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Clinical Trial Results:
A multi-center, open-label, non-randomized, phase I dose escalation study of regorafenib (BAY73-4506) in pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy

Summary
EudraCT number	2013-003579-36
Trial protocol	IT GB FR ES
Global end of trial date	13 Mar 2024

Results information
Results version number	v1(current)
This version publication date	13 Sep 2024
First version publication date	13 Sep 2024
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

15906

ISRCTN number

US NCT number

NCT02085148

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 30300139 003, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, +49 30300139 003, clinical-trials-contact@bayer.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001178-PIP01-11

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

13 Mar 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Mar 2024

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of the dose escalation phase were: - To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of regorafenib administered orally as a single agent in a 3 weeks on/1 week off schedule in repeating cycles of 28 days in pediatric subjects with solid malignant tumors recurrent or refractory to standard therapy - To characterize the Pharmacokinetics (PK) of regorafenib The primary objective of the dose expansion phase was: - To define the safety profile, MTD and the RP2D of regorafenib administered orally in combination vincristine and irinotecan in pediatric subjects with RMS and other solid malignant tumors recurrent or refractory to standard therapy

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. Participating subjects 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

11 Apr 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 26

Country: Number of subjects enrolled

United Kingdom: 27

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

Italy: 3

Worldwide total number of subjects

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

Study was conducted at 15 study centers in 4 countries worldwide, between 11-Apr-2014 (first subject first visit) and 13-Mar-2024 (last subject last visit).

Screening details

Dose escalation: 55 pediatric subjects were enrolled. Of these 12 premature discontinuations of screening and 43 subjects were assigned to treatment. 41 subjects received at least 1 dose of regorafenib and 2 subjects were never treated. Dose expansion: 28 pediatric subjects were screened and 21 subjects were assigned to treatment.

Period 1 title

Dose escalation and expansion phase (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)

Arm description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 60 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects received regorafenib 60 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects who were unable to swallow tablets received regorafenib as granulate follow the same regime: 60 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)

Arm description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects received regorafenib 72 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects who were unable to swallow tablets received regorafenib as granulate follow the same regime: 72 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)

Arm description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects received regorafenib 82 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects who were unable to swallow tablets received regorafenib as granulate follow the same regime: 82 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)

Arm description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 93 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects received regorafenib 93 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects who were unable to swallow tablets received regorafenib as granulate follow the same regime: 93 mg/m^2 once daily in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)

Arm description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 concomitantly administered with vincristine and irinotecan (VI) on a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

cellcristin

Pharmaceutical forms

Injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Pediatric subjects received Vincristine concomitantly 1.5 mg/m^2, maximum of 2 mg (0.05 mg/kg for subjects ≤ 10 kg), on Day 1 and Day 8 in 21 days cycles.

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

irinotecan cell pharm

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pediatric subjects received irinotecan concomitantly over 1 hour, at a starting dose of 50 mg/m^2/day, on Day 1 to Day 5 in 21 days cycles.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects received regorafenib concomitantly administered with vincristine and irinotecan (VI), in the order of vincristine, irinotecan and regorafenib if 2 or 3 agents of the study treatment were scheduled to be administered in the same day. Regorafenib was orally taken at a starting dose of 72 mg/m^2 once daily from Day 1 to Day 14 in 21 days cycles.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects who were unable to swallow tablets received regorafenib as granulate follow the same regime: at a starting dose of 72 mg/m^2 once daily from Day 1 to Day 14 in 21 days cycles.

Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)

Arm description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 sequentially followed by administration of VI on a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

cellcristin

Pharmaceutical forms

Injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Pediatric subjects received Vincristine sequentially 1.5 mg/m^2, maximum of 2 mg (0.05 mg/kg for subjects ≤ 10 kg), on Day 1 and Day 8 in 21 days cycles.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects who were unable to swallow tablets received regorafenib as granulate follow the same regime: at a starting dose of 72 mg/m^2 once daily from Day 8 to Day 21 in 21 days cycles.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects received regorafenib sequentially administered with vincristine and irinotecan (VI), in the order of vincristine, irinotecan and regorafenib if 2 or 3 agents of the study treatment were scheduled to be administered in the same day. Regorafenib was orally taken at a starting dose of 72 mg/m^2 once daily from Day 8 to Day 21 in 21 days cycles.

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

irinotecan cell pharm

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pediatric subjects received irinotecan sequentially over 1 hour, at a starting dose of 50 mg/m^2/day, on Day 1 to Day 5 in 21 days cycles.

Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)

Arm description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m^2 sequentially administered with VI on a 21-day cycle.

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

cellcristin

Pharmaceutical forms

Injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Pediatric subjects received Vincristine sequentially 1.5 mg/m^2, maximum of 2 mg (0.05 mg/kg for subjects ≤ 10 kg), on Day 1 and Day 8 in 21 days cycles.

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

irinotecan cell pharm

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pediatric subjects received irinotecan sequentially over 1 hour, at a starting dose of 50 mg/m^2/day, on Day 1 to Day 5 in 21 days cycles.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects received regorafenib sequentially administered with vincristine and irinotecan (VI), in the order of vincristine, irinotecan and regorafenib if 2 or 3 agents of the study treatment were scheduled to be administered in the same day. Regorafenib was orally taken at a starting dose of 82 mg/m^2 once daily from Day 8 to Day 21 in 21 days cycles.

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

Pediatric subjects who were unable to swallow tablets received regorafenib as granulate follow the same regime: at a starting dose of 82 mg/m^2 once daily from Day 8 to Day 21 in 21 days cycles.

