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Clinical Trial Results:
A Multi-indication, Single-treatment Arm, Open-label Phase 2 Study of Regorafenib and Nivolumab in Combination in Patients with Recurrent or Metastatic Solid Tumors

Summary
EudraCT number	2020-003359-13
Trial protocol	GB FR BE IT
Global end of trial date	29 Mar 2024

Results information
Results version number	v1(current)
This version publication date	05 Apr 2025
First version publication date	05 Apr 2025
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

BAY73-4506/21136

ISRCTN number

US NCT number

NCT04704154

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368

Public contact

Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.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

07 Oct 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Mar 2024

Was the trial ended prematurely?

Main objective of the trial

To evaluate efficacy of the regorafenib and nivolumab combination by cohort

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects (or their legally authorized representative according to local legislation). Participating subjects (or their legally authorized representative according to local legislation) signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Feb 2021

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

France: 46

Country: Number of subjects enrolled

Italy: 30

Country: Number of subjects enrolled

Japan: 29

Country: Number of subjects enrolled

Korea, Republic of: 22

Country: Number of subjects enrolled

Taiwan: 14

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

United States: 12

Worldwide total number of subjects

175

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 34 study centers in 8 countries/regions (6 centers in France, 5 centers in Italy, 2 centers in South Korea, 3 centers in Taiwan, 4 centers in the United Kingdom, 5 centers in Japan, 6 centers in the US and 3 centers in Belgium) from 03 February 2021 (first patient first visit) to 29 March 2024 (last patient last visit)

Screening details

175 participants were enrolled and received study treatment. Participants were enrolled in 6 cohorts: HNSCC IO naïve (N=30), HNSCC IO treated (N=20), ESCC (N=30), PDAC (N=20), BTC (N=45), and GBM/AA (N=30)

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

HNSCC (IO naive)

Arm description

Participants with confirmed recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) without Immune-oncology (IO), received 480 mg nivolumab intravenously on day 1 of every treatment cycle. Regorafenib was given as 30 mg tablets daily (QD) for 3 weeks of each treatment cycle (28 days cycle length) with a starting dose of 90 mg that could be escalated to 120 mg if well tolerated.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Opdivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg administered on Day 1 of each treatment cycle.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Intake orally, starting with 3x 30 mg tablets every day (once daily.) for 21 days of every 28-day cycle (21 days on, 7 days off). If the starting dose is well tolerated dose can be escalated to 120 mg (4x30 mg tablets).

HNSCC (IO treated)

Arm description

Participants with confirmed recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) and with Immune-oncology (IO) treated, received 480 mg nivolumab intravenously on day 1 of every treatment cycle. Regorafenib was given as 30 mg tablets daily (QD) for 3 weeks of each treatment cycle (28 days cycle length) with a starting dose of 90 mg that could be escalated to 120 mg if well tolerated.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Opdivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg administered on Day 1 of each treatment cycle.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

ESCC

Arm description

Participants with confirmed recurrent or metastatic Esophageal Squamous Cell Carcinoma (ESCC) received 480 mg nivolumab intravenously on day 1 of every treatment cycle. Regorafenib was given as 30 mg tablets daily (QD) for 3 weeks of each treatment cycle (28 days cycle length) with a starting dose of 90 mg that could be escalated to 120 mg if well tolerated.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Opdivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg administered on Day 1 of each treatment cycle.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PDAC

Arm description

Participants with confirmed recurrent or metastatic Pancreatic Duct Adenocarcinoma (PADC) received 480 mg nivolumab intravenously on day 1 of every treatment cycle. Regorafenib was given as 30 mg tablets daily (QD) for 3 weeks of each treatment cycle (28 days cycle length) with a starting dose of 90 mg that could be escalated to 120 mg if well tolerated.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Opdivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg administered on Day 1 of each treatment cycle.

Biliary Tract Cancer (BTC)

Arm description

Participants with confirmed recurrent or metastatic BTC received 480 mg nivolumab intravenously on day 1 of every treatment cycle. Regorafenib was given as 30 mg tablets daily (QD) for 3 weeks of each treatment cycle (28 days cycle length) with a starting dose of 90 mg that could be escalated to 120 mg if well tolerated.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Opdivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg administered on Day 1 of each treatment cycle.

