects affected / exposed ^[91]	6 / 16 (37.50%)	0 / 43 (0.00%)	10 / 47 (21.28%)	5 / 32 (15.63%)	7 / 30 (23.33%)
occurrences all number	6	0	10	11	13
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed ^[92]	3 / 16 (18.75%)	2 / 43 (4.65%)	3 / 47 (6.38%)	4 / 32 (12.50%)	5 / 30 (16.67%)
occurrences all number	5	2	5	6	7
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed ^[93]	2 / 16 (12.50%)	3 / 43 (6.98%)	3 / 47 (6.38%)	4 / 32 (12.50%)	6 / 30 (20.00%)
occurrences all number	4	5	4	7	7
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed ^[94]	1 / 16 (6.25%)	2 / 43 (4.65%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	5	1	0	0
PLATELET COUNT DECREASED
subjects affected / exposed ^[95]	1 / 16 (6.25%)	1 / 43 (2.33%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	1	2	0	1	0
HAEMOGLOBIN DECREASED
subjects affected / exposed ^[96]	1 / 16 (6.25%)	2 / 43 (4.65%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	2	1	0	0
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed ^[97]	0 / 16 (0.00%)	1 / 43 (2.33%)	3 / 47 (6.38%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	2	3	3	0
FIBRIN D DIMER INCREASED
subjects affected / exposed ^[98]	2 / 16 (12.50%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	0
SERUM FERRITIN INCREASED
subjects affected / exposed ^[99]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
WHITE BLOOD CELL COUNT INCREASED
subjects affected / exposed ^[100]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed ^[101]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	3 / 32 (9.38%)	0 / 30 (0.00%)
occurrences all number	0	0	0	9	0
MYOGLOBIN BLOOD INCREASED
subjects affected / exposed ^[102]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
NEUTROPHIL COUNT INCREASED
subjects affected / exposed ^[103]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
BLOOD THYROID STIMULATING HORMONE INCREASED
subjects affected / exposed ^[104]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	0	1
C-REACTIVE PROTEIN INCREASED
subjects affected / exposed ^[105]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	1	0	0	2	0
BLOOD PRESSURE INCREASED
subjects affected / exposed ^[106]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
Injury, poisoning and procedural complications
CHEST INJURY
subjects affected / exposed ^[107]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
INFUSION RELATED REACTION
subjects affected / exposed ^[108]	2 / 16 (12.50%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	0	0	0	0
Cardiac disorders
TACHYCARDIA
subjects affected / exposed ^[109]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	0	1	1	2
PALPITATIONS
subjects affected / exposed ^[110]	1 / 16 (6.25%)	1 / 43 (2.33%)	2 / 47 (4.26%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	1	2	0	0
Nervous system disorders
DYSGEUSIA
subjects affected / exposed ^[111]	1 / 16 (6.25%)	4 / 43 (9.30%)	7 / 47 (14.89%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	1	4	7	1	3
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed ^[112]	2 / 16 (12.50%)	9 / 43 (20.93%)	8 / 47 (17.02%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	2	12	12	1	2
PARAESTHESIA
subjects affected / exposed ^[113]	0 / 16 (0.00%)	5 / 43 (11.63%)	4 / 47 (8.51%)	4 / 32 (12.50%)	0 / 30 (0.00%)
occurrences all number	0	9	5	5	0
DYSMETRIA
subjects affected / exposed ^[114]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
NEUROTOXICITY
subjects affected / exposed ^[115]	0 / 16 (0.00%)	3 / 43 (6.98%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	4	0	0	0