Number of subjects in period 1	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Started	6	14	14	7	2	6	13
Completed	0	0	0	0	0	0	0
Not completed	6	14	14	7	2	6	13
Consent withdrawn by subject	-	-	1	-	-	-	1
Physician decision	-	-	-	-	1	-	3
Progressive disease - clinical progression	3	2	3	1	-	-	-
Completed	-	-	-	-	-	1	-
Adverse event, non-fatal	-	-	-	-	-	1	2
AE related with clinical disease progression	1	1	1	-	-	-	-
Unspecified	-	-	-	-	-	-	2
AE not related with clinical disease progression	-	2	-	1	-	-	-
Progressive disease	-	-	-	-	1	3	5
Progressive disease - radiological progression	2	9	9	5	-	-	-
Lack of efficacy	-	-	-	-	-	1	-

Baseline characteristics

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Reporting group title

Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 60 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 93 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)

Reporting group description

Reporting group title

Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 sequentially followed by administration of VI on a 21-day cycle.

Reporting group title

Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m^2 sequentially administered with VI on a 21-day cycle.

Reporting group values	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)	Total
Number of subjects	6	14	14	7	2	6	13	62
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	12.5 ( 2.3 )	13.2 ( 3.2 )	10.2 ( 4.7 )	10.6 ( 4.5 )	13.50 ( 4.95 )	10.50 ( 4.59 )	8.73 ( 4.74 )	-
Gender Categorical
Units: Subjects
Female	2	7	7	5	0	2	6	29
Male	4	7	7	2	2	4	7	33

End points

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Reporting group title

Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 60 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 93 mg/m^2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)

Reporting group description

Reporting group title

Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 sequentially followed by administration of VI on a 21-day cycle.

Reporting group title

Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m^2 sequentially administered with VI on a 21-day cycle.

Subject analysis set title

Safety Analysis Set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of the study drug (regorafenib) will be included in the safety evaluation (Dose escalation phase: 41, dose expansion phase: 21).

Subject analysis set title

MTD Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects who completed Cycle 1 or discontinued during Cycle 1 due to an adverse event or dose-limiting toxicity (DLT) in the dose expansion phase will be included in the maximum tolerated dose (MTD) evaluation (Dose escalation phase: 23, dose expansion phase: 20).

Subject analysis set title

Efficacy Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects who received at least 1 dose of regorafenib and either had at least one post-baseline efficacy evaluation or have clinical disease progression before the first post-baseline efficacy assessment (treatment failure) will be included in the efficacy evaluations (Dose escalation phase: 39, dose expansion phase: 21).

Subject analysis set title

PK Analysis Set regorafenib

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects with valid evaluable PK data under regorafenib will be included in the evaluation of PK parameters (Dose escalation phase: 41, dose expansion phase: 20).

Subject analysis set title

Regorafenib tablets

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pediatric subjects who taken regorafenib tablets

Subject analysis set title

Regorafenib granulate

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pediatric subjects who taken regorafenib granulate

Subject analysis set title

Regorafenib Seq + VI (dose expansion phase)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m^2 or 82 mg/m^2 sequentially followed by administration of VI on a 21-day cycle.

Primary: Number of subjects with treatment emergent adverse events (TEAE)

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End point title

Number of subjects with treatment emergent adverse events (TEAE) ^[1]

End point description

Adverse Events are considered treatment emergent if they have started or worsened after the first study treatment administration up to 30 days after the end of treatment with study treatment.

End point type

Primary

End point timeframe

Up to 17 cycles for both dose escalation phase and dose expansion phase

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	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	6 ^[2]	14 ^[3]	14 ^[4]	7 ^[5]	2 ^[6]	6 ^[7]	13 ^[8]
Units: Subjects
Any TEAE	6	14	14	7	2	6	13
Any Serious TEAE	3	10	9	1	2	5	9
Drug-related TEAE	6	14	14	6	2	6	13
Drug-related serious TEAE	0	5	1	1	2	2	3

Notes
[2] - SAF
[3] - SAF
[4] - SAF
[5] - SAF
[6] - SAF
[7] - SAF
[8] - SAF

No statistical analyses for this end point

Primary: Number of subject with DLT (MTD analysis set)

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End point title

Number of subject with DLT (MTD analysis set) ^[9]

End point description

For the assessment of the MTD, the incidence of DLTs occurring only during Cycle 1 per cohort (dose level) in the MTD analysis set was considered. In order to establish a recommended phase II dose (RP2D), the MTD cohort was expanded to have at least 12 evaluable subjects to confirm the RP2D.

End point type

Primary

End point timeframe

Up to 17 cycles for both dose escalation phase and dose expansion phase

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics were done, no inferential statistical analyses were performed.

End point values	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	6 ^[10]	6 ^[11]	6 ^[12]	5 ^[13]	2 ^[14]	6 ^[15]	12 ^[16]
Units: Subjects	1	1	1	2	2	1	1

Notes
[10] - MTD analysis set
[11] - MTD analysis set
[12] - MTD analysis set
[13] - MTD analysis set
[14] - MTD analysis set
[15] - MTD analysis set
[16] - MTD analysis set

No statistical analyses for this end point

Primary: Maximum Tolerated Dose

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End point title

Maximum Tolerated Dose ^[17]

End point description

MTD was defined as the dose level at which ≤1 of 6 subjects experienced a DLT, when at least 2 of 3-6 subjects experienced a DLT at the next highest dose.

End point type

Primary

End point timeframe

By cycle 1

Notes
[17] - 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	MTD Analysis Set
Number of subjects analysed	23
Units: mg/m^2	82

No statistical analyses for this end point

Primary: Recommended Phase II Dose (RP2D)

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End point title

Recommended Phase II Dose (RP2D) ^[18]

End point description

MTD cohort was expanded to have at least 12 evaluable subjects to confirm the RP2D. It was expected that at least 15 subjects evaluable for DLTs were necessary to establish the RP2D of the combination.