GBM/AA

Arm description

Participants with Glioblastoma Multiforme (GBM) or Anaplastic Astrocytoma (AA) received 480 mg nivolumab intravenously on day 1 of every treatment cycle. Regorafenib was given as 30 mg tablets daily (QD) for 3 weeks of each treatment cycle (28 days cycle length) with a starting dose of 90 mg that could be escalated to 120 mg if well tolerated.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Opdivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg administered on Day 1 of each treatment cycle.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Started	30	20	30	20	45	30
Completed	0	0	0	0	0	0
Not completed	30	20	30	20	45	30
Adverse event, serious fatal	3	-	-	-	3	-
Participant Decision	1	1	-	-	-	-
Completed max 24 infusions of Nivolumab	2	-	1	-	1	-
Physician decision	1	-	1	-	2	-
Adverse event, non-fatal	3	2	4	2	3	-
Progressive Disease	19	17	20	18	36	30
Continued in rollover study for regorafenib	1	-	4	-	-	-

Baseline characteristics

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Reporting group title

HNSCC (IO naive)

Reporting group description

Reporting group title

HNSCC (IO treated)

Reporting group description

Reporting group title

ESCC

Reporting group description

Reporting group title

PDAC

Reporting group description

Reporting group title

Biliary Tract Cancer (BTC)

Reporting group description

Reporting group title

GBM/AA

Reporting group description

Reporting group values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA	Total
Number of subjects	30	20	30	20	45	30	175
Age Categorical
Units: Subjects
Adults (18-64 years)	16	10	17	13	17	22	95
From 65-84 years	14	10	13	7	28	8	80
Age Continuous
Units: years
median (full range (min-max))	63.0 (26 to 76)	64.5 (44 to 81)	62.0 (49 to 76)	57.0 (42 to 74)	67.0 (32 to 81)	59.5 (21 to 75)	-
Gender Categorical
Units: Subjects
Female	5	6	3	11	20	10	55
Male	25	14	27	9	25	20	120
Race
Units: Subjects
Asian	15	11	21	5	11	2	65
Black or African American	0	0	0	0	1	0	1
White	6	6	7	13	27	26	85
Not Reported	9	3	2	2	6	2	24

Subject analysis set title

FAS (full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All participants who have received any dose of study intervention

Subject analysis set title

SAF (safety analysis set)

Subject analysis set type

Safety analysis

Subject analysis set description

All participants who have received any dose of study intervention. As the safety analysis set equals the full analysis, all safety related analysis were performed on the full analysis set.

Subject analysis sets values	FAS (full analysis set)	SAF (safety analysis set)
Number of subjects	175	175
Age Categorical
Units: Subjects
Adults (18-64 years)	95	95
From 65-84 years	80	80
Age Continuous
Units: years
median (full range (min-max))
Gender Categorical
Units: Subjects
Female	55	55
Male	120	120
Race
Units: Subjects
Asian	65	65
Black or African American	1	1
White	85	85
Not Reported	24	24

End points

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Reporting group title

HNSCC (IO naive)

Reporting group description

Reporting group title

HNSCC (IO treated)

Reporting group description

Reporting group title

ESCC

Reporting group description

Reporting group title

PDAC

Reporting group description

Reporting group title

Biliary Tract Cancer (BTC)

Reporting group description

Reporting group title

GBM/AA

Reporting group description

Subject analysis set title

FAS (full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All participants who have received any dose of study intervention

Subject analysis set title

SAF (safety analysis set)

Subject analysis set type

Safety analysis

Subject analysis set description

All participants who have received any dose of study intervention. As the safety analysis set equals the full analysis, all safety related analysis were performed on the full analysis set.

Primary: Overall response rate (ORR)

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End point title

Overall response rate (ORR) ^[1]

End point description

Tumor response was evaluated as ORR per RECIST 1.1 by local assessments for all tumor types, except for GBM/AA, where ORR per RANO by local assessment was used. ORR was defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR). Participants for whom best overall tumor response was not CR or PR, as well as participants without any post-baseline tumor assessment were considered non-responders. Descriptive statistics were done, no inferential statistical analyses were performed

End point type

Primary

End point timeframe

From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months

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: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	30	20	30	20	45	30
Units: Subjects
Overall Response Rate (ORR)	6	1	15	0	2	1

No statistical analyses for this end point

Secondary: Duration of response (DOR)

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End point title

Duration of response (DOR)

End point description

Defined as the time (in days) from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (if death occurs before progression is documented). DOR will be defined for responders only, i.e. participants with a CR or PR. 99999: Value cannot be estimated due to censored data, insufficient number of participants with events.

End point type

Secondary

End point timeframe

From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	6 ^[2]	1 ^[3]	15 ^[4]	0 ^[5]	2 ^[6]	1 ^[7]
Units: Days
median (confidence interval 80%)
DOR Median [80% CI]	99999 (654 to 99999)	99999 (99999 to 99999)	420 (112 to 617)	( to )	432 (112 to 99999)	140 (-99999 to 99999)

Notes
[2] - Subgroup of participants with best overall response of CR or PR who received the study treatment
[3] - Subgroup of participants with best overall response of CR or PR who received the study treatment
[4] - Subgroup of participants with best overall response of CR or PR who received the study treatment
[5] - Subgroup of participants with best overall response of CR or PR who received the study treatment
[6] - Subgroup of participants with best overall response of CR or PR who received the study treatment
[7] - Subgroup of participants with best overall response of CR or PR who received the study treatment

No statistical analyses for this end point

Secondary: Disease control rate (DCR)

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End point title

Disease control rate (DCR)

End point description

CR = Complete response; PR = Partial response; SD = Stable disease

End point type

Secondary

End point timeframe

From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	30	20	30	20	45	30
Units: Subjects
Disease Control Rate (DCR) CR, PR or SD	16	13	22	7	24	10

No statistical analyses for this end point

Secondary: Progression free survival (PFS)

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End point title

Progression free survival (PFS)

End point description

PFS was defined as the time (in days) from the start of study intervention to the date of first objectively documented progressive disease (PD) or death from any cause (if no progression was documented).