HYPOGEUSIA
subjects affected / exposed ^[116]	2 / 16 (12.50%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	0
HYPOAESTHESIA
subjects affected / exposed ^[117]	1 / 16 (6.25%)	2 / 43 (4.65%)	3 / 47 (6.38%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	2	3	0	0
DYSTONIC TREMOR
subjects affected / exposed ^[118]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
DIZZINESS
subjects affected / exposed ^[119]	3 / 16 (18.75%)	8 / 43 (18.60%)	7 / 47 (14.89%)	4 / 32 (12.50%)	3 / 30 (10.00%)
occurrences all number	3	9	9	4	3
HEADACHE
subjects affected / exposed ^[120]	3 / 16 (18.75%)	9 / 43 (20.93%)	7 / 47 (14.89%)	5 / 32 (15.63%)	4 / 30 (13.33%)
occurrences all number	3	14	14	7	6
NEUROPATHY PERIPHERAL
subjects affected / exposed ^[121]	1 / 16 (6.25%)	7 / 43 (16.28%)	4 / 47 (8.51%)	8 / 32 (25.00%)	7 / 30 (23.33%)
occurrences all number	1	10	4	9	11
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed ^[122]	2 / 16 (12.50%)	13 / 43 (30.23%)	8 / 47 (17.02%)	6 / 32 (18.75%)	8 / 30 (26.67%)
occurrences all number	16	43	21	6	18
LEUKOPENIA
subjects affected / exposed ^[123]	1 / 16 (6.25%)	1 / 43 (2.33%)	1 / 47 (2.13%)	0 / 32 (0.00%)	3 / 30 (10.00%)
occurrences all number	6	2	1	0	9
EOSINOPHILIA
subjects affected / exposed ^[124]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
ANAEMIA
subjects affected / exposed ^[125]	3 / 16 (18.75%)	6 / 43 (13.95%)	12 / 47 (25.53%)	14 / 32 (43.75%)	10 / 30 (33.33%)
occurrences all number	3	9	16	19	24
Ear and labyrinth disorders
TINNITUS
subjects affected / exposed ^[126]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	3 / 32 (9.38%)	0 / 30 (0.00%)
occurrences all number	0	0	0	3	0
Eye disorders
VITREOUS FLOATERS
subjects affected / exposed ^[127]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	0	1
VISION BLURRED
subjects affected / exposed ^[128]	0 / 16 (0.00%)	1 / 43 (2.33%)	10 / 47 (21.28%)	4 / 32 (12.50%)	4 / 30 (13.33%)
occurrences all number	0	1	11	4	5
CHORIORETINOPATHY
subjects affected / exposed ^[129]	1 / 16 (6.25%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	1	0	0
CATARACT CORTICAL
subjects affected / exposed ^[130]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
EPISCLERITIS
subjects affected / exposed ^[131]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
MACULAR OEDEMA
subjects affected / exposed ^[132]	0 / 16 (0.00%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	3
MACULAR FIBROSIS
subjects affected / exposed ^[133]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
EYE PAIN
subjects affected / exposed ^[134]	1 / 16 (6.25%)	0 / 43 (0.00%)	2 / 47 (4.26%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	2	0	1
EYELID OEDEMA
subjects affected / exposed ^[135]	1 / 16 (6.25%)	1 / 43 (2.33%)	2 / 47 (4.26%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	1	1	2	1	0
CATARACT
subjects affected / exposed ^[136]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
RETINAL DETACHMENT
subjects affected / exposed ^[137]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
RETINAL DRUSEN
subjects affected / exposed ^[138]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
CONJUNCTIVAL HAEMORRHAGE
subjects affected / exposed ^[139]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	1	0	0	1	0
DRY EYE
subjects affected / exposed ^[140]	0 / 16 (0.00%)	3 / 43 (6.98%)	4 / 47 (8.51%)	0 / 32 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	3	4	0	3
Gastrointestinal disorders
DRY MOUTH