End point type

Primary

End point timeframe

By cycle 1

Notes
[18] - 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	MTD Analysis Set
Number of subjects analysed	23
Units: mg/m^2	82

No statistical analyses for this end point

Primary: AUC(0-24)md based on nominal dosing of regorafenib (dose escalation phase)

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End point title

AUC(0-24)md based on nominal dosing of regorafenib (dose escalation phase) ^[19] ^[20]

End point description

Area under the concentration-time curve after multiple dose from time zero to 24 hours (AUC(0-24)md) based on nominal dosing. The PK parameters were calculated with a population pharmacokinetic (popPK) model using available data.

End point type

Primary

End point timeframe

Dose escalation phase: Cycle 1 Day 1, Day 15 and Day 21

Notes
[19] - 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.
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: AUC(0-24)md based on nominal dosing of regorafenib in dose escalation phase and dose expansion phase were analyzed for primary endpoint and secondary endpoint respectively.

End point values	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)
Number of subjects analysed	6 ^[21]	14 ^[22]	14 ^[23]	7 ^[24]
Units: mg*h/L
geometric mean (geometric coefficient of variation)	34.1 ( 34.6 )	47.3 ( 37.1 )	54.4 ( 35.8 )	49.6 ( 42.7 )

Notes
[21] - PK Analysis Set regorafenib
[22] - PK Analysis Set regorafenib
[23] - PK Analysis Set regorafenib
[24] - PK Analysis Set regorafenib

No statistical analyses for this end point

Secondary: AUC(0-24)md based on nominal dosing of regorafenib (dose expansion Phase)

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End point title

AUC(0-24)md based on nominal dosing of regorafenib (dose expansion Phase) ^[25]

End point description

99999 indicates the value could not be evaluated due to the low number of subjects. The PK parameters were calculated with a PopPK model using available data.

End point type

Secondary

End point timeframe

Expansion Phase: Cycle 1 Day1, Day 15 and Day 21

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was only analyzed in dose expansion phase.

End point values	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	2	6	12
Units: mg*h/L
geometric mean (geometric coefficient of variation)	99999 ( 99999 )	64.4 ( 41.3 )	55.6 ( 33.6 )

No statistical analyses for this end point

Secondary: Cmax(0-24)md of regorafenib based on actual dosing

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End point title

Cmax(0-24)md of regorafenib based on actual dosing

End point description

The variability in Cmax(0-24)md could not be robustly estimated by the current model. Thus, no result is available for this endpoint.

End point type

Secondary

End point timeframe

Dose escalation phase: Cycle 1 Day1, Day 15 and Day 21 Dose expansion phase: Cycle 1 Day1, Day 15 and Day 21

End point values	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	0 ^[26]	0 ^[27]	0 ^[28]	0 ^[29]	0 ^[30]	0 ^[31]	0 ^[32]
Units: mg*h/L
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )	( )	( )	( )

Notes
[26] - 99999 indicates the value is not available.
[27] - 99999 indicates the value is not available.
[28] - 99999 indicates the value is not available.
[29] - 99999 indicates the value is not available.
[30] - 99999 indicates the value is not available.
[31] - 99999 indicates the value is not available.
[32] - 99999 indicates the value is not available.

No statistical analyses for this end point

Secondary: Cav(0-24)md of regorafenib based on actual dosing

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End point title

Cav(0-24)md of regorafenib based on actual dosing

End point description

Cav(0-24)md = Average plasma concentration over the 24 h dosing interval after multiple dosing. 99999 indicates the value could not be evaluated due to the low number of subjects. The PK parameters were calculated with a PopPK model using available data.

End point type

Secondary

End point timeframe

Dose escalation phase: Cycle 1 Day1, Day 15 and Day 21 Dose expansion phase: Cycle 1 Day1, Day 15 and Day 21

End point values	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	6	14	14	7	2	6	12
Units: mg/L
geometric mean (geometric coefficient of variation)	1.42 ( 34.6 )	1.97 ( 37.1 )	2.27 ( 35.8 )	2.06 ( 42.7 )	99999 ( 99999 )	2.68 ( 41.3 )	2.32 ( 33.6 )

No statistical analyses for this end point

Secondary: t1/2eff,md of regorafenib based on actual dosing

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End point title

t1/2eff,md of regorafenib based on actual dosing

End point description

t1/2eff,md = effective half-life after multiple dosing. 99999 indicates the value could not be evaluated due to the low number of subjects. The PK parameters were calculated with a PopPK model using available data.

End point type

Secondary

End point timeframe

Dose expansion phase: Cycle 1 Day1, Day 15 and Day 21 Dose escalation phase: Cycle 1 Day1, Day 15 and Day 21

End point values	Regorafenib Level 1 (60 mg/m^2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m^2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m^2) (dose escalation phase)	Regorafenib Level 4 (93 mg/m^2) (dose escalation phase)	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	6	14	14	7	2	6	12
Units: hours
geometric mean (geometric coefficient of variation)	33.2 ( 35.6 )	36.1 ( 32.7 )	32.9 ( 30.0 )	26.1 ( 26.3 )	99999 ( 99999 )	44.3 ( 32.3 )	34.1 ( 37.1 )

No statistical analyses for this end point

Secondary: Clearance of irinotecan and SN-38

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End point title

Clearance of irinotecan and SN-38 ^[33]

End point description

The PK parameters were calculated with a PopPK model using available data.

End point type

Secondary

End point timeframe

Expansion Phase: Cycle 1 Day1, Day 15 and Day 21

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was only analyzed in dose expansion phase.