End point type

Secondary

End point timeframe

From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	30	20	30	20	45	30
Units: Days
median (confidence interval 80%)
Progression Free Survival (PFS) Median [80% CI]	79 (50 to 227)	105 (52 to 115)	259 (110 to 472)	53 (48 to 111)	98 (55 to 112)	55 (52 to 84)

No statistical analyses for this end point

Secondary: 6 months PFS

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End point title

6 months PFS

End point description

6 Months PFS rate

End point type

Secondary

End point timeframe

Up to last participant follow 6 months (approximately 22 months)

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	30	20	30	20	45	30
Units: Proportion of participants
number (confidence interval 80%)
Progression-free survival rate at month 6	0.455 (0.337 to 0.573)	0.263 (0.134 to 0.393)	0.533 (0.417 to 0.650)	0.050 (0.000 to 0.112)	0.148 (0.077 to 0.218)	0.167 (0.079 to 0.254)

No statistical analyses for this end point

Secondary: Overall survival (OS)

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End point title

Overall survival (OS)

End point description

OS was defined as the time (in days) from the start of study intervention to the date of death due to any cause.

End point type

Secondary

End point timeframe

From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	30	20	30	20	45	30
Units: Days
median (confidence interval 80%)
Overall Survival Median [80% CI]	358 (198 to 418)	355 (126 to 614)	627 (431 to 865)	259 (134 to 311)	246 (176 to 386)	245 (127 to 377)

No statistical analyses for this end point

Secondary: 1 year OS

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End point title

1 year OS

End point description

End point type

Secondary

End point timeframe

From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 month

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	30	20	30	20	45	30
Units: Proportion of patients
number (confidence interval 80%)
Overall survival rate at month 12	0.415 (0.298 to 0.532)	0.444 (0.294 to 0.595)	0.764 (0.664 to 0.864)	0.281 (0.145 to 0.418)	0.422 (0.323 to 0.521)	0.337 (0.223 to 0.451)

No statistical analyses for this end point

Secondary: Number of participants with adverse events

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End point title

Number of participants with adverse events

End point description

AEs were considered to be treatment-emergent (TEAEs) if they started or worsened after the start of first study drug administration until 30 days after regorafenib treatment discontinuation or 100 days after the last dose of nivolumab, whatever occurred later.

End point type

Secondary

End point timeframe

Up to the last participant has been followed for approximately 10 months, summed up to approximately 26 months

End point values	HNSCC (IO naive)	HNSCC (IO treated)	ESCC	PDAC	Biliary Tract Cancer (BTC)	GBM/AA
Number of subjects analysed	30	20	30	20	45	30
Units: Subjects
Any AE	30	20	30	20	45	30
Worst grade: Grade 1	1	0	2	0	1	0
Worst grade: Grade 2	4	1	6	2	9	8
Worst grade: Grade 3	16	16	18	11	23	11
Worst grade: Grade 4	6	2	2	2	1	2
Worst grade: Grade 5 (death)	3	1	2	5	11	9

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

After the start of first study drug administration until 30 days after regorafenib treatment discontinuation or 100 days after the last dose of nivolumab, whatever occurred later.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

HNSCC (IO naive)

Reporting group description

Participants with confirmed recurrent or metastatic HNSCC and IO naive, received regorafenib in combination with nivolumab. (treatment details refers to Description under Participant Flow section above)

Reporting group title

GBM/AA

Reporting group description

Participants with GBM or AA received regorafenib in combination with nivolumab. (treatment details refers to Description under Participant Flow section above)

Reporting group title

PDAC

Reporting group description

Participants with confirmed recurrent or metastatic PADC received regorafenib in combination with nivolumab. (treatment details refers to Description under Participant Flow section above)

Reporting group title

Biliary Tract Cancer (BTC)

Reporting group description

Participants with confirmed recurrent or metastatic BTC received regorafenib in combination with nivolumab. (treatment details refers to Description under Participant Flow section above)

Reporting group title

HNSCC (IO treated)

Reporting group description

Participants with confirmed recurrent or metastatic HNSCC and with IO treated, received regorafenib in combination with nivolumab. (treatment details refers to Description under Participant Flow section above)

Reporting group title

ESCC

Reporting group description

Participants with confirmed recurrent or metastatic ESCC received regorafenib in combination with nivolumab. (treatment details refers to Description under Participant Flow section above)