subjects affected / exposed ^[141]	2 / 16 (12.50%)	1 / 43 (2.33%)	6 / 47 (12.77%)	0 / 32 (0.00%)	2 / 30 (6.67%)
occurrences all number	2	1	6	0	2
APHTHOUS ULCER
subjects affected / exposed ^[142]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	1	0	0	1	0
VOMITING
subjects affected / exposed ^[143]	5 / 16 (31.25%)	7 / 43 (16.28%)	8 / 47 (17.02%)	9 / 32 (28.13%)	12 / 30 (40.00%)
occurrences all number	6	8	13	16	16
CONSTIPATION
subjects affected / exposed ^[144]	4 / 16 (25.00%)	9 / 43 (20.93%)	8 / 47 (17.02%)	6 / 32 (18.75%)	8 / 30 (26.67%)
occurrences all number	4	11	11	7	13
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed ^[145]	2 / 16 (12.50%)	1 / 43 (2.33%)	2 / 47 (4.26%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	6	1	2	2	0
DYSPHAGIA
subjects affected / exposed ^[146]	0 / 16 (0.00%)	2 / 43 (4.65%)	2 / 47 (4.26%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	2	2	2	0
MOUTH ULCERATION
subjects affected / exposed ^[147]	0 / 16 (0.00%)	0 / 43 (0.00%)	2 / 47 (4.26%)	2 / 32 (6.25%)	2 / 30 (6.67%)
occurrences all number	0	0	3	2	3
HAEMORRHOIDS
subjects affected / exposed ^[148]	1 / 16 (6.25%)	2 / 43 (4.65%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	2	2	0	0
ABDOMINAL PAIN UPPER
subjects affected / exposed ^[149]	1 / 16 (6.25%)	4 / 43 (9.30%)	6 / 47 (12.77%)	2 / 32 (6.25%)	1 / 30 (3.33%)
occurrences all number	1	5	6	2	1
STOMATITIS
subjects affected / exposed ^[150]	5 / 16 (31.25%)	5 / 43 (11.63%)	13 / 47 (27.66%)	5 / 32 (15.63%)	5 / 30 (16.67%)
occurrences all number	8	5	18	5	11
DIARRHOEA
subjects affected / exposed ^[151]	10 / 16 (62.50%)	13 / 43 (30.23%)	36 / 47 (76.60%)	21 / 32 (65.63%)	27 / 30 (90.00%)
occurrences all number	29	19	66	48	55
ABDOMINAL PAIN
subjects affected / exposed ^[152]	3 / 16 (18.75%)	3 / 43 (6.98%)	5 / 47 (10.64%)	6 / 32 (18.75%)	5 / 30 (16.67%)
occurrences all number	3	3	6	8	6
NAUSEA
subjects affected / exposed ^[153]	7 / 16 (43.75%)	18 / 43 (41.86%)	20 / 47 (42.55%)	13 / 32 (40.63%)	15 / 30 (50.00%)
occurrences all number	7	25	24	18	20
ABDOMINAL DISTENSION
subjects affected / exposed ^[154]	1 / 16 (6.25%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	0	1	0	2
DYSPEPSIA
subjects affected / exposed ^[155]	0 / 16 (0.00%)	3 / 43 (6.98%)	6 / 47 (12.77%)	1 / 32 (3.13%)	5 / 30 (16.67%)
occurrences all number	0	3	9	1	7
Skin and subcutaneous tissue disorders
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
subjects affected / exposed ^[156]	1 / 16 (6.25%)	1 / 43 (2.33%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	4	1	0	2	0
RASH
subjects affected / exposed ^[157]	8 / 16 (50.00%)	5 / 43 (11.63%)	22 / 47 (46.81%)	12 / 32 (37.50%)	17 / 30 (56.67%)
occurrences all number	18	6	34	22	22
SKIN LESION
subjects affected / exposed ^[158]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
PRURITUS
subjects affected / exposed ^[159]	2 / 16 (12.50%)	2 / 43 (4.65%)	12 / 47 (25.53%)	4 / 32 (12.50%)	4 / 30 (13.33%)
occurrences all number	2	2	17	5	9
DERMATITIS ACNEIFORM
subjects affected / exposed ^[160]	3 / 16 (18.75%)	3 / 43 (6.98%)	9 / 47 (19.15%)	8 / 32 (25.00%)	6 / 30 (20.00%)
occurrences all number	3	4	12	14	6
INGROWING NAIL
subjects affected / exposed ^[161]	1 / 16 (6.25%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	1	0	0
DRY SKIN
subjects affected / exposed ^[162]	1 / 16 (6.25%)	0 / 43 (0.00%)	6 / 47 (12.77%)	4 / 32 (12.50%)	5 / 30 (16.67%)
occurrences all number	1	0	7	5	7
ERYTHEMA
subjects affected / exposed ^[163]	1 / 16 (6.25%)	1 / 43 (2.33%)	2 / 47 (4.26%)	1 / 32 (3.13%)	3 / 30 (10.00%)
occurrences all number	1	1	3	1	4
RASH MACULO-PAPULAR
subjects affected / exposed ^[164]	0 / 16 (0.00%)	1 / 43 (2.33%)	1 / 47 (2.13%)	3 / 32 (9.38%)	1 / 30 (3.33%)
occurrences all number	0	1	1	3	2
NAIL DISCOLOURATION
subjects affected / exposed ^[165]	1 / 16 (6.25%)	1 / 43 (2.33%)	3 / 47 (6.38%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	1	3	0	1
SKIN FISSURES
subjects affected / exposed ^[166]	0 / 16 (0.00%)	0 / 43 (0.00%)	3 / 47 (6.38%)	1 / 32 (3.13%)	1 / 30 (3.33%)
occurrences all number	0	0	4	1	1
RASH PAPULAR
subjects affected / exposed ^[167]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	2
NAIL RIDGING
subjects affected / exposed ^[168]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0
ONYCHOMADESIS
subjects affected / exposed ^[169]	1 / 16 (6.25%)	0 / 43 (0.00%)	1 / 47 (2.13%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	1	0	1
ERYTHEMA NODOSUM
subjects affected / exposed ^[170]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	0
ALOPECIA
subjects affected / exposed ^[171]	5 / 16 (31.25%)	19 / 43 (44.19%)	21 / 47 (44.68%)	8 / 32 (25.00%)	10 / 30 (33.33%)
occurrences all number	5	20	22	8	10
Renal and urinary disorders
HAEMATURIA
subjects affected / exposed ^[172]	0 / 16 (0.00%)	0 / 43 (0.00%)	3 / 47 (6.38%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	3	0	0
ACUTE KIDNEY INJURY
subjects affected / exposed ^[173]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	0	0	3	2
DYSURIA
subjects affected / exposed ^[174]	1 / 16 (6.25%)	1 / 43 (2.33%)	4 / 47 (8.51%)	3 / 32 (9.38%)	1 / 30 (3.33%)
occurrences all number	1	1	5	3	1
Endocrine disorders
HYPOTHYROIDISM
subjects affected / exposed ^[175]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	5 / 32 (15.63%)	3 / 30 (10.00%)
occurrences all number	0	0	0	5	3
Musculoskeletal and connective tissue disorders
MUSCLE SPASMS
subjects affected / exposed ^[176]	1 / 16 (6.25%)	2 / 43 (4.65%)	1 / 47 (2.13%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	1	2	1	1	2
MUSCULAR WEAKNESS
subjects affected / exposed ^[177]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	2 / 32 (6.25%)	1 / 30 (3.33%)
occurrences all number	0	0	0	2	1
ARTHRALGIA
subjects affected / exposed ^[178]	2 / 16 (12.50%)	7 / 43 (16.28%)	2 / 47 (4.26%)	2 / 32 (6.25%)	4 / 30 (13.33%)
occurrences all number	2	9	4	2	4
BONE PAIN
subjects affected / exposed ^[179]	1 / 16 (6.25%)	4 / 43 (9.30%)	1 / 47 (2.13%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	5	1	0	1
NECK PAIN
subjects affected / exposed ^[180]	0 / 16 (0.00%)	1 / 43 (2.33%)	2 / 47 (4.26%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	1	2	2	0
BACK PAIN
subjects affected / exposed ^[181]	2 / 16 (12.50%)	2 / 43 (4.65%)	6 / 47 (12.77%)	4 / 32 (12.50%)	4 / 30 (13.33%)
occurrences all number	2	2	6	6	5
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed ^[182]	0 / 16 (0.00%)	2 / 43 (4.65%)	2 / 47 (4.26%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	2	2	2	0
MYALGIA
subjects affected / exposed ^[183]	2 / 16 (12.50%)	6 / 43 (13.95%)	6 / 47 (12.77%)	2 / 32 (6.25%)	4 / 30 (13.33%)
occurrences all number	2	8	8	4	4
JOINT SWELLING
subjects affected / exposed ^[184]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	1	0	0	1	0
PAIN IN EXTREMITY
subjects affected / exposed ^[185]	1 / 16 (6.25%)	5 / 43 (11.63%)	2 / 47 (4.26%)	4 / 32 (12.50%)	3 / 30 (10.00%)
occurrences all number	1	5	2	5	5
Infections and infestations
SINUSITIS
subjects affected / exposed ^[186]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	2 / 32 (6.25%)	2 / 30 (6.67%)
occurrences all number	0	0	0	2	2
RASH PUSTULAR
subjects affected / exposed ^[187]	0 / 16 (0.00%)	1 / 43 (2.33%)	1 / 47 (2.13%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	1	1	2	2
FURUNCLE
subjects affected / exposed ^[188]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	0	1
INFLUENZA
subjects affected / exposed ^[189]	1 / 16 (6.25%)	1 / 43 (2.33%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	1	0	0	0
NASOPHARYNGITIS
subjects affected / exposed ^[190]	1 / 16 (6.25%)	1 / 43 (2.33%)	2 / 47 (4.26%)	1 / 32 (3.13%)	4 / 30 (13.33%)
occurrences all number	1	1	4	2	8
PARONYCHIA
subjects affected / exposed ^[191]	1 / 16 (6.25%)	2 / 43 (4.65%)	4 / 47 (8.51%)	0 / 32 (0.00%)	3 / 30 (10.00%)
occurrences all number	1	4	5	0	3
VAGINAL INFECTION
subjects affected / exposed ^[192]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
LOCALISED INFECTION
subjects affected / exposed ^[193]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	0	1
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed ^[194]	2 / 16 (12.50%)	4 / 43 (9.30%)	3 / 47 (6.38%)	4 / 32 (12.50%)	5 / 30 (16.67%)
occurrences all number	4	6	3	5	5
PNEUMONIA
subjects affected / exposed ^[195]	0 / 16 (0.00%)	1 / 43 (2.33%)	3 / 47 (6.38%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	3	0	1
LYMPHANGITIS
subjects affected / exposed ^[196]	0 / 16 (0.00%)	0 / 43 (0.00%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0
CYSTITIS
subjects affected / exposed ^[197]	0 / 16 (0.00%)	1 / 43 (2.33%)	3 / 47 (6.38%)	1 / 32 (3.13%)	0 / 30 (0.00%)
occurrences all number	0	1	4	1	0
ORAL HERPES
subjects affected / exposed ^[198]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	1	0	3	0
PHARYNGITIS
subjects affected / exposed ^[199]	0 / 16 (0.00%)	0 / 43 (0.00%)	3 / 47 (6.38%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	0	3	2	0
CELLULITIS
subjects affected / exposed ^[200]	0 / 16 (0.00%)	1 / 43 (2.33%)	0 / 47 (0.00%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	1	0	1	3
NAIL INFECTION
subjects affected / exposed ^[201]	0 / 16 (0.00%)	0 / 43 (0.00%)	2 / 47 (4.26%)	1 / 32 (3.13%)	2 / 30 (6.67%)
occurrences all number	0	0	2	1	2
LARYNGITIS
subjects affected / exposed ^[202]	1 / 16 (6.25%)	0 / 43 (0.00%)	2 / 47 (4.26%)	0 / 32 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	2	0	1
IMPETIGO
subjects affected / exposed ^[203]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
URINARY TRACT INFECTION
subjects affected / exposed ^[204]	2 / 16 (12.50%)	1 / 43 (2.33%)	4 / 47 (8.51%)	3 / 32 (9.38%)	7 / 30 (23.33%)
occurrences all number	3	4	6	4	9
Metabolism and nutrition disorders
DEHYDRATION
subjects affected / exposed ^[205]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0
HYPOMAGNESAEMIA
subjects affected / exposed ^[206]	1 / 16 (6.25%)	0 / 43 (0.00%)	2 / 47 (4.26%)	4 / 32 (12.50%)	3 / 30 (10.00%)
occurrences all number	1	0	3	5	3
DECREASED APPETITE
subjects affected / exposed ^[207]	3 / 16 (18.75%)	10 / 43 (23.26%)	9 / 47 (19.15%)	4 / 32 (12.50%)	3 / 30 (10.00%)
occurrences all number	3	14	11	4	3
HYPOPHOSPHATAEMIA
subjects affected / exposed ^[208]	0 / 16 (0.00%)	1 / 43 (2.33%)	2 / 47 (4.26%)	2 / 32 (6.25%)	0 / 30 (0.00%)
occurrences all number	0	1	3	2	0
HYPOKALAEMIA
subjects affected / exposed ^[209]	0 / 16 (0.00%)	1 / 43 (2.33%)	5 / 47 (10.64%)	5 / 32 (15.63%)	3 / 30 (10.00%)
occurrences all number	0	1	8	5	4
DIABETES MELLITUS
subjects affected / exposed ^[210]	1 / 16 (6.25%)	0 / 43 (0.00%)	0 / 47 (0.00%)	0 / 32 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	0

Notes
[53] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[54] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[55] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[56] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[57] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[58] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[59] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[60] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[61] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[62] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[63] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[64] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[65] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[66] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[67] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[68] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[69] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[70] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[71] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[72] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[73] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[74] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[75] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[76] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[77] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[78] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[79] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[80] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[81] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[82] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[83] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[84] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[85] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[86] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[87] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[88] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[89] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[90] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[91] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[92] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[93] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[94] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[95] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[96] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[97] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[98] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[99] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[100] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[101] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[102] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[103] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[104] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[105] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[106] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[107] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[108] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[109] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[110] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[111] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[112] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[113] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[114] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[115] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[116] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[117] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[118] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[119] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[120] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[121] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[122] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[123] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[124] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[125] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[126] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[127] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[128] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[129] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[130] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[131] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[132] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[133] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[134] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[135] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[136] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[137] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[138] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[139] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[140] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[141] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[142] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[143] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[144] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[145] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[146] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[147] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[148] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[149] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[150] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[151] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[152] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[153] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[154] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[155] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[156] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[157] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[158] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[159] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[160] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[161] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[162] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[163] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[164] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[165] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[166] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[167] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[168] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[169] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[170] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[171] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[172] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[173] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[174] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[175] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[176] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[177] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[178] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[179] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[180] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[181] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[182] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[183] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[184] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[185] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[186] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[187] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[188] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[189] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[190] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[191] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[192] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[193] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[194] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[195] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[196] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[197] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[198] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[199] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[200] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[201] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[202] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[203] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[204] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[205] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[206] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[207] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[208] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[209] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.
[210] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The number of deaths displays information from the ITT population. One participant in Cohort III didn't receive treatment and is not counted in the AE tables. The safety population was defined as participants who received any amount of any study drug. The serious and non-serious AEs are reported with data from this population.

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Dec 2017

The following updates were made: [1] An exploratory patient-reported outcome (PRO) objective for Cohort I was corrected to align with the procotol version 4; [2] The risks associated with atezolizumab were updated; [3] Information and guidance for anticipated overlapping AEs for cobimetinib and atezolizumab along with atezolizumab treatment interruption were added; [4] Guidelines for managing participants who experience diarrhea was revised to clarify the management of diarrhea for all participants; [5] Management guidelines for AEs were revised; [6] Guidelines for managing participants who experienced atezolizumab-associated AEs was added.

25 Oct 2018

The following updates were made: [1] Subsequent reviews of the triplet treatment combinations for Cohorts II and III were updated to take place as needed; [2] The flexible wording that paclitaxel “may also be considered an IMP in this study, depending on local legislation” was removed; [3] Guidelines for managing participants who experienced atezolizumab-associated AEs was revised; [4] The reporting of the term "sudden death" was updated; [5] AE reporting for hospitalization was updated; [6] The reporting timeframe for SAEs and AESIs was updated for Cohorts II and III; [7] Language was updated for clarity in various sections of the protocol; [8] The process for reviewing and handling protocol deviations was updated; [9] Clarification was made regarding the predose atezolizumab serum sampling times.

17 Feb 2021

The following updates were made: [1] The list of approved indications for atezolizumab was updated; [2] "Immune-related" was changed to "immune-mediated" when describing events associated with atezolizumab; [3] Immunosuppressive medications were removed from the prohibited therapy section and added to the cautionary therapy; [4] List of atezolizumab was updated; [5] Guidelines for management of atezolizumab-associated dermatologic AEs was revised; [6] Language was added for clarity in various sections of the protocol; [7] Appendix 10 (Anaphylaxis Precautions) was modified to remove the requirement for use of a tourniquet; [8] Appendix 11 has been revised to indicate that caution should be used when considering atezolizumab for participants who previously experienced a severe or life-threatening skin adverse reaction while receiving another immunostimulatory anti-cancer agent.

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.

The sponsor decided to terminate this study.

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

Primary: Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

Primary: Cohort II, III: Percentage of Participants With Confirmed Overall Response (OR) (Partial Response [PR] or Complete Response [CR]), as Determined by the Investigator Using RECIST v1.1

Primary: Cohort II, III: Percentage of Participants With Confirmed Overall Response (OR) (Partial Response [PR] or Complete Response [CR]), as Determined by the Investigator Using RECIST v1.1

Secondary: Cohort I, II, III: Overall Survival (OS)

Secondary: Cohort I, II, III: Overall Survival (OS)

Secondary: Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1

Secondary: Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1

Secondary: Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1

Secondary: Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1

Secondary: Cohort I, II, III: Percentage of Participants With Unconfirmed Overall Response (OR_uc) (Unconfirmed PR or CR), as Determined by the Investigator Using RECIST v1.1

Secondary: Cohort I, II, III: Percentage of Participants With Unconfirmed Overall Response (OR_uc) (Unconfirmed PR or CR), as Determined by the Investigator Using RECIST v1.1

Secondary: Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1

Secondary: Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1

Secondary: Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)

Secondary: Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)

Secondary: Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib

Secondary: Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib

Secondary: Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib

Secondary: Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib

Secondary: Cohort I: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib

Secondary: Cohort I: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib

Secondary: Cohort I, II: Cmax of Paclitaxel

Secondary: Cohort I, II: Cmax of Paclitaxel

Secondary: Cohort I, II: Cmin of Paclitaxel

Secondary: Cohort I, II: Cmin of Paclitaxel

Secondary: Cohort I: AUC0-tau of Paclitaxel

Secondary: Cohort I: AUC0-tau of Paclitaxel

Secondary: Cohort III: Cmax of Nab-Paclitaxel

Secondary: Cohort III: Cmax of Nab-Paclitaxel

Secondary: Cohort III: Cmin of Nab-Paclitaxel

Secondary: Cohort III: Cmin of Nab-Paclitaxel

Secondary: Cohort III: AUC0-tau of Nab-Paclitaxel

Secondary: Cohort III: AUC0-tau of Nab-Paclitaxel

Secondary: Cohort II, III: Cmax (in Serum) of Atezolizumab

Secondary: Cohort II, III: Cmax (in Serum) of Atezolizumab

Secondary: Cohort II, III: Cmin (in Serum) of Atezolizumab

Secondary: Cohort II, III: Cmin (in Serum) of Atezolizumab

Secondary: Cohort II, III: AUC0-tau (in Serum) of Atezolizumab

Secondary: Cohort II, III: AUC0-tau (in Serum) of Atezolizumab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information