End point values	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib Seq + VI (dose expansion phase)
Number of subjects analysed	2 ^[34]	17
Units: L/h
geometric mean (geometric coefficient of variation)
Clearance of irinotecan	99999 ( 99999 )	22.3 ( 83.1 )
Clearance of SN-38	99999 ( 99999 )	46.5 ( 74 )

Notes
[34] - Could not be evaluated due to the low number of subjects

No statistical analyses for this end point

Secondary: Overall survival (OS) under the study treatment (regorafenib in combination with vincristine and irinotecan)

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End point title

Overall survival (OS) under the study treatment (regorafenib in combination with vincristine and irinotecan) ^[35]

End point description

OS was defined as the time (days) from the date of first dose of study treatment to death due to any cause. 99999 indicates the value could not be evaluated due to the low number of subjects.

End point type

Secondary

End point timeframe

60 months

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was only analyzed in dose expansion phase.

End point values	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	2	6	13
Units: Days
median (inter-quartile range (Q1-Q3))
25th percentile [95% CI]	477 (477 to 99999)	166 (121 to 222)	191 (42 to 391)
Median [95% CI]	813 (477 to 99999)	207 (121 to 99999)	497 (102 to 99999)
75th percentile [95% CI]	1149 (477 to 99999)	364 (166 to 99999)	99999 (391 to 99999)

No statistical analyses for this end point

Secondary: Time to progression (TTP) under the study treatment (regorafenib in combination with vincristine and irinotecan)

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End point title

Time to progression (TTP) under the study treatment (regorafenib in combination with vincristine and irinotecan) ^[36]

End point description

TTP was defined as the time (days) from the date of the first dose of study treatment to the date of the first observed radiological disease progression. 99999 indicates the value could not be evaluated due to the low number of subjects or censored data.

End point type

Secondary

End point timeframe

60 months

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was only analyzed in dose expansion phase.

End point values	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	2	6	13
Units: Days
median (inter-quartile range (Q1-Q3))
25th percentile [95% CI]	320 (320 to 99999)	88 (85 to 152)	89 (19 to 324)
Median [95% CI]	437 (320 to 99999)	127 (85 to 99999)	324 (37 to 457)
75th percentile [95% CI]	554 (320 to 99999)	198 (88 to 99999)	457 (214 to 99999)

No statistical analyses for this end point

Secondary: Tumor response: Best overall response RECIST 1.1

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End point title

Tumor response: Best overall response RECIST 1.1 ^[37]

End point description

Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as per investigator’s and/or local radiologists assessment [complete response (CR), partial response (PR), stable disease, progressive disease (PD)] and semi-quantitative iodine-123 metaiodobenzylguanidine (mIBG) scintigraphy score for neuro-blastoma subjects [International Society of Pediatric Oncology Europe Neuroblastoma Group (SIOPEN) score] in whom the disease is not evaluable per RECIST version 1.1.

End point type

Secondary

End point timeframe

Up to 60 months

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was only analyzed in dose expansion phase.

End point values	Regorafenib (72 mg/m^2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m^2) Seq + VI (dose expansion phase)	Regorafenib (82 mg/m^2) Seq + VI (dose expansion phase)
Number of subjects analysed	2	6	13
Units: Subjects
Completed response (CR)	0	0	3
Partial response (PR)	2	2	3
Stable disease (SD)	0	3	4
Non CR/Non PD	0	1	0
Progressive disease (PD)	0	0	2
Response rate (CR+PR)	2	2	6

No statistical analyses for this end point

Other pre-specified: Taste and texture questionnaire of the regorafenib formulations

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End point title

Taste and texture questionnaire of the regorafenib formulations

End point description

The taste and texture questionnaire was used to determine children’s acceptance of the tablets and granulate formulation.

End point type

Other pre-specified

End point timeframe

By cycle 1

End point values	Regorafenib tablets	Regorafenib granulate
Number of subjects analysed	11	8
Units: Subjects
Bad	1	0
Neutral	4	4
Good	3	1
Very good	3	2
Not Assessable	0	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

After the first study intervention up to 30 days after the end of study intervention. Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Regorafenib Level 1 (60 mg/m2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 60 mg/m2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 2 (72 mg/m2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib Level 3 (82 mg/m2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Reporting group title

Regorafenib (82 mg/m2) Seq + VI (dose expansion phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 82 mg/m2 sequentially administered with VI on a 21-day cycle.

Reporting group title

Regorafenib (72 mg/m2) Conc + VI (dose expansion phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m2 concomitantly administered with vincristine and irinotecan (VI) on a 21-day cycle.

Reporting group title

Regorafenib (72 mg/m2) Seq + VI (dose expansion phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 72 mg/m2 sequentially followed by administration of VI on a 21-day cycle.

Reporting group title

Regorafenib Level 4 (93 mg/m2) (dose escalation phase)

Reporting group description

Pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy received regorafenib 93 mg/m2 in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days.

Serious adverse events	Regorafenib Level 1 (60 mg/m2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m2) (dose escalation phase)	Regorafenib (82 mg/m2) Seq + VI (dose expansion phase)	Regorafenib (72 mg/m2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m2) Seq + VI (dose expansion phase)	Regorafenib Level 4 (93 mg/m2) (dose escalation phase)
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 6 (50.00%)	10 / 14 (71.43%)	9 / 14 (64.29%)	9 / 13 (69.23%)	2 / 2 (100.00%)	5 / 6 (83.33%)	1 / 7 (14.29%)
number of deaths (all causes)	6	14	13	8	2	6	7
number of deaths resulting from adverse events	1	5	2	1	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	1 / 6 (16.67%)	4 / 14 (28.57%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 4	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
Facial pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	4 / 14 (28.57%)	3 / 14 (21.43%)	4 / 13 (30.77%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	5 / 6	5 / 7	0 / 8	2 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 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	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Reproductive system and breast disorders
Oedema genital
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Investigations
General physical condition abnormal
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Shunt occlusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 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	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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 / 1	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	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	0 / 0
Hydrocephalus
subjects affected / exposed	2 / 6 (33.33%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 2	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	0 / 0
Neuralgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Lethargy
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Blood and lymphatic system disorders
Febrile bone marrow aplasia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Haemolysis
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal mass
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	2 / 2 (100.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	1 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Colitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	1 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic haematoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Hepatic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Renal and urinary disorders
Urinary retention
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cytomegalovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Ear infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Tooth infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Tonsillitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0
Hypophagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cerebral salt-wasting syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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	0 / 0