Serious adverse events	HNSCC (IO naive)	GBM/AA	PDAC	Biliary Tract Cancer (BTC)	HNSCC (IO treated)	ESCC
Total subjects affected by serious adverse events
subjects affected / exposed	22 / 30 (73.33%)	13 / 30 (43.33%)	13 / 20 (65.00%)	28 / 45 (62.22%)	15 / 20 (75.00%)	19 / 30 (63.33%)
number of deaths (all causes)	22	27	17	36	17	20
number of deaths resulting from adverse events	3	9	5	11	1	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	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
Metastases to central nervous system
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal cancer
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	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
Surgical and medical procedures
Bile duct stent insertion
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	2 / 30 (6.67%)	9 / 30 (30.00%)	1 / 20 (5.00%)	7 / 45 (15.56%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 10	0 / 1	0 / 7	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 9	0 / 1	0 / 7	0 / 1	0 / 0
Performance status decreased
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	2 / 45 (4.44%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Face oedema
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	2 / 45 (4.44%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal stenosis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	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
Respiratory failure
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device occlusion
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device deposit issue
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	3 / 3	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	3 / 3	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Skull fracture
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Coma
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiplegia
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasogenic cerebral oedema
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis ischaemic
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	4 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	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
Abdominal pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	5 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	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
Enteritis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 2	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
Intestinal obstruction
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral cavity fistula
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	5 / 45 (11.11%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune hepatitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 20 (10.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary obstruction
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Ureterolithiasis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypopituitarism
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	2 / 45 (4.44%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Crystal arthropathy
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Atypical pneumonia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	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
Pneumonia
subjects affected / exposed	4 / 30 (13.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	4 / 20 (20.00%)	4 / 30 (13.33%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 1	0 / 7	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Upper respiratory tract infection
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral infection
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Medical device site infection
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	2 / 2	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
Malnutrition
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	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	HNSCC (IO naive)	GBM/AA	PDAC	Biliary Tract Cancer (BTC)	HNSCC (IO treated)	ESCC
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 30 (100.00%)	29 / 30 (96.67%)	20 / 20 (100.00%)	45 / 45 (100.00%)	20 / 20 (100.00%)	30 / 30 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Peritumoural oedema
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Cancer pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	2	0	0	2
Tumour pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 20 (10.00%)	2 / 45 (4.44%)	3 / 20 (15.00%)	1 / 30 (3.33%)
occurrences all number	0	0	2	2	10	1
Vascular disorders
Hypotension
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 20 (0.00%)	2 / 45 (4.44%)	2 / 20 (10.00%)	0 / 30 (0.00%)
occurrences all number	1	2	0	2	2	0
Hypertension
subjects affected / exposed	5 / 30 (16.67%)	8 / 30 (26.67%)	6 / 20 (30.00%)	11 / 45 (24.44%)	7 / 20 (35.00%)	4 / 30 (13.33%)
occurrences all number	7	16	13	25	12	7
Haematoma
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Haemorrhage
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Deep vein thrombosis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Thrombophlebitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Jugular vein thrombosis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Hot flush
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	1	1	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 30 (13.33%)	5 / 30 (16.67%)	8 / 20 (40.00%)	19 / 45 (42.22%)	7 / 20 (35.00%)	9 / 30 (30.00%)
occurrences all number	5	10	18	43	16	19
Asthenia
subjects affected / exposed	10 / 30 (33.33%)	10 / 30 (33.33%)	4 / 20 (20.00%)	12 / 45 (26.67%)	2 / 20 (10.00%)	7 / 30 (23.33%)
occurrences all number	17	14	6	36	6	24
Chest discomfort
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	0	2
Chest pain
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	2 / 45 (4.44%)	0 / 20 (0.00%)	4 / 30 (13.33%)
occurrences all number	0	1	0	2	0	5
Chills
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	1	0	4
Generalised oedema
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Impaired healing
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Malaise
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1	1
Mucosal inflammation
subjects affected / exposed	4 / 30 (13.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	5 / 45 (11.11%)	1 / 20 (5.00%)	4 / 30 (13.33%)
occurrences all number	9	0	1	8	2	14
Oedema peripheral
subjects affected / exposed	2 / 30 (6.67%)	1 / 30 (3.33%)	2 / 20 (10.00%)	4 / 45 (8.89%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	2	1	2	6	1	2
Pain
subjects affected / exposed	2 / 30 (6.67%)	1 / 30 (3.33%)	0 / 20 (0.00%)	1 / 45 (2.22%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	2	2	0	4	1	0
