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Clinical Trial Results:
A Phase 1/2 Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered in Combination With Nivolumab in Select Advanced Cancers (ECHO-204)

Summary
EudraCT number	2016-002423-29
Trial protocol	GB
Global end of trial date	16 Jun 2020

Results information
Results version number	v1(current)
This version publication date	02 Jul 2021
First version publication date	02 Jul 2021
Other versions

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

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Trial information

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Sponsor protocol code

INCB 24360-204 / ECHO-204

ISRCTN number

US NCT number

NCT02327078

WHO universal trial number (UTN)

Sponsor organisation name

Incyte Corporation

Sponsor organisation address

1801 Augustine Cut-Off, Wilmington, United States, 19803

Public contact

Study Director, Incyte Corporation, +44 (0)330 100 3677, globalmedinfo@incyte.com

Scientific contact

Study Director, Incyte Corporation, +44 (0)330 100 3677, globalmedinfo@incyte.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

16 Jun 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Jun 2020

Was the trial ended prematurely?

Main objective of the trial

This is a Phase 1/2, open label study. Phase 1 consists of 2 parts. Part 1 is a dose-escalation assessment of the safety and tolerability of epacadostat administered with nivolumab in subjects with select advanced solid tumors and lymphomas. Phase 2 is comprised of 9 tumor specific expansion cohorts in including melanoma, NSCLC, SCCHN, colorectal cancer, ovarian cancer, glioblastoma and diffuse large B-cell lymphoma (DLBCL), and will further characterize the safety, efficacy, pharmacokinetics and pharmacodynamics of the combination of epacadostat and nivolumab.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Dec 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 301

Country: Number of subjects enrolled

United Kingdom: 6

Worldwide total number of subjects

307

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)

185

From 65 to 84 years

116

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 25 study sites in the United States and 2 study sites in United Kingdom. For each treatment group, results included data contributed by participants from Phase 1 Part 1, Phase 1 Part 2 and Phase 2.

Screening details

A total of 307 participants were enrolled in the study. Study enrollment was permanently discontinued on 25 Oct 2018 as a strategic decision. At the time of data cut-off date of 01Feb 2019, 22 participants were ongoing.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab

Arm description

Epacadostat 25mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab

Arm description

Epacadostat 50mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab

Arm description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab

Arm description

Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum

Arm description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360mg Q3W and 5-FU/Platinum( Carboplatin or Cisplatin+5-Fluorouracil) administered intravenously (IV).

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum

Arm description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Pemetrexed/Platinum (Carboplatin orCisplatin+Pemetrexed) administered intravenously (IV).

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum

Arm description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Paclitaxel/Platinum(Carboplatin+Cisplatin+Paclitaxel)administered intravenously (IV).

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 2 Epacadostat 100mg BID + Nivolumab

Arm description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W or 480 mg Q4W based on tumor type administered intravenously (IV).

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Phase 2 Epacadostat 300mg BID + Nivolumab

Arm description

Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Arm type

Experimental

Investigational medicinal product name

Epacadostat and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Epacadostat : oral twice daily continuous at the protocol-defined dose Nivolumab : specified dose and dosing schedule

Number of subjects in period 1	Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum	Phase 2 Epacadostat 100mg BID + Nivolumab	Phase 2 Epacadostat 300mg BID + Nivolumab
Started	3	6	14	13	6	3	3	83	176
Completed	0	0	0	0	0	0	0	0	0
Not completed	3	6	14	13	6	3	3	83	176
completed 100 days of safety FU period	-	-	-	1	-	-	1	3	11
Consent withdrawn by subject	-	1	2	1	1	-	-	11	25
Physician decision	-	-	-	1	1	-	-	-	1
Death	2	4	10	6	4	3	2	51	97
Unknown	-	-	-	-	-	-	-	5	12
Study Terminated by Sponsor	1	-	1	4	-	-	-	11	25
Lost to follow-up	-	1	1	-	-	-	-	2	5

Baseline characteristics

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Reporting group title

Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab

Reporting group description

Epacadostat 25mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W

Reporting group title

Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab

Reporting group description

Epacadostat 50mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Reporting group title

Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Reporting group title

Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab

Reporting group description

Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360mg Q3W and 5-FU/Platinum( Carboplatin or Cisplatin+5-Fluorouracil) administered intravenously (IV).

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Pemetrexed/Platinum (Carboplatin orCisplatin+Pemetrexed) administered intravenously (IV).

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Paclitaxel/Platinum(Carboplatin+Cisplatin+Paclitaxel)administered intravenously (IV).

Reporting group title

Phase 2 Epacadostat 100mg BID + Nivolumab

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W or 480 mg Q4W based on tumor type administered intravenously (IV).

Reporting group title

Phase 2 Epacadostat 300mg BID + Nivolumab

Reporting group description

Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Reporting group values	Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum	Phase 2 Epacadostat 100mg BID + Nivolumab	Phase 2 Epacadostat 300mg BID + Nivolumab	Total
Number of subjects	3	6	14	13	6	3	3	83	176	307
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	2	3	9	9	3	1	1	65	92	185
From 65-84 years	1	3	5	4	3	2	2	18	78	116
85 years and over	0	0	0	0	0	0	0	0	6	6
Age Continuous
Units: years
arithmetic mean (standard deviation)	50.0 ± 26.00	62.5 ± 12.41	57.5 ± 13.27	61.6 ± 10.67	64.3 ± 6.38	67.7 ± 6.43	70.3 ± 11.37	56.5 ± 13.45	62.6 ± 12.12	-
Sex: Female, Male
Units:
Female	2	1	11	5	1	1	1	46	77	145
Male	1	5	3	8	5	2	2	37	99	162
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0	0	6	11	17
Not Hispanic or Latino	3	5	14	13	6	3	3	77	159	283
Unknown or Not Reported	0	1	0	0	0	0	0	0	6	7
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0	0	3	3
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	1	1
Black or African American	0	0	0	0	1	0	0	2	4	7
White	3	6	13	13	5	3	3	76	160	282
More than one race	0	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	1	0	0	0	0	5	8	14
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) scale describes a patient's level of functioning in terms of their ability to care for themselves, activity, and ability. The scale is from 0 to 5; 0 - Fully active; 1 - Restricted in physically strenuous activity but ambulatory; 2- Ambulatory and capable of all selfcare but unable to carry out any work activities; 3- Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours; 4 - Completely disabled; 5 - Dead.
Units: Subjects
zero	3	5	6	8	2	1	1	40	73	139
one	0	1	8	5	4	2	2	43	101	166
two	0	0	0	0	0	0	0	0	1	1
missing	0	0	0	0	0	0	0	0	1	1

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Colorectal Cancer

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in DLBCL

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Melanoma(I/O Naive)

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Relapsed)

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 480mg Q4W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Refractory)

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 480mg Q4W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in NSCLC