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

Non-serious adverse events	Regorafenib Level 1 (60 mg/m2) (dose escalation phase)	Regorafenib Level 2 (72 mg/m2) (dose escalation phase)	Regorafenib Level 3 (82 mg/m2) (dose escalation phase)	Regorafenib (82 mg/m2) Seq + VI (dose expansion phase)	Regorafenib (72 mg/m2) Conc + VI (dose expansion phase)	Regorafenib (72 mg/m2) Seq + VI (dose expansion phase)	Regorafenib Level 4 (93 mg/m2) (dose escalation phase)
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	14 / 14 (100.00%)	14 / 14 (100.00%)	13 / 13 (100.00%)	2 / 2 (100.00%)	6 / 6 (100.00%)	7 / 7 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Tumour haemorrhage
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Tumour fistulisation
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hot flush
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	1	0	0	1	0
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Peripheral coldness
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Poor peripheral circulation
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Hypertension
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	3 / 14 (21.43%)	2 / 13 (15.38%)	0 / 2 (0.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)
occurrences all number	1	3	3	3	0	2	2
General disorders and administration site conditions
Feeling cold
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Fatigue
subjects affected / exposed	5 / 6 (83.33%)	5 / 14 (35.71%)	4 / 14 (28.57%)	2 / 13 (15.38%)	2 / 2 (100.00%)	2 / 6 (33.33%)	3 / 7 (42.86%)
occurrences all number	10	8	5	4	4	3	3
Facial pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	3	0	0	0	0
Chills
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1	1
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	3 / 14 (21.43%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	5	3	0	0	0	2
Asthenia
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	1 / 14 (7.14%)	2 / 13 (15.38%)	0 / 2 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	1	10	1	4	0	1	3
Application site rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	4 / 13 (30.77%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	2	0	5	0	1	0
Gait disturbance
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Generalised oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Hypothermia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	4 / 14 (28.57%)	6 / 14 (42.86%)	8 / 13 (61.54%)	1 / 2 (50.00%)	3 / 6 (50.00%)	4 / 7 (57.14%)
occurrences all number	1	6	7	11	2	4	6
Malaise
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	1	0	0	2
Oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1	1	0	0	1
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Vaccination site erythema
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Vaccination site pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Allergy to immunoglobulin therapy
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Perineal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Vaginal discharge
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Laryngeal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Choking
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Cough
subjects affected / exposed	1 / 6 (16.67%)	4 / 14 (28.57%)	1 / 14 (7.14%)	3 / 13 (23.08%)	1 / 2 (50.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)
occurrences all number	1	4	1	5	1	3	2
Dysphonia
subjects affected / exposed	1 / 6 (16.67%)	2 / 14 (14.29%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	2	1	0	0	0	0
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	2 / 14 (14.29%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	1	5	2	0	0	1	1
Epistaxis
subjects affected / exposed	2 / 6 (33.33%)	3 / 14 (21.43%)	2 / 14 (14.29%)	3 / 13 (23.08%)	0 / 2 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	2	3	2	3	0	2	1
Nasal congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Nasal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	2	0	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	2	0	5	0	0
Sneezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Anxiety
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	2 / 14 (14.29%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	3	2	0	0	0
Confusional state
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	0
Depressed mood
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	1	0	0	0	0
Hallucination
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	3	0	0	1	1	0
Sleep disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	18	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	5 / 14 (35.71%)	5 / 14 (35.71%)	4 / 13 (30.77%)	2 / 2 (100.00%)	3 / 6 (50.00%)	5 / 7 (71.43%)
occurrences all number	2	7	6	35	11	13	7
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	5 / 14 (35.71%)	7 / 14 (50.00%)	4 / 13 (30.77%)	2 / 2 (100.00%)	3 / 6 (50.00%)	4 / 7 (57.14%)
occurrences all number	3	8	10	41	12	15	4
Bilirubin conjugated increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	1 / 6 (16.67%)	4 / 14 (28.57%)	8 / 14 (57.14%)	2 / 13 (15.38%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	2	12	17	10	4	2	0
Blood bilirubin unconjugated increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	5	0	0	0	0
Blood chloride increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Blood creatinine increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	3 / 13 (23.08%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	4	0	0	0
Blood fibrinogen decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	4	6	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	2	0	3	0	2	0
Blood urea increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
C-reactive protein increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Fibrin D dimer increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 6 (16.67%)	2 / 14 (14.29%)	0 / 14 (0.00%)	3 / 13 (23.08%)	2 / 2 (100.00%)	2 / 6 (33.33%)	2 / 7 (28.57%)
occurrences all number	3	2	0	18	4	3	3
Haemoglobin increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Lipase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0	2	0	3	0
Lymphocyte count decreased
subjects affected / exposed	2 / 6 (33.33%)	2 / 14 (14.29%)	1 / 14 (7.14%)	1 / 13 (7.69%)	1 / 2 (50.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	3	3	4	39	9	1	3
Lymphocyte count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	3 / 13 (23.08%)	1 / 2 (50.00%)	3 / 6 (50.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	25	11	8	0
Platelet count decreased
subjects affected / exposed	0 / 6 (0.00%)	4 / 14 (28.57%)	2 / 14 (14.29%)	2 / 13 (15.38%)	0 / 2 (0.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)
occurrences all number	0	8	8	32	0	8	1
Prothrombin time prolonged
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Prothrombin time ratio increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Prothrombin time shortened
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Thyroxine increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	3 / 14 (21.43%)	4 / 14 (28.57%)	5 / 13 (38.46%)	1 / 2 (50.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	4	8	7	5	6	0
General physical condition abnormal
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	2	0	0
Breath sounds abnormal
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
White blood cell count decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	2	0	0	49	4	6	0
Injury, poisoning and procedural complications
Sunburn
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Fall
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	1	1	0	0	0	0
Ligament sprain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Thermal burn
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Contusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Stoma site pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Skin laceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Vascular access complication
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Radiation skin injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Procedural pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Skin wound
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Congenital, familial and genetic disorders
Primary insulin like growth factor-1 deficiency