Pyrexia
subjects affected / exposed	6 / 30 (20.00%)	5 / 30 (16.67%)	7 / 20 (35.00%)	17 / 45 (37.78%)	6 / 20 (30.00%)	12 / 30 (40.00%)
occurrences all number	6	6	14	43	10	20
Immune system disorders
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Reproductive system and breast disorders
Cervix haemorrhage uterine
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Pelvic pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	0	0	0	0	0
Alveolitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Dysphonia
subjects affected / exposed	0 / 30 (0.00%)	3 / 30 (10.00%)	3 / 20 (15.00%)	9 / 45 (20.00%)	2 / 20 (10.00%)	5 / 30 (16.67%)
occurrences all number	0	4	3	9	2	6
Cough
subjects affected / exposed	1 / 30 (3.33%)	3 / 30 (10.00%)	2 / 20 (10.00%)	4 / 45 (8.89%)	2 / 20 (10.00%)	4 / 30 (13.33%)
occurrences all number	1	4	3	4	2	5
Dyspnoea
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	1 / 20 (5.00%)	4 / 45 (8.89%)	2 / 20 (10.00%)	5 / 30 (16.67%)
occurrences all number	7	0	1	6	2	7
Dyspnoea exertional
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	1 / 20 (5.00%)	2 / 30 (6.67%)
occurrences all number	1	0	0	1	1	3
Epistaxis
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	1	3	0	0
Haemoptysis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	0	2
Pleural effusion
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	2 / 20 (10.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	1	0	2	0	1	1
Pneumonitis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	5 / 30 (16.67%)
occurrences all number	3	0	0	0	0	10
Pneumothorax
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Productive cough
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	1	0	0
Rales
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	1	0
Wheezing
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	2 / 20 (10.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	2	2	1	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 30 (3.33%)	3 / 30 (10.00%)	3 / 20 (15.00%)	7 / 45 (15.56%)	4 / 20 (20.00%)	2 / 30 (6.67%)
occurrences all number	1	3	3	8	4	2
Depression
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	1	0	0	0
Confusional state
subjects affected / exposed	1 / 30 (3.33%)	4 / 30 (13.33%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	4	0	1	0	0
Anxiety
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	1	1	0	1
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	2 / 45 (4.44%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	4	1	1
Alanine aminotransferase increased
subjects affected / exposed	7 / 30 (23.33%)	3 / 30 (10.00%)	2 / 20 (10.00%)	4 / 45 (8.89%)	2 / 20 (10.00%)	4 / 30 (13.33%)
occurrences all number	14	12	5	7	8	10
Amylase increased
subjects affected / exposed	0 / 30 (0.00%)	4 / 30 (13.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	5	0	0	0	4
Aspartate aminotransferase increased
subjects affected / exposed	5 / 30 (16.67%)	4 / 30 (13.33%)	1 / 20 (5.00%)	5 / 45 (11.11%)	2 / 20 (10.00%)	3 / 30 (10.00%)
occurrences all number	10	12	2	9	6	6
Blood bilirubin increased
subjects affected / exposed	1 / 30 (3.33%)	6 / 30 (20.00%)	0 / 20 (0.00%)	6 / 45 (13.33%)	2 / 20 (10.00%)	1 / 30 (3.33%)
occurrences all number	2	11	0	10	2	1
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	3	0	0	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 20 (0.00%)	0 / 45 (0.00%)	2 / 20 (10.00%)	0 / 30 (0.00%)
occurrences all number	6	1	0	0	3	0
Heart rate increased
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	1	0	0	0
Lipase increased
subjects affected / exposed	1 / 30 (3.33%)	6 / 30 (20.00%)	0 / 20 (0.00%)	2 / 45 (4.44%)	1 / 20 (5.00%)	3 / 30 (10.00%)
occurrences all number	1	13	0	4	1	6
Lymphocyte count decreased
subjects affected / exposed	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	12	0	0	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	2 / 45 (4.44%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	2	3	0	1
Neutrophil count increased
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	1	0
Platelet count decreased
subjects affected / exposed	2 / 30 (6.67%)	3 / 30 (10.00%)	0 / 20 (0.00%)	3 / 45 (6.67%)	2 / 20 (10.00%)	3 / 30 (10.00%)
occurrences all number	2	4	0	5	2	5
Weight decreased
subjects affected / exposed	6 / 30 (20.00%)	1 / 30 (3.33%)	2 / 20 (10.00%)	5 / 45 (11.11%)	3 / 20 (15.00%)	6 / 30 (20.00%)
occurrences all number	11	2	3	6	3	7
White blood cell count decreased
subjects affected / exposed	0 / 30 (0.00%)	3 / 30 (10.00%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	4	1	1	0	0
White blood cell count increased
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Platelet count increased
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
General physical condition abnormal
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	2	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1	1
Subcutaneous haematoma
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Wound dehiscence
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Wound secretion
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Stoma site pain
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	0	0	0	0	1
Procedural pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	3	0	2
Atrial fibrillation
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	3 / 20 (15.00%)	2 / 30 (6.67%)
occurrences all number	1	0	0	0	3	2
Pericarditis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Tachycardia
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	1	3	0	1
Nervous system disorders
Hyperaesthesia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Hemiparesis
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0
Hemianopia homonymous
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0
Headache
subjects affected / exposed	1 / 30 (3.33%)	6 / 30 (20.00%)	2 / 20 (10.00%)	3 / 45 (6.67%)	1 / 20 (5.00%)	2 / 30 (6.67%)
occurrences all number	2	13	2	3	1	2
Epilepsy
subjects affected / exposed	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	4	0	0	0	0
Dysgeusia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	0	0	5	0	2
Dizziness
subjects affected / exposed	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	4	0	1	0	2
Apraxia
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0
Aphasia
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	0	2
Memory impairment
subjects affected / exposed	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	4	0	1	0	0
Neuropathy peripheral
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	1	0
Balance disorder
subjects affected / exposed	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	3	0	0	0	0