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Ovarian Cancer

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in SCCHN

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Glioblastoma

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis sets values	Phase 2 Epacadostat + Nivolumab in Colorectal Cancer	Phase 2 Epacadostat + Nivolumab in DLBCL	Phase 2 Epacadostat + Nivolumab in Melanoma(I/O Naive)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Relapsed)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Refractory)	Phase 2 Epacadostat + Nivolumab in NSCLC	Phase 2 Epacadostat + Nivolumab in Ovarian Cancer	Phase 2 Epacadostat + Nivolumab in SCCHN	Phase 2 Epacadostat + Nivolumab in Glioblastoma
Number of subjects	26	18	50	7	7	58	29	31	33
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	23	11	28	5	4	26	18	17	25
From 65-84 years	3	6	21	2	3	29	11	13	8
85 years and over	0	1	1	0	0	3	0	1	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	1 ±	0 ±	31 ±	1 ±	2 ±	12 ±	4 ±	8 ±	0 ±
Sex: Female, Male
Units:
Female
Male
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino
Not Hispanic or Latino
Unknown or Not Reported
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native
Asian
Native Hawaiian or Other Pacific Islander
Black or African American
White
More than one race
Unknown or Not Reported
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) scale describes a patient's level of functioning in terms of their ability to care for themselves, activity, and ability. The scale is from 0 to 5; 0 - Fully active; 1 - Restricted in physically strenuous activity but ambulatory; 2- Ambulatory and capable of all selfcare but unable to carry out any work activities; 3- Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours; 4 - Completely disabled; 5 - Dead.
Units: Subjects
zero
one
two
missing

End points

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Reporting group title

Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab

Reporting group description

Epacadostat 25mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W

Reporting group title

Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab

Reporting group description

Epacadostat 50mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Reporting group title

Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Reporting group title

Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab

Reporting group description

Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360mg Q3W and 5-FU/Platinum( Carboplatin or Cisplatin+5-Fluorouracil) administered intravenously (IV).

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Pemetrexed/Platinum (Carboplatin orCisplatin+Pemetrexed) administered intravenously (IV).

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Paclitaxel/Platinum(Carboplatin+Cisplatin+Paclitaxel)administered intravenously (IV).

Reporting group title

Phase 2 Epacadostat 100mg BID + Nivolumab

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W or 480 mg Q4W based on tumor type administered intravenously (IV).

Reporting group title

Phase 2 Epacadostat 300mg BID + Nivolumab

Reporting group description

Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Colorectal Cancer

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in DLBCL

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Melanoma(I/O Naive)

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Relapsed)

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 480mg Q4W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Refractory)

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100mg or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 480mg Q4W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in NSCLC

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Ovarian Cancer

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in SCCHN

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Subject analysis set title

Phase 2 Epacadostat + Nivolumab in Glioblastoma

Subject analysis set type

Full analysis

Subject analysis set description

Epacadostat 100 or 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Primary: Phase 1, Part 1: Safety and tolerability of epacadostat and nivolumab assessed by number of subjects with dose limiting toxicities (DLTs)

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End point title

Phase 1, Part 1: Safety and tolerability of epacadostat and nivolumab assessed by number of subjects with dose limiting toxicities (DLTs) ^[1] ^[2]

End point description

A DLT was defined as the occurrence of any of the toxicities occurring up to and including Day 42 in Phase 1 Parts 1 and 2.

End point type

Primary

End point timeframe

42 days

Notes
[1] - 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
[2] - 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: No statistical analyses for this end point

End point values	Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab
Number of subjects analysed	3	6	14	13
Units: participants	0	0	0	0

No statistical analyses for this end point

Primary: Phase 1, Part 2: Safety and tolerability of epacadostat administered in combination with nivolumab and chemotherapy regimen assessed by number of subjects with DLTs

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End point title

Phase 1, Part 2: Safety and tolerability of epacadostat administered in combination with nivolumab and chemotherapy regimen assessed by number of subjects with DLTs ^[3] ^[4]

End point description

A DLT was defined as the occurrence of any of the toxicities occurring up to and including Day 42 in Phase 1 Parts 1 and 2.

End point type

Primary

End point timeframe

42 days

Notes
[3] - 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
[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: No statistical analyses for this end point

End point values	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum
Number of subjects analysed	6	3	3
Units: participants
number (not applicable)	0	0	1

No statistical analyses for this end point

Primary: Phase 1, Part 1 and 2: Safety assessed by number of Treatment Emergent Adverse Events (TEAEs)

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End point title

Phase 1, Part 1 and 2: Safety assessed by number of Treatment Emergent Adverse Events (TEAEs) ^[5] ^[6]

End point description

A treatment-emergent adverse event (TEAE) is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and up to 100 days after last dose of study drug.

End point type

Primary

End point timeframe

up to 27 months

Notes
[5] - 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
[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: No statistical analyses for this end point

End point values	Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum
Number of subjects analysed	3	6	14	13	6	3	3
Units: participants	3	6	14	13	6	3	3

No statistical analyses for this end point

Primary: Phase 2: Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for subjects with solid tumors and per Cheson criteria for subjects with DLBCL

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End point title

Phase 2: Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for subjects with solid tumors and per Cheson criteria for subjects with DLBCL ^[7]

End point description

ORR was defined as the percentage of participants having a complete response (CR) or partial response (PR) as determined by investigator assessment of radiographic disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Cheson criteria for DLBCL and RANO criteria for Glioblastoma.

End point type

Primary

End point timeframe

Response is assessed every 8 weeks up to 24 months

Notes
[7] - 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

End point values	Phase 2 Epacadostat + Nivolumab in Colorectal Cancer	Phase 2 Epacadostat + Nivolumab in DLBCL	Phase 2 Epacadostat + Nivolumab in Melanoma(I/O Naive)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Relapsed)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Refractory)	Phase 2 Epacadostat + Nivolumab in NSCLC	Phase 2 Epacadostat + Nivolumab in Ovarian Cancer	Phase 2 Epacadostat + Nivolumab in SCCHN	Phase 2 Epacadostat + Nivolumab in Glioblastoma
Number of subjects analysed	26	18	50	7	7	58	29	31	33
Units: participants
number (not applicable)	1	0	31	1	2	12	4	8	0

No statistical analyses for this end point

Primary: Phase 2: Progression free survival (PFS)

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End point title

Phase 2: Progression free survival (PFS) ^[8]

End point description

PFS is defined as the time from randomization to the first documented progressive disease per RECIST v1.1 or death due to any cause, whichever occurs first.

End point type

Primary

End point timeframe

Response is assessed every 8 weeks up to 24 months

Notes
[8] - 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

End point values	Phase 2 Epacadostat + Nivolumab in Colorectal Cancer	Phase 2 Epacadostat + Nivolumab in DLBCL	Phase 2 Epacadostat + Nivolumab in Melanoma(I/O Naive)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Relapsed)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Refractory)	Phase 2 Epacadostat + Nivolumab in NSCLC	Phase 2 Epacadostat + Nivolumab in Ovarian Cancer	Phase 2 Epacadostat + Nivolumab in SCCHN	Phase 2 Epacadostat + Nivolumab in Glioblastoma
Number of subjects analysed	26	18	50	7	7	58	29	31	33
Units: months
median (confidence interval 95%)	1.78 (1.74 to 1.81)	1.64 (1.35 to 3.52)	9.99999 (9.51 to 99999)	1.76 (0.46 to 999999)	2.55 (0.59 to 999999)	1.88 (1.78 to 2.04)	1.88 (1.68 to 3.52)	3.62 (1.78 to 9.08)	1.84 (1.78 to 2.63)

No statistical analyses for this end point

Primary: Phase 2: Overall survival (OS) for subjects with Glioblastoma

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End point title

Phase 2: Overall survival (OS) for subjects with Glioblastoma ^[9]

End point description

Overall survival (OS) at 9 months defined as the proportion of patients alive 9 months after the start of treatment

End point type

Primary

End point timeframe

Subjects will be followed-up for survival every 12 weeks for up to 9 months.

Notes
[9] - 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 data is being reported for other tumor types in Phase 2 of the study as the end point applies to only Glioblastoma population in Phase 2 of the study

End point values	Phase 2 Epacadostat + Nivolumab in Glioblastoma
Number of subjects analysed	33
Units: Survival Rate
number (confidence interval 90%)	0.458 (0.297 to 0.605)

No statistical analyses for this end point

Secondary: Phase 1, Part 1: ORR per RECIST v1.1 and mRECIST for subjects with solid tumors; per Cheson and mCheson criteria for subjects with B-cell NHL; and per RANO and mRANO criteria for subjects with GBM

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End point title

Phase 1, Part 1: ORR per RECIST v1.1 and mRECIST for subjects with solid tumors; per Cheson and mCheson criteria for subjects with B-cell NHL; and per RANO and mRANO criteria for subjects with GBM ^[10]

End point description

End point type

Secondary

End point timeframe

Response will be assessed every 8 weeks during study participation which is estimated to be up to 24 months.

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: No statistical analyses for this end point

End point values	Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab
Number of subjects analysed	0 ^[11]	0 ^[12]	0 ^[13]	0 ^[14]
Units: participants
number (not applicable)

Notes
[11] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[12] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[13] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[14] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.

No statistical analyses for this end point

Secondary: Phase 1, Part 2: ORR per RECIST v1.1 and modified RECIST for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

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End point title

Phase 1, Part 2: ORR per RECIST v1.1 and modified RECIST for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC ^[15]

End point description

End point type

Secondary

End point timeframe

Response will be assessed every 8 weeks during study participation which is estimated to be to be up to 24 months.

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: No data is being reported for Phase part 1 of the stud y as the end point applies to only Phase 1 Part 2 of the study

End point values	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum
Number of subjects analysed	0 ^[16]	0 ^[17]	0 ^[18]
Units: participants
number (not applicable)

Notes
[16] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[17] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[18] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.

No statistical analyses for this end point

Secondary: Phase 1, Part 2: Duration of response (DOR) for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

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End point title

Phase 1, Part 2: Duration of response (DOR) for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC ^[19]

End point description

End point type

Secondary

End point timeframe

Response will be assessed every 8 weeks during study participation which is estimated to be up to 24 months.

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: No data is being reported for Phase part 1 of the stud y as the end point applies to only Phase 1 Part 2 of the study

End point values	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum
Number of subjects analysed	0 ^[20]	0 ^[21]	0 ^[22]
Units: participants
number (not applicable)

Notes
[20] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[21] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[22] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.

No statistical analyses for this end point

Secondary: Phase 1, Part 2: PFS for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

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End point title

Phase 1, Part 2: PFS for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC ^[23]

End point description

End point type

Secondary

End point timeframe

Response will be assessed every 8 weeks during study participation which is estimated to be up to 24 months.

Notes
[23] - 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: No data is being reported for Phase part 1 of the stud y as the end point applies to only Phase 1 Part 2 of the study

End point values	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum
Number of subjects analysed	0 ^[24]	0 ^[25]	0 ^[26]
Units: participants
number (not applicable)

Notes
[24] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[25] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.
[26] - Phase 1 had small sample size & heterogeneous population, hence efficacy was not summarized.

No statistical analyses for this end point

Secondary: Phase 2: Duration of response (DOR)

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End point title

Phase 2: Duration of response (DOR)

End point description

End point type

Secondary

End point timeframe

Response will be assessed every 8 weeks during study participation which is estimated to be up to 24 months.

End point values	Phase 2 Epacadostat + Nivolumab in Colorectal Cancer	Phase 2 Epacadostat + Nivolumab in DLBCL	Phase 2 Epacadostat + Nivolumab in Melanoma(I/O Naive)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Relapsed)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Refractory)	Phase 2 Epacadostat + Nivolumab in NSCLC	Phase 2 Epacadostat + Nivolumab in Ovarian Cancer	Phase 2 Epacadostat + Nivolumab in SCCHN	Phase 2 Epacadostat + Nivolumab in Glioblastoma
Number of subjects analysed	1	^[27]	31	1	2	12	4	8	^[28]
Units: months
median (confidence interval 95%)	0.8888888 (-9999999 to 9999999)	0.888888 (-9999999 to 9999999)	8.888888 (7.37 to 9999999)	0.88888 (-9999999 to 9999999)	0.888888 (-9999999 to 9999999)	8.888888 (1.94 to 9999999)	3.93 (3.13 to 5.53)	8.8888888 (7.37 to 9999999)	0.8888888 (-9999999 to 9999999)

Notes
[27] - No responders
[28] - No responders

No statistical analyses for this end point

Secondary: Phase 2: Duration of disease control, defined as CR, PR, and stable disease (SD)

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End point title

Phase 2: Duration of disease control, defined as CR, PR, and stable disease (SD)

End point description

End point type

Secondary

End point timeframe

Response will be assessed every 8 weeks during study participation which is estimated to be up to 24 months.

End point values	Phase 2 Epacadostat + Nivolumab in Colorectal Cancer	Phase 2 Epacadostat + Nivolumab in DLBCL	Phase 2 Epacadostat + Nivolumab in Melanoma(I/O Naive)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Relapsed)	Phase 2 Epacadostat + Nivolumab in Melanoma (I/O Refractory)	Phase 2 Epacadostat + Nivolumab in NSCLC	Phase 2 Epacadostat + Nivolumab in Ovarian Cancer	Phase 2 Epacadostat + Nivolumab in SCCHN	Phase 2 Epacadostat + Nivolumab in Glioblastoma
Number of subjects analysed									26
Units: months
median (confidence interval 95%)	3.72 (2.86 to 9999999)	4.57 (3.52 to 10.26)	9999999 (9999999 to 9999999)	9999999 (9999999 to 9999999)	9999999 (3.19 to 9999999)	9999999 (9.11 to 9999999)	5.86 (3.52 to 7.47)	10.89 (4.84 to 9999999)	3.72 (3.49 to 5.59)

No statistical analyses for this end point

Secondary: Phase 2: Safety and tolerability measured by the frequency of adverse events (AEs), serious adverse events (SAEs), and deaths

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End point title

Phase 2: Safety and tolerability measured by the frequency of adverse events (AEs), serious adverse events (SAEs), and deaths ^[29]

End point description

End point type

Secondary

End point timeframe

AEs are assessed for the duration of the study participation which is estimated to be up to 27 months (24 months +100 day safety FU).

Notes
[29] - 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: No statistical analyses for this end point

End point values	Phase 2 Epacadostat 100mg BID + Nivolumab	Phase 2 Epacadostat 300mg BID + Nivolumab
Number of subjects analysed	83	176
Units: participants
number (not applicable)
Subjects with Treatment Emergent Adverse Events	82	176
Subjects with Serious Treatment Emergent AEs	40	89
Subjects with fatal Treatment Emergent AEs	4	5

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 27 months

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab

Reporting group description

Epacadostat 25mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W

Reporting group title

Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab

Reporting group description

Epacadostat 50mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W

Reporting group title

Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W

Reporting group title

Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab

Reporting group description

pacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360mg Q3W and 5-FU/Platinum( Carboplatin or Cisplatin+5-Fluorouracil) administered intravenously (IV).

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Paclitaxel/Platinum(Carboplatin+Cisplatin+Paclitaxel)administered intravenously (IV).

Reporting group title

Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Pemetrexed/Platinum (Carboplatin orCisplatin+Pemetrexed) administered intravenously (IV).

Reporting group title

Phase 2 Epacadostat 100mg BID + Nivolumab

Reporting group description

Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W or 480 mg Q4W based on tumor type administered intravenously (IV).

Reporting group title

Phase 2 Epacadostat 300mg BID + Nivolumab

Reporting group description

Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Reporting group title

Total

Reporting group description

Total

Serious adverse events	Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 2 Epacadostat 100mg BID + Nivolumab	Phase 2 Epacadostat 300mg BID + Nivolumab	Total
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 3 (0.00%)	3 / 6 (50.00%)	4 / 14 (28.57%)	4 / 13 (30.77%)	4 / 6 (66.67%)	2 / 3 (66.67%)	2 / 3 (66.67%)	40 / 83 (48.19%)	89 / 176 (50.57%)	148 / 307 (48.21%)
number of deaths (all causes)	2	4	11	7	4	2	3	52	97	182
number of deaths resulting from adverse events	0	1	0	0	0	0	1	4	5	11
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm malignant
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Arterial haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exsanguination
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Flushing
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	2 / 176 (1.14%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	4 / 176 (2.27%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	4 / 4	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 83 (2.41%)	6 / 176 (3.41%)	11 / 307 (3.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 3	1 / 6	1 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	5 / 176 (2.84%)	6 / 307 (1.95%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 5	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 83 (1.20%)	5 / 176 (2.84%)	7 / 307 (2.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 6	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Pneumonia aspiration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	4 / 176 (2.27%)	6 / 307 (1.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 5	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	4 / 176 (2.27%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	1 / 176 (0.57%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 6	0 / 1	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle rupture
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiation necrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Myocardial infarction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain compression
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cauda equina syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Convulsion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	6 / 176 (3.41%)	7 / 307 (2.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 6	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	3 / 176 (1.70%)	7 / 307 (2.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 4	1 / 3	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Facial paresis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	4 / 176 (2.27%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 4	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemianopia homonymous
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myoclonus
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VIIth nerve paralysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasogenic cerebral oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	4 / 176 (2.27%)	4 / 307 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 4	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	1 / 176 (0.57%)	4 / 307 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	4 / 307 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	1 / 3	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterovesical fistula
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	5 / 176 (2.84%)	7 / 307 (2.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	3 / 7	3 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	1 / 176 (0.57%)	7 / 307 (2.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 1	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	6 / 176 (3.41%)	8 / 307 (2.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	3 / 8	3 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	2 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	3 / 176 (1.70%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	4 / 4	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Swelling face
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	3 / 176 (1.70%)	6 / 307 (1.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	1 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adrenocortical insufficiency acute
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	4 / 307 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	2 / 3 (66.67%)	0 / 3 (0.00%)	3 / 83 (3.61%)	8 / 176 (4.55%)	15 / 307 (4.89%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 3	0 / 0	0 / 3	1 / 9	1 / 17
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	5 / 307 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	4 / 176 (2.27%)	9 / 307 (2.93%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 4	0 / 4	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	2 / 307 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Type 2 diabetes mellitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab	Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum	Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Phase 2 Epacadostat 100mg BID + Nivolumab	Phase 2 Epacadostat 300mg BID + Nivolumab	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	6 / 6 (100.00%)	14 / 14 (100.00%)	13 / 13 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	81 / 83 (97.59%)	173 / 176 (98.30%)	302 / 307 (98.37%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	4 / 176 (2.27%)	8 / 307 (2.61%)
occurrences all number	0	0	1	0	0	0	0	4	4	9
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	13 / 83 (15.66%)	16 / 176 (9.09%)	31 / 307 (10.10%)
occurrences all number	0	0	1	1	0	0	0	17	32	51
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 83 (7.23%)	16 / 176 (9.09%)	23 / 307 (7.49%)
occurrences all number	0	0	0	0	1	0	0	7	18	26
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	2 / 176 (1.14%)	5 / 307 (1.63%)
occurrences all number	0	0	0	1	0	0	0	2	2	5
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	1	0	0	0	0	0	1	2
Chills
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	10 / 83 (12.05%)	8 / 176 (4.55%)	22 / 307 (7.17%)
occurrences all number	1	1	0	1	0	1	0	11	10	25
Face oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	1	0	0	0	1	2
Facial pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Fatigue
subjects affected / exposed	3 / 3 (100.00%)	3 / 6 (50.00%)	4 / 14 (28.57%)	2 / 13 (15.38%)	4 / 6 (66.67%)	2 / 3 (66.67%)	3 / 3 (100.00%)	36 / 83 (43.37%)	123 / 176 (69.89%)	180 / 307 (58.63%)
occurrences all number	3	3	4	3	6	2	4	38	131	194
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	1	0	0	0	0	0	2	3
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	2 / 176 (1.14%)	7 / 307 (2.28%)
occurrences all number	0	0	0	1	0	0	0	4	4	9
Localised oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	1	0	0	0	0	0	0	2	3
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	15 / 83 (18.07%)	17 / 176 (9.66%)	37 / 307 (12.05%)
occurrences all number	0	2	1	1	0	1	0	18	18	41
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	4 / 307 (1.30%)
occurrences all number	0	0	0	1	0	0	0	0	3	4
Pyrexia
subjects affected / exposed	2 / 3 (66.67%)	0 / 6 (0.00%)	3 / 14 (21.43%)	2 / 13 (15.38%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	12 / 83 (14.46%)	29 / 176 (16.48%)	48 / 307 (15.64%)
occurrences all number	2	0	3	4	0	0	0	16	41	66
Suprapubic pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	1	0	0	0	0	0	0	0	0	1
Immune system disorders
Contrast media allergy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Reproductive system and breast disorders
Scrotal oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Vaginal odour
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	1	0	0	0	0	0	0	0	0	1
Vulvovaginal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	0	1	0	0	1	2
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	1	0	0	0	0	0	0	2	3
Aspiration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	1	0	0	0	0	1	2
Cough
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 14 (14.29%)	4 / 13 (30.77%)	2 / 6 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	19 / 83 (22.89%)	41 / 176 (23.30%)	72 / 307 (23.45%)
occurrences all number	1	1	2	4	2	3	0	23	50	86
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	5 / 176 (2.84%)	8 / 307 (2.61%)
occurrences all number	0	0	1	0	1	0	0	1	5	8
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 14 (7.14%)	4 / 13 (30.77%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	21 / 83 (25.30%)	30 / 176 (17.05%)	59 / 307 (19.22%)
occurrences all number	1	0	1	5	4	0	1	22	34	68
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	4 / 307 (1.30%)
occurrences all number	0	0	1	0	0	0	0	0	3	4
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 83 (0.00%)	5 / 176 (2.84%)	6 / 307 (1.95%)
occurrences all number	0	0	0	0	0	0	1	0	7	8
Haemoptysis
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	3 / 176 (1.70%)	5 / 307 (1.63%)
occurrences all number	1	0	0	0	0	0	0	1	3	5
Hiccups
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	0	0	0	1	0	1	1	3
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 13 (15.38%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 83 (2.41%)	9 / 176 (5.11%)	15 / 307 (4.89%)
occurrences all number	0	0	1	2	0	0	1	3	10	17
Increased upper airway secretion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 83 (6.02%)	20 / 176 (11.36%)	26 / 307 (8.47%)
occurrences all number	0	0	1	0	0	0	0	5	24	30
Oropharyngeal pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	13 / 176 (7.39%)	19 / 307 (6.19%)
occurrences all number	1	0	1	0	1	0	0	6	16	25
Oropharyngeal swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Paranasal sinus hypersecretion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 83 (6.02%)	3 / 176 (1.70%)	8 / 307 (2.61%)
occurrences all number	0	0	0	0	0	0	0	5	3	8
Pleuritic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	1	0	0	0	0	1	2
Pneumonia aspiration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	4 / 307 (1.30%)
occurrences all number	0	0	0	0	1	0	0	0	5	6
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	3 / 176 (1.70%)	6 / 307 (1.95%)
occurrences all number	0	0	1	1	0	0	0	1	3	6
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	10 / 176 (5.68%)	12 / 307 (3.91%)
occurrences all number	0	0	0	0	0	0	0	2	11	13
Respiration abnormal
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	1	0	0	0	0	0	0	0	0	1
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Rhinitis allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	4 / 176 (2.27%)	9 / 307 (2.93%)
occurrences all number	0	0	0	0	1	0	0	4	5	10
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	4 / 176 (2.27%)	5 / 307 (1.63%)
occurrences all number	0	0	1	0	0	0	0	0	4	5
Throat tightness
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	1	0	0	0	0	0	0	0	0	1
Tracheal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	7 / 176 (3.98%)	11 / 307 (3.58%)
occurrences all number	0	0	1	0	0	0	0	3	9	13
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	4 / 307 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1	2	4
Anxiety
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 83 (6.02%)	12 / 176 (6.82%)	19 / 307 (6.19%)
occurrences all number	1	0	0	0	0	0	1	6	12	20
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 83 (2.41%)	7 / 176 (3.98%)	11 / 307 (3.58%)
occurrences all number	0	0	0	1	0	1	0	2	10	14
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	11 / 176 (6.25%)	18 / 307 (5.86%)
occurrences all number	0	0	0	0	3	0	0	4	11	18
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 14 (21.43%)	3 / 13 (23.08%)	3 / 6 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 83 (10.84%)	25 / 176 (14.20%)	43 / 307 (14.01%)
occurrences all number	0	0	3	3	3	0	0	9	25	43
Mental status changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	1	0	0	1	0	2
Panic attack
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 13 (15.38%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	12 / 83 (14.46%)	37 / 176 (21.02%)	53 / 307 (17.26%)
occurrences all number	0	0	1	3	1	0	0	17	51	73
Amylase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	2 / 13 (15.38%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 83 (10.84%)	16 / 176 (9.09%)	29 / 307 (9.45%)
occurrences all number	0	1	0	4	2	0	0	15	21	43
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	3 / 13 (23.08%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	17 / 83 (20.48%)	39 / 176 (22.16%)	61 / 307 (19.87%)
occurrences all number	0	0	2	5	1	0	0	27	58	93
Blood albumin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 83 (7.23%)	1 / 176 (0.57%)	7 / 307 (2.28%)
occurrences all number	0	0	0	0	0	0	0	6	1	7
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	15 / 83 (18.07%)	23 / 176 (13.07%)	40 / 307 (13.03%)
occurrences all number	0	0	1	1	0	0	0	25	27	54
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	4 / 176 (2.27%)	9 / 307 (2.93%)
occurrences all number	0	1	0	0	0	0	0	7	4	12
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	0	1	0	0	0	0	2	3
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 14 (14.29%)	2 / 13 (15.38%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	16 / 83 (19.28%)	13 / 176 (7.39%)	35 / 307 (11.40%)
occurrences all number	1	1	2	2	0	0	0	26	21	53
Blood uric acid increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	4 / 307 (1.30%)
occurrences all number	0	1	0	0	0	0	0	3	2	6
Carcinoembryonic antigen increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	0	1	0	0	0	1	1	3
Hepatic enzyme increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Lipase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 14 (7.14%)	4 / 13 (30.77%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 83 (9.64%)	20 / 176 (11.36%)	35 / 307 (11.40%)
occurrences all number	2	0	1	12	1	0	0	11	28	55
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 83 (7.23%)	14 / 176 (7.95%)	20 / 307 (6.51%)
occurrences all number	0	0	0	0	0	0	0	12	18	30
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 83 (6.02%)	5 / 176 (2.84%)	13 / 307 (4.23%)
occurrences all number	0	0	0	0	2	1	0	14	5	22
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Troponin I increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	0	0	0	1	0	0	0	1	0	2
Vitamin B1 decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 14 (14.29%)	1 / 13 (7.69%)	2 / 6 (33.33%)	0 / 3 (0.00%)	2 / 3 (66.67%)	9 / 83 (10.84%)	26 / 176 (14.77%)	44 / 307 (14.33%)
occurrences all number	0	2	2	1	2	0	2	9	29	47
Weight increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 83 (7.23%)	5 / 176 (2.84%)	12 / 307 (3.91%)
occurrences all number	0	0	0	1	0	0	0	8	5	14
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	9 / 176 (5.11%)	13 / 307 (4.23%)
occurrences all number	0	0	0	0	0	0	0	4	12	16
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 83 (3.61%)	3 / 176 (1.70%)	7 / 307 (2.28%)
occurrences all number	0	0	0	0	0	0	1	3	3	7
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	21 / 176 (11.93%)	28 / 307 (9.12%)
occurrences all number	0	0	1	1	1	0	0	4	24	31
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 83 (4.82%)	8 / 176 (4.55%)	15 / 307 (4.89%)
occurrences all number	0	0	0	2	0	1	0	6	10	19
Stoma site haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Stoma site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	1	0	0	0	1	2
Sunburn
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	1	0	0	1	0	0	0	0	0	2
Wound
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 83 (6.02%)	10 / 176 (5.68%)	15 / 307 (4.89%)
occurrences all number	0	0	0	0	0	0	0	7	10	17
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	1 / 13 (7.69%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 83 (7.23%)	6 / 176 (3.41%)	16 / 307 (5.21%)
occurrences all number	0	1	1	1	1	0	0	6	8	18
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	4 / 176 (2.27%)	5 / 307 (1.63%)
occurrences all number	0	0	1	0	0	0	0	0	4	5
Convulsion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	1	0	0	0	0	0	4	5
Dizziness
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	12 / 83 (14.46%)	28 / 176 (15.91%)	42 / 307 (13.68%)
occurrences all number	3	0	1	0	0	0	0	13	32	49
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	3 / 6 (50.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	3 / 83 (3.61%)	14 / 176 (7.95%)	24 / 307 (7.82%)
occurrences all number	0	0	1	0	4	2	1	3	14	25
Head discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	1	0	0	0	0	1	1	3
Headache
subjects affected / exposed	2 / 3 (66.67%)	2 / 6 (33.33%)	2 / 14 (14.29%)	2 / 13 (15.38%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	15 / 83 (18.07%)	40 / 176 (22.73%)	64 / 307 (20.85%)
occurrences all number	4	2	2	2	1	0	0	17	52	80
Hemiparesis
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	9 / 176 (5.11%)	11 / 307 (3.58%)
occurrences all number	1	0	0	1	0	0	0	0	12	14
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	5 / 176 (2.84%)	7 / 307 (2.28%)
occurrences all number	0	0	0	0	2	0	0	0	5	7
Myasthenia gravis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	4 / 307 (1.30%)
occurrences all number	0	0	0	1	0	0	0	0	3	4
Neuropathy peripheral
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 83 (1.20%)	7 / 176 (3.98%)	10 / 307 (3.26%)
occurrences all number	1	0	0	0	0	1	0	1	7	10
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	11 / 176 (6.25%)	15 / 307 (4.89%)
occurrences all number	0	0	0	0	1	0	0	3	13	17
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	3 / 83 (3.61%)	5 / 176 (2.84%)	12 / 307 (3.91%)
occurrences all number	0	0	0	2	0	2	0	3	5	12
Post herpetic neuralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	0	0	0	1	0	0	0	1	0	2
Sinus headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	3 / 176 (1.70%)	6 / 307 (1.95%)
occurrences all number	0	0	1	0	0	0	0	2	3	6
Tremor
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 83 (2.41%)	6 / 176 (3.41%)	11 / 307 (3.58%)
occurrences all number	0	0	0	1	0	1	1	2	6	11
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 6 (33.33%)	3 / 14 (21.43%)	2 / 13 (15.38%)	4 / 6 (66.67%)	2 / 3 (66.67%)	1 / 3 (33.33%)	17 / 83 (20.48%)	30 / 176 (17.05%)	62 / 307 (20.20%)
occurrences all number	1	2	3	2	4	2	2	22	42	80
Increased tendency to bruise
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	0	0	1	0	0	0	2	3
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	1	0	2	0	0	0	2	5
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	0	0	1	0	0	1
Lymphadenopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	0	0	0	1	0	0	2	3
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	3 / 176 (1.70%)	6 / 307 (1.95%)
occurrences all number	0	0	0	1	0	0	0	3	3	7
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	1	0	0	0	1	2
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	5 / 176 (2.84%)	8 / 307 (2.61%)
occurrences all number	0	0	0	0	2	0	0	1	6	9
Vestibular disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	0	1	0	0	0	1
Eye disorders
Diplopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	7 / 176 (3.98%)	9 / 307 (2.93%)
occurrences all number	0	0	0	2	0	0	0	0	7	9
Eye pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Periorbital oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 83 (4.82%)	9 / 176 (5.11%)	18 / 307 (5.86%)
occurrences all number	0	0	1	0	2	2	1	4	10	20
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	3 / 176 (1.70%)	6 / 307 (1.95%)
occurrences all number	0	0	0	1	0	0	0	5	3	9
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 14 (28.57%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 83 (7.23%)	2 / 176 (1.14%)	13 / 307 (4.23%)
occurrences all number	0	0	4	1	0	0	0	6	2	13
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	5 / 14 (35.71%)	3 / 13 (23.08%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	14 / 83 (16.87%)	18 / 176 (10.23%)	43 / 307 (14.01%)
occurrences all number	1	1	5	3	0	0	1	19	20	50
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	0	0	1	0	0	0	0	1	0	2
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	7 / 176 (3.98%)	12 / 307 (3.91%)
occurrences all number	0	0	2	0	0	0	0	3	7	12
Anorectal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Ascites
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	0 / 176 (0.00%)	5 / 307 (1.63%)
occurrences all number	0	1	2	0	0	0	0	2	0	5
Colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	0	0	0	1	0	1	1	3
Constipation
subjects affected / exposed	2 / 3 (66.67%)	2 / 6 (33.33%)	2 / 14 (14.29%)	3 / 13 (23.08%)	2 / 6 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	25 / 83 (30.12%)	51 / 176 (28.98%)	90 / 307 (29.32%)
occurrences all number	3	2	3	3	2	2	1	26	57	99
Diarrhoea
subjects affected / exposed	2 / 3 (66.67%)	1 / 6 (16.67%)	3 / 14 (21.43%)	2 / 13 (15.38%)	4 / 6 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	25 / 83 (30.12%)	58 / 176 (32.95%)	96 / 307 (31.27%)
occurrences all number	7	1	5	4	6	0	3	32	91	149
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	7 / 83 (8.43%)	10 / 176 (5.68%)	19 / 307 (6.19%)
occurrences all number	0	0	0	0	1	0	1	7	11	20
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 14 (14.29%)	4 / 13 (30.77%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	13 / 176 (7.39%)	24 / 307 (7.82%)
occurrences all number	0	0	2	4	1	0	0	4	13	24
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	8 / 176 (4.55%)	14 / 307 (4.56%)
occurrences all number	0	0	1	1	0	0	0	5	8	15
Faecal incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	0	0	0	1	0	0	2	3
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	4 / 176 (2.27%)	7 / 307 (2.28%)
occurrences all number	0	0	0	0	1	0	0	2	4	7
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 83 (6.02%)	9 / 176 (5.11%)	16 / 307 (5.21%)
occurrences all number	0	0	1	1	0	0	0	5	9	16
Gingival bleeding
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	1	0	0	0	0	1	2
Glossodynia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	1	0	0	0	1	2
Inguinal hernia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Melaena
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	1	0	0	0	0	0	0	0	0	1
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	2	0	0	0	0	1	3
Nausea
subjects affected / exposed	2 / 3 (66.67%)	1 / 6 (16.67%)	6 / 14 (42.86%)	3 / 13 (23.08%)	3 / 6 (50.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	30 / 83 (36.14%)	75 / 176 (42.61%)	122 / 307 (39.74%)
occurrences all number	3	1	6	3	6	2	0	35	99	155
Oral mucosal eruption
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Oral pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	2 / 6 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	6 / 307 (1.95%)
occurrences all number	0	0	0	1	2	2	0	1	0	6
Pancreatic insufficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Pancreatitis acute
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Proctalgia
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	0 / 176 (0.00%)	3 / 307 (0.98%)
occurrences all number	1	0	0	0	0	0	0	2	0	3
Rectal discharge
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	0	0	1	0	0	0	0	1	0	2
Salivary duct inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	2	0	0	0	0	2
Salivary hypersecretion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	5 / 6 (83.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 83 (6.02%)	14 / 176 (7.95%)	25 / 307 (8.14%)
occurrences all number	0	0	0	1	9	0	0	5	15	30
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 14 (28.57%)	4 / 13 (30.77%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	17 / 83 (20.48%)	43 / 176 (24.43%)	71 / 307 (23.13%)
occurrences all number	0	0	4	6	5	1	0	21	64	101
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	0	1	0	0	0	0	0	1	0	2
Jaundice
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	3 / 83 (3.61%)	2 / 176 (1.14%)	8 / 307 (2.61%)
occurrences all number	1	0	0	0	0	2	0	4	2	9
Dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	7 / 176 (3.98%)	9 / 307 (2.93%)
occurrences all number	0	0	0	0	1	0	0	1	9	11
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	2 / 176 (1.14%)	4 / 307 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1	2	4
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	8 / 176 (4.55%)	10 / 307 (3.26%)
occurrences all number	0	0	1	0	0	0	0	1	8	10
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 83 (3.61%)	4 / 176 (2.27%)	8 / 307 (2.61%)
occurrences all number	0	0	0	0	1	0	0	3	4	8
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	9 / 176 (5.11%)	11 / 307 (3.58%)
occurrences all number	0	0	0	0	0	0	0	2	9	11
Photosensitivity reaction
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	1	0	0	0	0	0	0	0	2	3
Pruritus
subjects affected / exposed	2 / 3 (66.67%)	1 / 6 (16.67%)	1 / 14 (7.14%)	4 / 13 (30.77%)	4 / 6 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	16 / 83 (19.28%)	34 / 176 (19.32%)	62 / 307 (20.20%)
occurrences all number	4	1	1	4	5	0	0	27	44	86
Pruritus generalised
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 83 (1.20%)	4 / 176 (2.27%)	7 / 307 (2.28%)
occurrences all number	0	0	1	0	0	0	1	1	5	8
Purpura
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Rash
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	5 / 14 (35.71%)	4 / 13 (30.77%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	19 / 83 (22.89%)	39 / 176 (22.16%)	69 / 307 (22.48%)
occurrences all number	0	1	7	4	0	2	0	25	50	89
Rash generalised
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 83 (2.41%)	1 / 176 (0.57%)	5 / 307 (1.63%)
occurrences all number	1	0	0	0	0	0	1	4	1	7
Rash macular
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	1	0	0	0	0	1	2
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	3 / 13 (23.08%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	11 / 83 (13.25%)	29 / 176 (16.48%)	43 / 307 (14.01%)
occurrences all number	0	0	0	3	0	0	0	14	32	49
Rash papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	3 / 176 (1.70%)	8 / 307 (2.61%)
occurrences all number	0	0	0	0	1	0	0	7	3	11
Skin hypopigmentation
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	0	1	0	0	0	0	2	3
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	0 / 176 (0.00%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	1	0	0	1	0	2
Urticaria
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	5 / 307 (1.63%)
occurrences all number	1	1	1	0	0	0	0	1	2	6
Renal and urinary disorders
Chromaturia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	1	0	0	0	0	1	1	3
Dysuria
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	4 / 307 (1.30%)
occurrences all number	1	0	0	0	1	0	0	1	1	4
Haematuria
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 83 (4.82%)	0 / 176 (0.00%)	8 / 307 (2.61%)
occurrences all number	1	1	0	0	0	1	1	6	0	10
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 83 (1.20%)	3 / 176 (1.70%)	7 / 307 (2.28%)
occurrences all number	0	1	1	0	0	1	0	1	3	7
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 83 (2.41%)	3 / 176 (1.70%)	8 / 307 (2.61%)
occurrences all number	0	0	0	0	0	1	2	2	3	8
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 83 (2.41%)	1 / 176 (0.57%)	5 / 307 (1.63%)
occurrences all number	0	0	0	0	1	0	1	2	1	5
Urinary tract obstruction
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	1	0	0	0	0	0	0	0	1	2
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	5 / 176 (2.84%)	8 / 307 (2.61%)
occurrences all number	0	0	0	1	0	0	0	2	5	8
Hypogonadism
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	0	1	0	0	0	0	2	3
Hypothyroidism
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	12 / 83 (14.46%)	20 / 176 (11.36%)	37 / 307 (12.05%)
occurrences all number	1	0	1	0	2	0	1	13	21	39
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 3 (66.67%)	0 / 6 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	12 / 83 (14.46%)	25 / 176 (14.20%)	42 / 307 (13.68%)
occurrences all number	4	0	3	1	0	0	0	13	33	54
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 14 (21.43%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	11 / 83 (13.25%)	30 / 176 (17.05%)	45 / 307 (14.66%)
occurrences all number	0	0	3	0	1	0	0	12	35	51
Costochondritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	2	0	0	0	0	0	2
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	1	0	0	0	0	1	1	3
Groin pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 83 (2.41%)	2 / 176 (1.14%)	6 / 307 (1.95%)
occurrences all number	1	0	0	0	0	0	1	2	2	6
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	1	0	0	0	0	0	2	3
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	6 / 176 (3.41%)	10 / 307 (3.26%)
occurrences all number	0	1	0	2	0	0	0	2	6	11
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 83 (2.41%)	6 / 176 (3.41%)	10 / 307 (3.26%)
occurrences all number	0	0	0	0	1	1	0	2	6	10
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 83 (4.82%)	6 / 176 (3.41%)	12 / 307 (3.91%)
occurrences all number	0	0	1	0	0	1	0	4	6	12
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 83 (3.61%)	13 / 176 (7.39%)	18 / 307 (5.86%)
occurrences all number	0	0	1	0	0	1	0	3	13	18
Myalgia
subjects affected / exposed	2 / 3 (66.67%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 6 (16.67%)	2 / 3 (66.67%)	1 / 3 (33.33%)	12 / 83 (14.46%)	10 / 176 (5.68%)	29 / 307 (9.45%)
occurrences all number	4	0	1	0	1	2	1	12	13	34
Myositis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	1 / 13 (7.69%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 83 (7.23%)	8 / 176 (4.55%)	18 / 307 (5.86%)
occurrences all number	0	1	1	1	1	0	0	6	8	18
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	11 / 176 (6.25%)	17 / 307 (5.54%)
occurrences all number	0	0	1	0	1	0	0	4	13	19
Pain in jaw
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	3 / 176 (1.70%)	5 / 307 (1.63%)
occurrences all number	0	0	1	0	1	0	0	0	3	5
Tendonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	1 / 176 (0.57%)	5 / 307 (1.63%)
occurrences all number	0	0	0	2	0	0	0	2	3	7
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	5 / 307 (1.63%)
occurrences all number	0	1	1	1	0	0	0	1	1	5
Ear infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	1	0	0	1	0	0	0	0	1	3
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	2 / 176 (1.14%)	3 / 307 (0.98%)
occurrences all number	0	0	0	0	2	0	0	0	2	4
Mucosal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	1	0	0	0	0	1	2
Nasopharyngitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 83 (2.41%)	3 / 176 (1.70%)	7 / 307 (2.28%)
occurrences all number	1	0	0	1	0	0	0	2	5	9
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	0	0	1	0	0	1	1	3
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	3 / 176 (1.70%)	5 / 307 (1.63%)
occurrences all number	0	0	0	1	0	0	0	1	3	5
Paronychia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Pharyngitis streptococcal
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Pneumonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	11 / 176 (6.25%)	12 / 307 (3.91%)
occurrences all number	1	0	0	0	0	0	0	0	11	12
Rhinitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	1 / 176 (0.57%)	6 / 307 (1.95%)
occurrences all number	1	0	0	0	0	0	0	4	1	6
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	6 / 176 (3.41%)	13 / 307 (4.23%)
occurrences all number	0	0	2	1	0	0	0	7	7	17
Subcutaneous abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	2	0	0	0	0	1	3
Upper respiratory tract infection
subjects affected / exposed	3 / 3 (100.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 83 (8.43%)	13 / 176 (7.39%)	24 / 307 (7.82%)
occurrences all number	4	0	1	0	0	0	0	8	20	33
Urinary tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 13 (15.38%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	6 / 83 (7.23%)	13 / 176 (7.39%)	25 / 307 (8.14%)
occurrences all number	1	0	1	2	4	0	1	14	20	43
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	1 / 176 (0.57%)	2 / 307 (0.65%)
occurrences all number	0	0	0	0	1	0	0	0	1	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	2 / 6 (33.33%)	7 / 14 (50.00%)	1 / 13 (7.69%)	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 3 (66.67%)	22 / 83 (26.51%)	62 / 176 (35.23%)	98 / 307 (31.92%)
occurrences all number	2	2	7	1	2	0	2	24	69	109
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 83 (3.61%)	19 / 176 (10.80%)	25 / 307 (8.14%)
occurrences all number	0	0	0	0	2	1	0	3	28	34
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	4 / 176 (2.27%)	6 / 307 (1.95%)
occurrences all number	0	0	1	0	0	0	0	2	4	7
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	8 / 83 (9.64%)	12 / 176 (6.82%)	21 / 307 (6.84%)
occurrences all number	0	0	0	0	0	0	1	10	17	28
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 83 (8.43%)	3 / 176 (1.70%)	12 / 307 (3.91%)
occurrences all number	0	1	1	0	0	0	0	14	8	24
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 83 (6.02%)	14 / 176 (7.95%)	21 / 307 (6.84%)
occurrences all number	0	1	0	0	0	0	1	6	16	24
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 83 (3.61%)	9 / 176 (5.11%)	14 / 307 (4.56%)
occurrences all number	0	1	0	0	0	0	1	3	13	18
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 14 (14.29%)	2 / 13 (15.38%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	12 / 83 (14.46%)	14 / 176 (7.95%)	33 / 307 (10.75%)
occurrences all number	0	1	2	2	2	0	1	20	18	46
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 83 (6.02%)	7 / 176 (3.98%)	14 / 307 (4.56%)
occurrences all number	0	0	1	1	0	0	0	9	12	23
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	13 / 83 (15.66%)	28 / 176 (15.91%)	45 / 307 (14.66%)
occurrences all number	0	2	1	1	0	0	0	23	35	62
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 83 (4.82%)	10 / 176 (5.68%)	14 / 307 (4.56%)
occurrences all number	0	0	0	0	0	0	0	5	16	21
Vitamin B12 deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 83 (0.00%)	0 / 176 (0.00%)	1 / 307 (0.33%)
occurrences all number	0	0	0	1	0	0	0	0	0	1
Vitamin D deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 83 (1.20%)	1 / 176 (0.57%)	3 / 307 (0.98%)
occurrences all number	0	0	0	1	0	0	0	1	1	3

More information

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Were there any global substantial amendments to the protocol? Yes

01 Oct 2014

The primary purpose of the amendment is to address FDA queries, including clarifications and requested changes to the inclusion criteria, updates to the definition of dose-limiting toxicities, ECG monitoring and to add regularly scheduled urine pregnancy testing for females of childbearing potential.

03 Apr 2015

The primary purpose of Amendment 2 is to include an additional expansion cohort in subjects with glioblastoma

16 Jul 2015

The primary purpose of this amendment is to change the dose for nivolumab for Phase 2 to a flat dose (240 mg) and to update the study design to allow the Phase 2 NSCLC and melanoma expansion cohorts to open with the 100 mg BID dose of INCB024360 once 100 mg BID is determined to be safe in Phase 1.

12 Feb 2016

The primary purpose of this amendment is to include epacadostat updates at the program level as well as clarify Phase 1 and Phase 2 cohort enrollments.

05 Jul 2017

Addition of new immunotherapy/chemotherapy combination cohorts in Phase 1 toevaluate the safety and tolerability of and to determine the recommended Phase 2dose for epacadostat (INCB24360) and nivolumab in combination with standard-of-care (SOC) chemotherapy regimens in subjects with advanced or metastaticsquamous cell carcinoma of the head and neck (SCCHN) and non−small lung cancer(NSCLC). Phase 1 is now divided into 2 parts: Part 1 is the original combinationimmunotherapy regimen, and Part 2 describes the new combination immunotherapyand chemotherapy regimens. Addition of 2 new melanoma (MEL) cohorts in Phase 2 to evaluate the safety andefficacy of epacadostat in combination with nivolumab

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2 Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered in Combination With Nivolumab in Select Advanced Cancers (ECHO-204)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1, Part 1: Safety and tolerability of epacadostat and nivolumab assessed by number of subjects with dose limiting toxicities (DLTs)

Primary: Phase 1, Part 1: Safety and tolerability of epacadostat and nivolumab assessed by number of subjects with dose limiting toxicities (DLTs)

Primary: Phase 1, Part 2: Safety and tolerability of epacadostat administered in combination with nivolumab and chemotherapy regimen assessed by number of subjects with DLTs

Primary: Phase 1, Part 2: Safety and tolerability of epacadostat administered in combination with nivolumab and chemotherapy regimen assessed by number of subjects with DLTs

Primary: Phase 1, Part 1 and 2: Safety assessed by number of Treatment Emergent Adverse Events (TEAEs)

Primary: Phase 1, Part 1 and 2: Safety assessed by number of Treatment Emergent Adverse Events (TEAEs)

Primary: Phase 2: Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for subjects with solid tumors and per Cheson criteria for subjects with DLBCL

Primary: Phase 2: Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for subjects with solid tumors and per Cheson criteria for subjects with DLBCL

Primary: Phase 2: Progression free survival (PFS)

Primary: Phase 2: Progression free survival (PFS)

Primary: Phase 2: Overall survival (OS) for subjects with Glioblastoma

Primary: Phase 2: Overall survival (OS) for subjects with Glioblastoma

Secondary: Phase 1, Part 1: ORR per RECIST v1.1 and mRECIST for subjects with solid tumors; per Cheson and mCheson criteria for subjects with B-cell NHL; and per RANO and mRANO criteria for subjects with GBM

Secondary: Phase 1, Part 1: ORR per RECIST v1.1 and mRECIST for subjects with solid tumors; per Cheson and mCheson criteria for subjects with B-cell NHL; and per RANO and mRANO criteria for subjects with GBM

Secondary: Phase 1, Part 2: ORR per RECIST v1.1 and modified RECIST for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

Secondary: Phase 1, Part 2: ORR per RECIST v1.1 and modified RECIST for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

Secondary: Phase 1, Part 2: Duration of response (DOR) for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

Secondary: Phase 1, Part 2: Duration of response (DOR) for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

Secondary: Phase 1, Part 2: PFS for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

Secondary: Phase 1, Part 2: PFS for subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC

Secondary: Phase 2: Duration of response (DOR)

Secondary: Phase 2: Duration of response (DOR)

Secondary: Phase 2: Duration of disease control, defined as CR, PR, and stable disease (SD)

Secondary: Phase 2: Duration of disease control, defined as CR, PR, and stable disease (SD)

Secondary: Phase 2: Safety and tolerability measured by the frequency of adverse events (AEs), serious adverse events (SAEs), and deaths

Secondary: Phase 2: Safety and tolerability measured by the frequency of adverse events (AEs), serious adverse events (SAEs), and deaths

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1/2 Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered in Combination With Nivolumab in Select Advanced Cancers (ECHO-204)