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Bradycardia
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Tachycardia
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	2 / 14 (14.29%)	3 / 13 (23.08%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	1	1	2	3	0	0	3
Sinus tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	1	0	0	0
Nervous system disorders
Facial paralysis
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	1	0	0	0
Ataxia
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	1	2	0	0	0	0
Burning sensation
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Dizziness
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	3	0
Drooling
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Dysarthria
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Dysgeusia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	1	0	0
Aphasia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Haemorrhage intracranial
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Presyncope
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	1	0	0
Hemiparesis
subjects affected / exposed	1 / 6 (16.67%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	3	0	0	0	0	0
Hydrocephalus
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Hyperaesthesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Hypersomnia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
IIIrd nerve paralysis
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Lethargy
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	2 / 13 (15.38%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	1	2	0	3	0
Monoplegia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Neuralgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	8	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	4	0	0	0
Paraesthesia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	3	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Headache
subjects affected / exposed	6 / 6 (100.00%)	5 / 14 (35.71%)	5 / 14 (35.71%)	2 / 13 (15.38%)	1 / 2 (50.00%)	2 / 6 (33.33%)	2 / 7 (28.57%)
occurrences all number	14	13	8	3	2	2	2
Seizure
subjects affected / exposed	1 / 6 (16.67%)	2 / 14 (14.29%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	2	1	1	0	0	0
Restless legs syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Pyramidal tract syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Taste disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Phantom limb syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	4	0	0	0	0
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	2	0	0	0	0
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	5 / 14 (35.71%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	3	7	0	0	0	3
Lymph node pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	1 / 14 (7.14%)	2 / 13 (15.38%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	6	2	87	0	11	0
Leukocytosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Febrile neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	3 / 14 (21.43%)	5 / 14 (35.71%)	9 / 13 (69.23%)	2 / 2 (100.00%)	4 / 6 (66.67%)	2 / 7 (28.57%)
occurrences all number	0	5	7	79	4	7	3
Monocytosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hypofibrinogenaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	5	0
Thrombocytopenia
subjects affected / exposed	2 / 6 (33.33%)	4 / 14 (28.57%)	3 / 14 (21.43%)	5 / 13 (38.46%)	1 / 2 (50.00%)	3 / 6 (50.00%)	1 / 7 (14.29%)
occurrences all number	9	7	3	12	3	22	5
Neutrophilia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Neutropenia
subjects affected / exposed	1 / 6 (16.67%)	7 / 14 (50.00%)	3 / 14 (21.43%)	5 / 13 (38.46%)	1 / 2 (50.00%)	4 / 6 (66.67%)	0 / 7 (0.00%)
occurrences all number	4	14	7	60	5	27	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)	1 / 2 (50.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	2	1	1	0	1
Otorrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Hypoacusis
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	0
Ear discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	0	0	2
Ear pruritus
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Diplopia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Periorbital oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Miosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Eyelid ptosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	3	0	0	0	1	0
Visual acuity reduced
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	0	0	1
Orbital swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	1	0	1	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 6 (33.33%)	2 / 14 (14.29%)	5 / 14 (35.71%)	8 / 13 (61.54%)	2 / 2 (100.00%)	4 / 6 (66.67%)	3 / 7 (42.86%)
occurrences all number	3	2	14	17	5	7	5
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	1	0
Constipation
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	5 / 14 (35.71%)	2 / 13 (15.38%)	1 / 2 (50.00%)	1 / 6 (16.67%)	3 / 7 (42.86%)
occurrences all number	1	4	7	2	2	1	3
Cheilitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Anal fissure
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	2	4	0	0	0	1
Dental caries
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Gastrointestinal disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	0
Dysphagia
subjects affected / exposed	2 / 6 (33.33%)	2 / 14 (14.29%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	2	3	1	0	0	0	1
Dyspepsia
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	3	0	1	3	1	0
Diarrhoea
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	5 / 14 (35.71%)	13 / 13 (100.00%)	2 / 2 (100.00%)	5 / 6 (83.33%)	2 / 7 (28.57%)
occurrences all number	1	5	11	35	11	18	2
Gingival pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Glossitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Glossodynia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Odynophagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Oral pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	3	0	1	0	5	2
Lip pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Haemorrhoids
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Haematochezia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Nausea
subjects affected / exposed	2 / 6 (33.33%)	6 / 14 (42.86%)	4 / 14 (28.57%)	6 / 13 (46.15%)	0 / 2 (0.00%)	3 / 6 (50.00%)	5 / 7 (71.43%)
occurrences all number	5	7	5	14	0	14	6
Proctalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Faeces soft
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Lip exfoliation
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Large intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Anal inflammation
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Vomiting
subjects affected / exposed	3 / 6 (50.00%)	8 / 14 (57.14%)	7 / 14 (50.00%)	8 / 13 (61.54%)	2 / 2 (100.00%)	3 / 6 (50.00%)	1 / 7 (14.29%)
occurrences all number	7	13	12	28	5	15	4
Toothache
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	3	0
Tongue ulceration
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Stomatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)
occurrences all number	1	0	1	1	0	2	1
Saliva altered
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Oral hyperaesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Anal incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hyperaesthesia teeth
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	2 / 6 (33.33%)	1 / 14 (7.14%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	2	1	2	0	0	3	0
Jaundice cholestatic
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Hepatic cytolysis
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Gallbladder obstruction
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Hepatotoxicity
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Decubitus ulcer
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Acne
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Alopecia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	5 / 14 (35.71%)	4 / 13 (30.77%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	1	5	6	0	2	0
Alopecia universalis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Blister
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Petechiae
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Dermatitis atopic