Brain oedema
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	1	0	0	0
Speech disorder
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0
Somnolence
subjects affected / exposed	1 / 30 (3.33%)	2 / 30 (6.67%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	3	1	1	0	0
Seizure
subjects affected / exposed	0 / 30 (0.00%)	5 / 30 (16.67%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	5	1	0	0	0
Presyncope
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	3 / 20 (15.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	3	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	1	0	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 30 (33.33%)	2 / 30 (6.67%)	6 / 20 (30.00%)	7 / 45 (15.56%)	3 / 20 (15.00%)	5 / 30 (16.67%)
occurrences all number	24	3	16	8	7	12
Eosinophilia
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	0	0
Leukocytosis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	1	0	0	0
Neutrophilia
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	2	1	1	0	0
Thrombocytopenia
subjects affected / exposed	1 / 30 (3.33%)	5 / 30 (16.67%)	3 / 20 (15.00%)	9 / 45 (20.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	4	9	6	11	0	1
Lymphopenia
subjects affected / exposed	2 / 30 (6.67%)	2 / 30 (6.67%)	0 / 20 (0.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	2	0	1	0	0
Ear and labyrinth disorders
Tympanic membrane perforation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Eye disorders
Cataract
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastrointestinal disorders
Aptyalism
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Abdominal distension
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	2 / 45 (4.44%)	1 / 20 (5.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	2	1	2
Abdominal pain
subjects affected / exposed	0 / 30 (0.00%)	4 / 30 (13.33%)	7 / 20 (35.00%)	11 / 45 (24.44%)	1 / 20 (5.00%)	4 / 30 (13.33%)
occurrences all number	0	4	13	16	2	5
Abdominal pain upper
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	2 / 20 (10.00%)	8 / 45 (17.78%)	1 / 20 (5.00%)	5 / 30 (16.67%)
occurrences all number	1	1	3	12	1	5
Aphthous ulcer
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	3	0	0	0	0
Ascites
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	3 / 20 (15.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	6	1	0	0
Cheilitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Constipation
subjects affected / exposed	7 / 30 (23.33%)	11 / 30 (36.67%)	7 / 20 (35.00%)	15 / 45 (33.33%)	8 / 20 (40.00%)	7 / 30 (23.33%)
occurrences all number	8	15	9	20	10	10
Diarrhoea
subjects affected / exposed	7 / 30 (23.33%)	6 / 30 (20.00%)	3 / 20 (15.00%)	17 / 45 (37.78%)	3 / 20 (15.00%)	11 / 30 (36.67%)
occurrences all number	10	11	5	31	6	25
Dry mouth
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	1 / 20 (5.00%)	3 / 45 (6.67%)	1 / 20 (5.00%)	2 / 30 (6.67%)
occurrences all number	0	2	1	5	1	2
Dysphagia
subjects affected / exposed	4 / 30 (13.33%)	2 / 30 (6.67%)	0 / 20 (0.00%)	3 / 45 (6.67%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	4	2	0	5	1	0
Oral discomfort
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	2 / 20 (10.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	4 / 30 (13.33%)
occurrences all number	2	0	2	2	0	4
Glossitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Large intestine perforation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Mouth haemorrhage
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	1	0
Nausea
subjects affected / exposed	3 / 30 (10.00%)	4 / 30 (13.33%)	7 / 20 (35.00%)	14 / 45 (31.11%)	2 / 20 (10.00%)	5 / 30 (16.67%)
occurrences all number	3	4	10	19	2	6
Odynophagia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	1	0	0	1
Eructation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Oral pain
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	4	0	0	0	2	0
Pancreatitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	0	7
Periodontal disease
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Stomatitis
subjects affected / exposed	5 / 30 (16.67%)	1 / 30 (3.33%)	1 / 20 (5.00%)	3 / 45 (6.67%)	3 / 20 (15.00%)	3 / 30 (10.00%)
occurrences all number	16	1	4	4	7	8
Toothache
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	1	0	0	1
Vomiting
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	5 / 20 (25.00%)	8 / 45 (17.78%)	1 / 20 (5.00%)	3 / 30 (10.00%)
occurrences all number	2	0	8	9	1	3
Subileus
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Oral cavity fistula
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	4	0	0	0	0	0
Anal inflammation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	8	0	0
Cholestasis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	1	3	0	1
Hepatic function abnormal
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	0	4
Hyperbilirubinaemia
subjects affected / exposed	1 / 30 (3.33%)	5 / 30 (16.67%)	1 / 20 (5.00%)	4 / 45 (8.89%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	9	3	9	0	0
Jaundice
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	2	1	0	0
Hepatic cytolysis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	2 / 45 (4.44%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	0	1	2	0	2
Bile duct stenosis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Drug-induced liver injury
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Immune-mediated hepatitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	5	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	2 / 45 (4.44%)	3 / 20 (15.00%)	1 / 30 (3.33%)
occurrences all number	1	0	1	2	3	1
Decubitus ulcer
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	2 / 45 (4.44%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	2	1	1
Dry skin
subjects affected / exposed	3 / 30 (10.00%)	0 / 30 (0.00%)	2 / 20 (10.00%)	6 / 45 (13.33%)	1 / 20 (5.00%)	3 / 30 (10.00%)
occurrences all number	3	0	2	6	1	3
Erythema
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	2 / 45 (4.44%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	0	2	0	2	1	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	8 / 30 (26.67%)	8 / 30 (26.67%)	5 / 20 (25.00%)	15 / 45 (33.33%)	9 / 20 (45.00%)	22 / 30 (73.33%)
occurrences all number	11	18	16	37	28	45
Skin toxicity
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	1	0
Palmoplantar keratoderma
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Pruritus
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	1 / 20 (5.00%)	5 / 45 (11.11%)	2 / 20 (10.00%)	3 / 30 (10.00%)
occurrences all number	2	0	2	5	3	4
Psoriasis
subjects affected / exposed	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	2	0	0	0	0
Purpura
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	1	0
Rash
subjects affected / exposed	6 / 30 (20.00%)	5 / 30 (16.67%)	8 / 20 (40.00%)	10 / 45 (22.22%)	2 / 20 (10.00%)	14 / 30 (46.67%)
occurrences all number	7	8	14	22	2	23
Rash maculo-papular
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	5 / 45 (11.11%)	3 / 20 (15.00%)	0 / 30 (0.00%)
occurrences all number	0	2	1	8	3	0
Skin exfoliation
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	1	0
Scar pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	6	0	1
Urinary retention
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	1	0	0	0	1	0
Proteinuria
subjects affected / exposed	2 / 30 (6.67%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	4 / 20 (20.00%)	1 / 30 (3.33%)
occurrences all number	5	4	0	0	4	2
Hydronephrosis
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	1	0	0	0
Haematuria
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	1	0	0	2
Glycosuria
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	5 / 30 (16.67%)	1 / 30 (3.33%)	1 / 20 (5.00%)	6 / 45 (13.33%)	1 / 20 (5.00%)	2 / 30 (6.67%)
occurrences all number	6	1	1	6	1	2
Hypopituitarism
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	2	6	0	0
Hypothyroidism
subjects affected / exposed	3 / 30 (10.00%)	3 / 30 (10.00%)	3 / 20 (15.00%)	5 / 45 (11.11%)	5 / 20 (25.00%)	8 / 30 (26.67%)
occurrences all number	6	3	3	7	6	10
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	2 / 20 (10.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	3	6	0	2
Neck pain
subjects affected / exposed	3 / 30 (10.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	4 / 20 (20.00%)	1 / 30 (3.33%)
occurrences all number	3	0	0	0	4	1
Myalgia
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	5 / 45 (11.11%)	1 / 20 (5.00%)	4 / 30 (13.33%)
occurrences all number	0	1	1	8	1	4
Musculoskeletal pain
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Muscular weakness
subjects affected / exposed	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	4	0	0	0	0
Muscle spasms
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	2 / 20 (10.00%)	7 / 45 (15.56%)	2 / 20 (10.00%)	1 / 30 (3.33%)
occurrences all number	1	0	4	10	2	2
Back pain
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	1 / 20 (5.00%)	10 / 45 (22.22%)	0 / 20 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	2	1	12	0	4
Arthritis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	5	0	0
Arthralgia
subjects affected / exposed	1 / 30 (3.33%)	3 / 30 (10.00%)	1 / 20 (5.00%)	6 / 45 (13.33%)	1 / 20 (5.00%)	5 / 30 (16.67%)
occurrences all number	1	3	1	8	1	6
Amyotrophy
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscle atrophy
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Sarcopenia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Infections and infestations
Bacteraemia
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	1	0	1	0	0	0
Bronchitis
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	2 / 45 (4.44%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	1	1	2	1	0
Conjunctivitis
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Vascular device infection
subjects affected / exposed	3 / 30 (10.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	0	0	0	0	0
Paronychia
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	8	0	0	0	1	2
Pneumonia
subjects affected / exposed	2 / 30 (6.67%)	1 / 30 (3.33%)	0 / 20 (0.00%)	2 / 45 (4.44%)	2 / 20 (10.00%)	4 / 30 (13.33%)
occurrences all number	3	1	0	3	2	8
Skin infection
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0
Urinary tract infection
subjects affected / exposed	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 20 (5.00%)	3 / 45 (6.67%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	0	1	1	4	1	2
Oral fungal infection
subjects affected / exposed	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0
Acinetobacter bacteraemia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Influenza
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
COVID-19
subjects affected / exposed	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 20 (0.00%)	4 / 45 (8.89%)	0 / 20 (0.00%)	3 / 30 (10.00%)
occurrences all number	1	2	0	4	0	4
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 30 (3.33%)	0 / 30 (0.00%)	3 / 20 (15.00%)	1 / 45 (2.22%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	1	0	6	1	1	0
Electrolyte imbalance
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypercalcaemia
subjects affected / exposed	3 / 30 (10.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	3	0	0	0	0	4
Hyperglycaemia
subjects affected / exposed	0 / 30 (0.00%)	6 / 30 (20.00%)	3 / 20 (15.00%)	1 / 45 (2.22%)	0 / 20 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	10	3	2	0	2
Hyperkalaemia
subjects affected / exposed	2 / 30 (6.67%)	2 / 30 (6.67%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	2	0	0	0	1
Hypoalbuminaemia
subjects affected / exposed	5 / 30 (16.67%)	1 / 30 (3.33%)	5 / 20 (25.00%)	5 / 45 (11.11%)	0 / 20 (0.00%)	4 / 30 (13.33%)
occurrences all number	6	1	8	10	0	9
Hypocalcaemia
subjects affected / exposed	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 20 (0.00%)	4 / 45 (8.89%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	2	1	0	4	2	2
Hypoglycaemia
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Decreased appetite
subjects affected / exposed	8 / 30 (26.67%)	6 / 30 (20.00%)	7 / 20 (35.00%)	14 / 45 (31.11%)	9 / 20 (45.00%)	11 / 30 (36.67%)
occurrences all number	8	10	10	25	16	26
Hyponatraemia
subjects affected / exposed	3 / 30 (10.00%)	2 / 30 (6.67%)	1 / 20 (5.00%)	4 / 45 (8.89%)	0 / 20 (0.00%)	3 / 30 (10.00%)
occurrences all number	3	3	1	8	0	6
Hypophosphataemia
subjects affected / exposed	3 / 30 (10.00%)	1 / 30 (3.33%)	0 / 20 (0.00%)	5 / 45 (11.11%)	1 / 20 (5.00%)	1 / 30 (3.33%)
occurrences all number	3	1	0	5	1	1
Refeeding syndrome
subjects affected / exposed	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	0	0	0	0	0
Cell death
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	3 / 45 (6.67%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	5	0	0
Malnutrition
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	1 / 45 (2.22%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	1	0
Hypokalaemia
subjects affected / exposed	4 / 30 (13.33%)	1 / 30 (3.33%)	1 / 20 (5.00%)	5 / 45 (11.11%)	1 / 20 (5.00%)	4 / 30 (13.33%)
occurrences all number	9	3	1	6	1	4
Type 2 diabetes mellitus
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 20 (5.00%)	0 / 45 (0.00%)	0 / 20 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0
Steroid diabetes
subjects affected / exposed	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 20 (0.00%)	0 / 45 (0.00%)	1 / 20 (5.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

21 Jan 2021

Global amendment 01 introduced the following changes: The Schedule of Activities were updated to more clearly define the timing of the CT/MRIs and the collection of AEs during follow-up. Additional wording on trial stop was added. Additional inclusion criteria for Stage 2 participants were added to clarify previous therapies allowed. Updated guidance regarding male contraception based on the updated nivolumab Investigator’s Brochure. Dose modification tables for regorafenib were updated. Nivolumab toxicity management guidelines updated to reflect incorporation of CTCAE v.5.0, as well as changes consistent with updated nivolumab immune-mediated AE management algorithms. Recommended dose modification for nivolumab updated according to the newest management algorithms for studies, under CTCAE v5.0. AE management algorithms were updated.

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 Trial Results:
A Multi-indication, Single-treatment Arm, Open-label Phase 2 Study of Regorafenib and Nivolumab in Combination in Patients with Recurrent or Metastatic Solid Tumors

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Primary: Overall response rate (ORR)

Primary: Overall response rate (ORR)

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Clinical trials

Clinical Trial Results: A Multi-indication, Single-treatment Arm, Open-label Phase 2 Study of Regorafenib and Nivolumab in Combination in Patients with Recurrent or Metastatic Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall response rate (ORR)

Primary: Overall response rate (ORR)

Secondary: Duration of response (DOR)

Secondary: Duration of response (DOR)

Secondary: Disease control rate (DCR)

Secondary: Disease control rate (DCR)

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Substantial protocol amendments (globally)

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Clinical Trial Results:
A Multi-indication, Single-treatment Arm, Open-label Phase 2 Study of Regorafenib and Nivolumab in Combination in Patients with Recurrent or Metastatic Solid Tumors