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Dermatitis diaper
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Dermatitis exfoliative generalised
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	2
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 14 (14.29%)	6 / 13 (46.15%)	0 / 2 (0.00%)	2 / 6 (33.33%)	2 / 7 (28.57%)
occurrences all number	0	1	3	8	0	5	2
Eczema
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Erythema
subjects affected / exposed	4 / 6 (66.67%)	3 / 14 (21.43%)	4 / 14 (28.57%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	10	3	4	3	0	0	0
Hair colour changes
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	3	1	0	0	0	0
Hair texture abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Ingrowing nail
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Pain of skin
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	3	0	1	0	1	0
Palmar erythema
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 6 (16.67%)	5 / 14 (35.71%)	4 / 14 (28.57%)	0 / 13 (0.00%)	0 / 2 (0.00%)	3 / 6 (50.00%)	3 / 7 (42.86%)
occurrences all number	3	10	7	0	0	7	3
Dermatitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Pruritus
subjects affected / exposed	2 / 6 (33.33%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)	1 / 2 (50.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	2	0	3	1	2	1	1
Rash
subjects affected / exposed	0 / 6 (0.00%)	4 / 14 (28.57%)	4 / 14 (28.57%)	4 / 13 (30.77%)	2 / 2 (100.00%)	3 / 6 (50.00%)	4 / 7 (57.14%)
occurrences all number	0	4	11	5	2	3	13
Rash macular
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	1 / 6 (16.67%)	5 / 14 (35.71%)	2 / 14 (14.29%)	2 / 13 (15.38%)	1 / 2 (50.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	1	9	3	7	1	1	2
Rash morbilliform
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Skin depigmentation
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Telangiectasia
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Skin exfoliation
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	0
Skin fissures
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Skin hyperpigmentation
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Skin hypopigmentation
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Skin reaction
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	2	0	0	0	0
Solar dermatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Skin disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	3	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Skin induration
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	1	0	0	0	0
Pruritus allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	6	0	0	0
Glycosuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Proteinuria
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	2 / 13 (15.38%)	1 / 2 (50.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)
occurrences all number	0	1	0	2	5	3	1
Urinary incontinence
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	1	1	1	0	0	0	1
Urinary retention
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Leukocyturia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	3	0	2	0
Acute kidney injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	0
Glucocorticoid deficiency
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 6 (0.00%)	3 / 14 (21.43%)	3 / 14 (21.43%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	4	3	6	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	3 / 14 (21.43%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	4	6	0	0	2	0
Back pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	4	3	0	0	1	1
Pain in jaw
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	2	0
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	6	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	5	0	2	0
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	3	0
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	2 / 14 (14.29%)	1 / 13 (7.69%)	0 / 2 (0.00%)	2 / 6 (33.33%)	2 / 7 (28.57%)
occurrences all number	1	3	3	5	0	3	4
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	3	0	1	0
Torticollis
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Spinal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Infections and infestations
Gingivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Folliculitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Epstein-Barr virus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Ear infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	5	0	0	0
Cytomegalovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	3	0	1	0	0	0
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Paronychia
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Otitis media
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Oral candidiasis
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 14 (14.29%)	2 / 14 (14.29%)	1 / 13 (7.69%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	2	2	1	0	2	0
Pharyngitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 14 (14.29%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	4	0	1	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Laryngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Influenza
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Molluscum contagiosum
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Tooth infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Wound infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Varicella
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	3 / 7 (42.86%)
occurrences all number	0	1	1	1	0	0	3
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 2 (50.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	2	3	1	1
Tonsillitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	2	0
Rhinitis
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	3	0	0	0	0	0
Pustule
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Stoma site infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Device related infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Mucosal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Oral herpes
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Periorbital cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Viraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Rhinovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Clostridium difficile infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Candida infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	4	0	0	0
COVID-19
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	2
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	1	0
Hypermagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Hypernatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hyperphosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 2 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hypertriglyceridaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Hyperuricaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	1	0	5	0	3	1
Increased appetite
subjects affected / exposed	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	5 / 13 (38.46%)	2 / 2 (100.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	1	11	9	1	0
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	3 / 14 (21.43%)	3 / 14 (21.43%)	2 / 13 (15.38%)	1 / 2 (50.00%)	1 / 6 (16.67%)	2 / 7 (28.57%)
occurrences all number	1	8	4	3	4	2	2
Hypophosphataemia
subjects affected / exposed	2 / 6 (33.33%)	1 / 14 (7.14%)	4 / 14 (28.57%)	3 / 13 (23.08%)	2 / 2 (100.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)
occurrences all number	2	2	9	8	10	5	1
Hypoproteinaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Hypocalcaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	3 / 13 (23.08%)	1 / 2 (50.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	8	4	0	1
Decreased appetite
subjects affected / exposed	1 / 6 (16.67%)	6 / 14 (42.86%)	1 / 14 (7.14%)	5 / 13 (38.46%)	2 / 2 (100.00%)	5 / 6 (83.33%)	3 / 7 (42.86%)
occurrences all number	1	6	6	10	6	8	5
Hypophagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Hyperlipasaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 2 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Feeding intolerance
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 2 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

08 Jul 2014

- Addition of pediatric granulate formulation - Revised eligibility criteria - Updated storage conditions - Corrected study procedures (weight, temperature, hematology, urinalysis) - Updated regulatory status and clinical data - Addition of Active Follow-up period - Updated Study Medical Expert contact details - Updated language on re-screening of subjects - Removal of adverse events of special interest - Updated language on tumor assessments

25 Mar 2015

- Clarified guidance on the initial choice and later change of regorafenib formulation - Clarified guidance on drug interruption and cycle delay - Addition of body surface area (BSA) ranges for children 2-5 years old

29 May 2017

- Structural changes - Addition of the objectives of the dose expansion phase - Addition of backbone chemotherapy for the dose expansion phase - Updated introduction section - Addition of doses and dosing schedules for the dose expansion phase - Addition of duration of treatment for the dose expansion phase - Addition of indications for the dose expansion phase - Revised eligibility criteria for the dose expansion phase - Updated methodology - Addition of Pharmacokinetics (PK) sampling schedule for the dose expansion phase - Updated recommended phase 2 dose information for the dose expansion phase - Clarified the period for follow-up long-term effects - Clarified tumor response evaluation period for the dose expansion phase - Addition of number of subjects for the dose expansion phase - Addition of primary variable for the dose expansion phase - Updated language on safety follow-up visit/contact of the dose expansion phase - Clarified duration of each cycle for the dose escalation phase - Removal of optional retrospective independent review - Clarified that radiological progression were determined per local assessment - Updated plan for statistical analysis for the dose expansion phase - Updated data handling and quality assurance section - Updated list of CYP3A4 inhibitors and inducers - Updated regorafenib dosing based on BSA and dose level

13 Jun 2018

- PK sampling schedule for Irinotecan for the sequential dosing schedule changed - Updated language for use of Granulocyte colony-stimulating factor (G-CSF)

20 Mar 2019

- Removed the list of regorafenib Adverse drug reaction (ADR) information from the background and reference the Investigator’s Brochure (IB) - Clarified re-screening criteria - Clarified on dose delay requirement to up to 2 weeks instead of 1-2 weeks - Add the requirement for the tumor response assessment for patients that stay on treatment after Cycle 12 - Included lower BSA range for tablet dosing

13 Jul 2020

- Sentence added to clarify when subjects enter the active follow up phase - Clarification added that days 2-5 were not mandatory provided that a patient was no longer receiving irinotecan - Modified sentence to allow local control via surgery and/or radiotherapy and continued study treatment, provided response to treatment is significant enough for local therapy to be considered potentially curative.

01 Mar 2022

- Modified table to allow plasma sample for biomarker analysis and collection. Where appropriate the second sample may be collected during a routine visit prior to discontinuation of study treatment - Modified footnote to add language for height, weight, and BSA fields - Added language about Day 1 and Day 8 laboratory samples for patients receiving regorafenib alone

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.

Occurrence of "±” in relation with geometric CV is auto-generated and cannot be deleted.

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Clinical trials

Clinical Trial Results: A multi-center, open-label, non-randomized, phase I dose escalation study of regorafenib (BAY73-4506) in pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with treatment emergent adverse events (TEAE)

Primary: Number of subjects with treatment emergent adverse events (TEAE)

Primary: Number of subject with DLT (MTD analysis set)

Primary: Number of subject with DLT (MTD analysis set)

Primary: Maximum Tolerated Dose

Primary: Maximum Tolerated Dose

Primary: Recommended Phase II Dose (RP2D)

Primary: Recommended Phase II Dose (RP2D)

Primary: AUC(0-24)md based on nominal dosing of regorafenib (dose escalation phase)

Primary: AUC(0-24)md based on nominal dosing of regorafenib (dose escalation phase)

Secondary: AUC(0-24)md based on nominal dosing of regorafenib (dose expansion Phase)

Secondary: AUC(0-24)md based on nominal dosing of regorafenib (dose expansion Phase)

Secondary: Cmax(0-24)md of regorafenib based on actual dosing

Secondary: Cmax(0-24)md of regorafenib based on actual dosing

Secondary: Cav(0-24)md of regorafenib based on actual dosing

Secondary: Cav(0-24)md of regorafenib based on actual dosing

Secondary: t1/2eff,md of regorafenib based on actual dosing

Secondary: t1/2eff,md of regorafenib based on actual dosing

Secondary: Clearance of irinotecan and SN-38

Secondary: Clearance of irinotecan and SN-38

Secondary: Overall survival (OS) under the study treatment (regorafenib in combination with vincristine and irinotecan)

Secondary: Overall survival (OS) under the study treatment (regorafenib in combination with vincristine and irinotecan)

Secondary: Time to progression (TTP) under the study treatment (regorafenib in combination with vincristine and irinotecan)

Secondary: Time to progression (TTP) under the study treatment (regorafenib in combination with vincristine and irinotecan)

Secondary: Tumor response: Best overall response RECIST 1.1

Secondary: Tumor response: Best overall response RECIST 1.1

Other pre-specified: Taste and texture questionnaire of the regorafenib formulations

Other pre-specified: Taste and texture questionnaire of the regorafenib formulations

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multi-center, open-label, non-randomized, phase I dose escalation study of regorafenib (BAY73-4506) in pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy