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Clinical Trial Results:
Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults with Osteosarcoma

Summary
EudraCT number	2013-005534-38
Trial protocol	GB ES DE FR IT Outside EU/EEA
Global end of trial date	20 Jul 2022

Results information
Results version number	v1(current)
This version publication date	21 Jan 2023
First version publication date	21 Jan 2023
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

E7080-G000-207

ISRCTN number

US NCT number

NCT02432274

WHO universal trial number (UTN)

Sponsor organisation name

Eisai Ltd.

Sponsor organisation address

Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN

Public contact

Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_oncmedinfo@eisai.com

Scientific contact

Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_oncmedinfo@eisai.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001119-PIP02-12

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?

Yes

Analysis stage

Final

Date of interim/final analysis

20 Jul 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Jul 2022

Was the trial ended prematurely?

Main objective of the trial

Cohort 1 (Single-agent Dose-Finding) -Identify the recommended dose (RD) of lenvatinib as a single agent in children and adolescents with relapsed or refractory solid malignant tumors. Cohort 2 (Single-agent Expansion) -Evaluate the activity of lenvatinib in 2 separate malignancy groups: Cohort 2A: 131 iodine- refractory differentiated thyroid cancer (DTC): by objective response rate (ORR) for subjects with measurable disease and by best overall response (BOR) for all subjects. Cohort 2B: Relapsed or refractory osteosarcoma: by progression-free survival at 4 months (PFS)-4. Cohort 3 (Combination Dose-Finding and Expansion) Cohort 3A (Combination Dose-Finding) -To identify the RD of lenvatinib in combination with ifosfamide and etoposide in osteosarcoma subjects. Cohort 3B (Combination Expansion) -Evaluate the activity of lenvatinib in combination with ifosfamide and etoposide in osteosarcoma subjects by PFS-4.

Protection of trial subjects

This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Dec 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 16

Country: Number of subjects enrolled

United Kingdom: 20

Country: Number of subjects enrolled

United States: 6

Country: Number of subjects enrolled

France: 34

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Italy: 18

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

Subjects took part at 19 investigative sites in France, Germany, Italy, Spain, United Kingdom and the United States. Total 117 subjects were enrolled and screened, of which 20 subjects were screen failures and 97 subjects received study treatment.

Screening details

Prior to entering Cohort 1, subjects aged 2 to less than (<) 6 years underwent a run-in period and received lenvatinib 5 milligram per square meter (mg/m^2) per body surface area (BSA) as capsules or suspension once daily for 21 days.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2

Arm description

Subjects (of age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (administered per body surface area[BSA]) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by subject at any time, or study termination by the sponsor, whichever occurred first. Eligible subjects of age group 2 to <6 years first underwent a 21-day run-in period with 5 mg/m^2 lenvatinib before receiving lenvatinib 11 mg/m^2 in Cycle 1 in Cohort 1. Duration of each cycle in Cohort 1=28 days. After determining recommended dose (RD) in Cohort 1,subjects were enrolled in Cohorts 2A, 2B and 3A.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received lenvatinib 11 mg/m^2, capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28. 2 subjects from arm Cohort 1 lenvatinib 17 mg/m^2 actually received lenvatinib 11 mg/m^2.

Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2

Arm description

Subjects (of age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (administered per BSA) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by subject at any time, or study termination by the sponsor, whichever occurred first. Eligible subjects of age group 2 to <6 years first underwent a 21-day run-in period with 5 mg/m^2 lenvatinib before receiving lenvatinib 14 mg/m^2 in Cycle 1 in Cohort 1. Duration of each cycle in Cohort 1=28 days. After determining RD in Cohort 1, subjects were enrolled in Cohorts 2A, 2B and 3A.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received lenvatinib 14 mg/m^2, capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28. 2 subjects from arm Cohort 1 lenvatinib 17 mg/m^2 actually received lenvatinib 14 mg/m^2.

Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2

Arm description

Subjects (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever occurred first. Duration of each cycle in Cohort 1=28 days. After determining the RD in Cohort 1, subjects were enrolled in Cohorts 2A, 2B and 3A.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received lenvatinib 17 mg/m^2, capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28.

Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2

Arm description

Subjects with 131 iodine-refractory differentiated thyroid cancer (DTC) received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 milligram per day [mg/day]) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2A=28 days.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2

Arm description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever occurred first. Duration of each treatment cycle in Cohort 2B=28 days.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2

Arm description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20 percent [%] lower than the recommended dose from Cohort 1; administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 milligram per square meter per day (mg/m^2/day) intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, subjects were enrolled in Cohort 3B.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received lenvatinib 11 mg/m^2, capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21. 4 subjects from arm Cohort 3A lenvatinib 14 mg/m^2 actually received lenvatinib 11 mg/m^2.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Etoposide 100 mg/m^2/day, intravenous infusion, once daily on Days 1 to 3.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Ifosfamide 3000 mg/m^2/day, intravenous infusion, once daily on Days 1 to 3.

Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2

Arm description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, subjects were enrolled in Cohort 3B.

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received Lenvatinib 14 mg/m^2, capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Ifosfamide 3000 mg/m^2/day, intravenous infusion, once daily on Days 1 to 3.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Etoposide 100 mg/m^2/day, intravenous infusion, once daily on Days 1 to 3.

Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2

Arm description

Arm type

Experimental

Investigational medicinal product name

Lenvatinib

Investigational medicinal product code

Other name

E7080

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received Lenvatinib 14 mg/m^2, capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Ifosfamide 3000 mg/m^2/day, intravenous infusion, once daily on Days 1 to 3.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Etoposide 100 mg/m^2/day, intravenous infusion, once daily on Days 1 to 3.

Number of subjects in period 1	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Started	3	9	11	1	31	7	15	20
Underwent Run-in Period	1	1 ^[1]	0 ^[2]	0 ^[3]	0 ^[4]	0	0 ^[5]	0 ^[6]
Completed	1	3	4	1	2	0	5	4
Not completed	2	6	7	0	29	7	10	16
Consent withdrawn by subject	-	-	-	-	2	-	1	2
Death	2	6	7	-	27	7	9	14

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestone signifies subjects who were exclusively assigned to run-in period from respective arms.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestone signifies subjects who were exclusively assigned to run-in period from respective arms.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestone signifies subjects who were exclusively assigned to run-in period from respective arms.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestone signifies subjects who were exclusively assigned to run-in period from respective arms.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestone signifies subjects who were exclusively assigned to run-in period from respective arms.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Milestone signifies subjects who were exclusively assigned to run-in period from respective arms.

Baseline characteristics

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Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2

Reporting group description

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2

Reporting group description

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2

Reporting group description

Reporting group title

Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2

Reporting group description

Reporting group title

Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2

Reporting group description

Reporting group title

Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2

Reporting group description

Reporting group title

Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2

Reporting group description

Reporting group title

Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2

Reporting group description

Reporting group values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2	Total
Number of subjects	3	9	11	1	31	7	15	20	97
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0
Children (2-11 years)	1	4	5	0	4	1	3	2	20
Adolescents (12-17 years)	2	5	6	1	20	4	9	13	60
Adults (18-64 years)	0	0	0	0	7	2	3	5	17
From 65-84 years	0	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	10.7 ± 7.09	11.4 ± 4.80	12.0 ± 3.35	17.0 ± 17.0	14.9 ± 3.27	15.1 ± 3.63	14.2 ± 4.74	15.8 ± 4.05	-
Gender categorical
Units: Subjects
Female	1	5	5	0	18	2	5	7	43
Male	2	4	6	1	13	5	10	13	54
Ethnicity
Units: Subjects
Hispanic or Latino	1	1	2	0	4	1	4	3	16
Not Hispanic or Latino	1	4	4	0	15	5	8	10	47
Unknown or Not Reported	1	4	5	1	12	1	3	7	34
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0	0	0
White	2	5	3	1	20	6	14	13	64
More than one race	0	0	1	0	2	0	0	3	6
Unknown or Not Reported	1	4	7	0	9	1	1	4	27

End points

Top of page

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2

Reporting group description

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2

Reporting group description

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2

Reporting group description

Reporting group title

Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2

Reporting group description

Reporting group title

Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2

Reporting group description

Reporting group title

Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2

Reporting group description

Reporting group title

Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2

Reporting group description

Reporting group title

Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2

Reporting group description

Subject analysis set title

Cohort 1: All Subjects

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects (of age group 2 to <6 years [following the completion of run-in period] and 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 11 mg/m^2, 14 mg/m^2 or 17 mg/m^2 (administered per BSA) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever occurred first. Duration of each cycle in Cohort 1=28 days.

Subject analysis set title

Cohort 3A: All Subjects

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20% lower than the recommended dose from Cohort 1) or 14 mg/m^2, administered per BSA with daily dose capped at 24 mg/day as capsule or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as lenvatinib suspension), orally, once daily on Days 1 to 21 of each treatment cycle, in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as combination therapy. Duration of each cycle=21 days.

Subject analysis set title

Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects (of age group 2 to <6 years and 6 to <18 years)with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2(administered per body surface area[BSA])as capsules or suspension(lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension),orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by subject at any time, or study termination by sponsor, whichever occurred first. Eligible subject of age group 2 to <6 years first underwent 21-day run-in period with 5 mg/m^2 lenvatinib before receiving lenvatinib 11 mg/m^2 in Cycle 1 in Cohort 1. Duration of each cycle in Cohort 1=28 days. After determining RD in Cohort 1, subjects were enrolled in Cohorts 2A,2B and 3A.

Subject analysis set title

Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects (of age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (administered per BSA) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by subject at any time, or study termination by sponsor, whichever occurred first. Eligible subjects of age group 2 to <6 years first underwent 21-day run-in period with 5 mg/m^2 lenvatinib before receiving lenvatinib 14 mg/m^2 in Cycle 1 in Cohort 1. Duration of each treatment cycle in Cohort 1=28 days. After determining RD in Cohort 1, subjects were enrolled in Cohorts 2A, 2B and 3A.

Subject analysis set title

Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: Cohort 1: Recommended Dose (RD) of Lenvatinib

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End point title

Cohort 1: Recommended Dose (RD) of Lenvatinib ^[1]

End point description

RD:dose that had dose limiting toxicity(DLT)rate closest to 20% rate.DLT:adverse drug reaction and assessed according to common terminology criteria for adverse events(CTCAE)version (v) 4.03 defined as 1) Grade4 neutropenia for greater than or equal to(>=)7 days,2) Grade>=3 thrombocytopenia with bleeding,or lasting greater than(>)7 days,3)Grade>=3 febrile neutropenia,4) Next course chemotherapy delayed>=7 days,5) Grade>=3 nonhematologic toxicity persisting >7 days optimal supportive care,6) Grade 4 hypertension,confirmed systolic/diastolic blood pressure>25 millimeters of mercury(mmHg)above 95th percentile for age, or elevated diastolic blood pressure(>95th percentile for age)not controlled by single antihypertensive medication within 14 days use,7) Grade3 proteinuria,8) Any recurrent Grade2 nonhematological toxicity requiring>=2 interruption and dose reductions.Safety analysis set included all subjects who received any study drug and had at least one post-baseline safety evaluation.

End point type

Primary

End point timeframe

Cycle 1 (28 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.

End point values	Cohort 1: All Subjects
Number of subjects analysed	23
Units: milligram per meter square (mg/m^2)
number (not applicable)	14

No statistical analyses for this end point

Primary: Cohort 2A: Number of Subjects With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)

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End point title

Cohort 2A: Number of Subjects With Objective Response (OR) of Complete Response (CR) or Partial Response (PR) ^[2] ^[3]

End point description

OR was defined as subjects with best overall response (BOR) of CR or PR as assessed by investigator based on response evaluation criteria in solid tumors (RECIST) version (v) 1.1. For OR, the BOR was defined as the best response (CR or PR for >4 weeks) recorded from start of treatment until PD or death whichever occurred first. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 millimeters (mm). PR: at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Full analysis set included all enrolled subjects who have not failed study screening.

End point type

Primary

End point timeframe

From date of first dose of study drug until first documentation of disease progression, or date of death, whichever occurred first (up to approximately 4 years 7 months)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this endpoint.

End point values	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2
Number of subjects analysed	1
Units: subjects	1

No statistical analyses for this end point

Primary: Cohort 2A: Number of Subjects With Best Overall Response (BOR)

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End point title

Cohort 2A: Number of Subjects With Best Overall Response (BOR) ^[4] ^[5]

End point description

BOR was defined as the best response of CR or PR for >4 weeks or SD for >=7 weeks recorded from the start of the treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Full analysis set included all enrolled subjects who have not failed study screening.

End point type

Primary

End point timeframe

From first dose of study drug until disease progression or recurrence of lesions (up to approximately 4 years 7 months)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this endpoint.

End point values	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2
Number of subjects analysed	1
Units: subjects
Complete Response	0
Partial Response	1
Stable Disease	0

No statistical analyses for this end point

Primary: Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4

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End point title

Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4 ^[6] ^[7]

End point description

Progression free survival at Month 4 (PFS-4) rate was defined as the percentage of subjects who were alive and without PD at Month 4 after the first dose of study drug, based on RECIST v1.1, using a binomial proportion with corresponding 95% confidence interval (CI). PD: >= 20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD. Progression free survival at Month 4(PFS-4) evaluable set included all subjects treated with study drug for at least 4 months or those who died or radiologically progressed within 4 months after first dose or received anticancer treatment within 4 months after first dose.

End point type

Primary

End point timeframe

Month 4

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this endpoint.

End point values	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	28	15
Units: percentage of subjects
number (confidence interval 95%)	32.1 (15.9 to 52.4)	66.7 (38.4 to 88.2)

No statistical analyses for this end point

Primary: Cohort 3A: Recommended Dose of Lenvatinib When Given in Combination With Etoposide and Ifosfamide

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End point title

Cohort 3A: Recommended Dose of Lenvatinib When Given in Combination With Etoposide and Ifosfamide ^[8]

End point description

RD:dose that had dose limiting toxicity(DLT)rate closest to 20% rate.DLT:adverse drug reaction and assessed according to common terminology criteria for adverse events(CTCAE)version (v) 4.03 defined as 1) Grade4 neutropenia for more than or equal to(>=)7 days,2) Grade>=3 thrombocytopenia with bleeding,or lasting greater than(>)7 days,3)Grade>=3 febrile neutropenia,4) Next course chemotherapy delayed>=7 days,5) Grade>=3 nonhematologic toxicity persisting >7 days optimal supportive care,6) Grade 4 hypertension,confirmed systolic/diastolic blood pressure>25 millimeters of mercury(mmHg)above 95th percentile for age, or elevated diastolic blood pressure(>95th percentile for age)not controlled by single antihypertensive medication within 14 days use,7) Grade3 proteinuria,8)Any recurrent Grade2 nonhematological toxicity requiring>=2 interruption and dose reductions.Safety analysis set included all subjects who received any study drug and had at least one post-baseline safety evaluation.

End point type

Primary

End point timeframe

Cycle 1 (21 days)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.

End point values	Cohort 3A: All Subjects
Number of subjects analysed	22
Units: milligram per meter square (mg/m^2)
number (not applicable)	14

No statistical analyses for this end point

Secondary: Cohorts 1, 2B, 3A, and 3B: Number of Subjects With Best Overall Response (BOR)

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End point title

Cohorts 1, 2B, 3A, and 3B: Number of Subjects With Best Overall Response (BOR) ^[9]

End point description

BOR: best response of CR or PR for >4 weeks or SD for >=7 weeks from first dose, recorded from start of treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: disappearance of all target and non-target lesions. All pathological lymph nodes must have reduction in their short axis <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Not evaluable means BOR of NE or SD of <7 weeks duration. Full analysis set:all enrolled subjects who have not failed study screening. Number of subjects analysed"=subjects evaluable for endpoint.

End point type

Secondary

End point timeframe

From the date of first dose of study drug until disease progression or recurrence (up to approximately 4 years 7 months)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this endpoint.

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	9	10	30	7	14	18
Units: subjects
Complete Response	0	0	0	0	0	0	0
Partial Response	0	0	0	2	2	0	3
Stable Disease	2	5	4	13	3	10	9
Progressive Disease	1	2	4	12	2	2	4
Not Evaluable	0	2	2	3	0	2	2

No statistical analyses for this end point

Secondary: Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR)

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End point title

Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR) ^[10]

End point description

ORR was defined as the percentage of subjects with a BOR of CR or PR for >4 weeks or SD for >=7 weeks as assessed by investigator based on RECIST v1.1, recorded from start of study treatment until PD or death whichever occurred first. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. 95% CI of the ORR were calculated according to Clopper and Pearson method. Full analysis set included all enrolled subjects who have not failed study screening. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

From the date of first dose of study drug to the date of first documentation of disease progression, or date of death, whichever occurred first (up to approximately 4 years 7 months)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this endpoint.

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	9	10	30	7	14	18
Units: percentage of subjects
number (confidence interval 95%)	0 (0.0 to 70.8)	0 (0.0 to 33.6)	0 (0.0 to 30.8)	6.7 (0.8 to 22.1)	28.6 (3.7 to 71.0)	0 (0.0 to 23.2)	16.7 (3.6 to 41.4)

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)

End point description

DOR was defined as time in months from the first documentation confirmed CR or PR until the first documentation of confirmed PD as assessed by investigator based on RECIST v1.1. CR: disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. 95% CI for the median were calculated according to Brookmeyer and Crowley method. Full analysis set. Number of subjects analysed=subjects evaluable for endpoint. Here, 99999 and -99999 indicates data could not be estimated as insufficient subjects were available for analysis.

End point type

Secondary

End point timeframe

From the date of first dose of study drug to first documentation of CR or PR until first documentation of PD (up to approximately 4 years 7 months)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	0 ^[11]	0 ^[12]	0 ^[13]	1	2	2	0 ^[14]	3
Units: months
median (confidence interval 95%)	( to )	( to )	( to )	1.9 (-99999 to 99999)	4.6 (-99999 to 99999)	99999 (-99999 to 99999)	( to )	99999 (-99999 to 99999)

Notes
[11] - No subject was analysed for this group.
[12] - No subject was analysed for this group.
[13] - No subject was analysed for this group.
[14] - No subject was analysed for this group.

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Who Experienced Disease Control

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Who Experienced Disease Control

End point description

Subjects were defined as having disease control if they had a BOR of CR or PR for >4 weeks, or SD (minimum duration from first dose to SD >=7 weeks) or if subjects had a BOR of CR or Non-CR/Non-PD (minimum duration from first dose to Non-CR/Non-PD >=7 weeks) per RECIST v1.1, recorded from first dose until PD or death whichever occurred first. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (target/non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest SOD. Non-CR/Non-PD: persistence of 1 or more non-target lesions, maintenance of tumor marker level above the normal limits. Full analysis set: all enrolled subjects who have not failed study screening.

End point type

Secondary

End point timeframe

From the date of first dose of study drug until the date of first documented PD, or date of death, whichever occurred first (up to approximately 4 years and 7 months)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	9	11	1	31	7	15	20
Units: subjects	2	5	5	1	16	5	11	14

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Experienced Clinical Benefit

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Experienced Clinical Benefit

End point description

Subjects were defined as having clinical benefit if they had BOR of CR or PR or durable SD (lasting >=23 weeks) or subjects with evaluable disease who have BOR of CR or durable Non-CR/Non-PD (lasting >=23 weeks) as per RECIST v1.1. BOR: CR or PR for >4 weeks or SD for >5 weeks from first dose,until PD or recurrence based on RECIST v1.1 for target/non-target lesions. CR: disappearance of all target/non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target/non-target) must have reduction in short axis <10 mm. PR: at least 30% decrease in SOD of target lesions, taking reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor increase to qualify for PD,taking reference smallest SOD.Non-CR/Non-PD:persistence of 1 or more non-target lesions and maintenance of tumor marker level above normal limits.Full analysis set included all enrolled subjects who have not failed study screening.

End point type

Secondary

End point timeframe

From the date of first dose of study drug until date of first documentation of disease progression, or date of death, whichever occurred first (up to approximately 4 years 7 months)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	9	11	1	31	7	15	20
Units: subjects	0	3	4	1	7	4	5	8

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS)

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS)

End point description

PFS was defined as the time (in months) from the date of first dose of study drug to the date of first documentation of disease progression or date of death, whichever occurred first, based on RECIST v1.1. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley. Full analysis set included all enrolled subjects who have not failed study screening. Here, 99999 and -99999 indicates data could not be estimated as insufficient subjects were available for analysis.

End point type

Secondary

End point timeframe

From the date of first dose of study drug until date of first documentation of disease progression or date of death, whichever occurred first (up to approximately 4 years 7 months)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	9	11	1	31	7	15	20
Units: months
median (confidence interval 95%)	3.7 (0.5 to 5.0)	6.3 (0.6 to 10.6)	5.5 (1.4 to 11.3)	5.5 (-99999 to 99999)	3.0 (1.8 to 5.4)	7.1 (2.1 to 99999)	12.0 (11.1 to 16.1)	6.9 (4.2 to 99999)

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP)

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP)

End point description

TTP was defined as the time from the date of first dose of study drug to the date of first documentation of disease progression based on RECIST 1.1. Disease progression was defined as at least a 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the baseline sum of diameters of target lesions. 95% CI of median were calculated according to Brookmeyer and Crowley method. Full analysis set included all enrolled subjects who have not failed study screening. Here, 99999 and -99999 indicates data could not be estimated as insufficient subjects were available for analysis.

End point type

Secondary

End point timeframe

From the date of first dose of study drug until the date of first documentation of disease progression (up to approximately 4 years 7 months)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	9	11	1	31	7	15	20
Units: months
median (confidence interval 95%)	3.7 (0.5 to 5.0)	6.3 (0.6 to 10.6)	5.5 (1.4 to 11.3)	5.5 (-99999 to 99999)	3.0 (1.8 to 5.4)	7.1 (2.1 to 99999)	12.0 (11.1 to 16.1)	6.9 (4.2 to 99999)

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS)

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS)

End point description

OS was defined as the time from the date of the first dose of study drug until the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cutoff were censored at the date the subject was last known to be alive (or the data cutoff date). 95% CI of median were calculated according to Brookmeyer and Crowley method. Full analysis set included all enrolled subjects who have not failed study screening. Here, 99999 indicates data could not be estimated due to low number of subjects with events.

End point type

Secondary

End point timeframe

From date of the first dose of study drug until the date of death (up to approximately 4 years 7 months)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,SingleagentExpansion, Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	9	11	1	31	7	15	20
Units: months
median (confidence interval 95%)	8.1 (3.8 to 99999)	7.4 (1.3 to 99999)	7.7 (2.7 to 99999)	99999 (99999 to 99999)	10.0 (5.6 to 12.3)	13.6 (2.4 to 28.0)	99999 (8.8 to 99999)	99999 (7.3 to 99999)

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

End point description

Number of subjects with TEAEs (serious and non-serious adverse events) and SAEs were reported based on their safety assessments of hematology, clinical chemistry, urine values, proximal tibial growth, fecal occult blood, physical examinations, regular measurement of vital signs and electrocardiogram parameter values. Safety analysis set included all subjects who received any study drug and had at least one post-baseline safety evaluation.

End point type

Secondary

End point timeframe

From the date of first dose of study drug up to 30 days after the last dose (up to approximately 7 years)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	5	11	7	1	31	11	11	20
Units: subjects
TEAEs	5	11	7	1	29	11	11	20
SAEs	3	7	5	1	21	7	9	16

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A, and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Measurements on Urine DipStick for Proteinuria

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End point title

Cohorts 1, 2A, 2B, 3A, and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Measurements on Urine DipStick for Proteinuria

End point description

An aliquot of the urine samples were collected to analyze protein by dipstick method, microscopic examination (if protein is abnormal). The dipstick test gives results in a semi-quantitative manner and results for urinalysis parameters of urine protein can be read as “negative, Trace, plus (+) 1, +2, +3 and +4” indicating proportional concentrations in the urine sample. The plus sign increases with a higher level of proteins in the urine. Safety analysis set included all subjects who received any study drug and had at least one post-baseline safety evaluation. Here "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to approximately 4 years 7 months

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	5	11	7	1	30	11	11	20
Units: subjects
Baseline: Trace, Worst Post baseline: Negative	2	2	0	0	0	0	0	0
Baseline: Trace, Worst Post baseline: Trace	1	0	0	0	1	0	1	1
Baseline: +1, Worst Post baseline: Negative	2	3	1	0	0	0	0	0
Baseline: +1, Worst Post baseline: +1	0	0	1	0	0	0	0	0
Baseline: Negative, Worst Post baseline: Negative	0	1	0	1	4	0	4	2
Baseline: +2, Worst Post baseline: Negative	0	2	1	0	1	0	0	0
Baseline: +3, Worst Post baseline: Negative	0	1	1	0	0	0	0	0
Baseline: +3, Worst Post baseline: +1	0	1	0	0	0	0	0	0
Baseline: +3, Worst Post baseline: +2	0	1	0	0	0	0	0	0
Baseline: +3, Worst Post baseline: Trace	0	0	1	0	0	0	0	0
Baseline: +4, Worst Post baseline: Trace	0	0	1	0	0	0	0	0
Baseline: +4, Worst Post baseline: +1	0	0	1	0	1	0	0	0
Baseline: Negative, Worst Post baseline: Trace	0	0	0	0	5	0	1	3
Baseline: Negative, Worst Post baseline: +1	0	0	0	0	7	7	1	1
Baseline: Negative, Worst Post baseline: +2	0	0	0	0	1	1	1	6
Baseline: Negative, Worst Post baseline: +3	0	0	0	0	1	1	2	2
Baseline: Trace, Worst Post baseline: +1	0	0	0	0	2	1	0	0
Baseline: Trace, Worst Post baseline: +2	0	0	0	0	1	0	0	1
Baseline: Trace, Worst Post baseline: +3	0	0	0	0	1	0	0	1
Baseline: +1, Worst Post baseline: Trace	0	0	0	0	1	0	0	0
Baseline: +1, Worst Post baseline: +2	0	0	0	0	3	0	0	1
Baseline: +1, Worst Post baseline: +3	0	0	0	0	1	1	0	0
Baseline: Negative, Worst Post baseline: +4	0	0	0	0	0	0	1	1
Baseline: +1, Worst Post baseline: +4	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Lansky Performance Play Score

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Lansky Performance Play Score

End point description

Lansky Performance Play Scale:rates a child’s activity level for <16 years of age.Scores on scale range from 0(unresponsive)to 100(fully active, normal),where 100=fully active,normal;90=minor restrictions in physically strenuous activity;80=active,but tires more quickly;70=both greater restriction of and less time spent in play activity;60=up and around, but minimal active play,keeps busy with quieter activities;50=gets dressed,but lies around much of day,no active play,able to subject in quiet play and activities;40=mostly in bed,participates in quiet activities;30=in bed,needs assistance even for quiet play;20=often sleeping,play entirely limited to very passive activities;10=no play,does not get out of bed;0=unresponsive.Higher score indicates more activity and lower indicates less or no activity.Safety analysis set:all subjects who received drug and had at least 1 postbaseline safety evaluation. Number of subjects analysed=subjects evaluable for endpoint.

End point type

Secondary

End point timeframe

Baseline up to approximately 4 years 7 months

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	3	7	7	1	15	6	7	9
Units: subjects
Baseline score:100%, Worst Postbaseline score:90%	3	0	0	0	1	1	1	0
Baseline score: 70%, Worst Postbaseline score: 60%	0	1	0	0	0	0	0	0
Baseline score: 80%, Worst Postbaseline score: 60%	0	1	1	0	1	1	0	0
Baseline score: 100%, Worst Postbaseline score:60%	0	1	0	0	0	0	0	0
Baseline score: 80%, Worst Postbaseline score: 70%	0	1	0	0	0	0	3	0
Baseline score: 90%, Worst Postbaseline score: 70%	0	1	0	0	1	0	0	0
Baseline score: 90%, Worst Postbaseline score: 80%	0	1	1	0	1	0	0	0
Baseline score:100%, Worst Postbaseline score:100%	0	1	0	1	0	0	0	5
Baseline score: 80%, Worst Postbaseline score: 40%	0	0	1	0	0	0	0	0
Baseline score: 70%, Worst Postbaseline score: 80%	0	0	1	0	0	0	1	0
Baseline score: 80%, Worst Postbaseline score: 80%	0	0	1	0	2	2	0	2
Baseline score: 100%, Worst Postbaseline score:80%	0	0	1	0	0	1	0	0
Baseline score: 90%, Worst Postbaseline score: 90%	0	0	1	0	4	0	1	2
Baseline score: 60%, Worst Postbaseline score: 60%	0	0	0	0	1	0	0	0
Baseline score: 90%, Worst Postbaseline score: 60%	0	0	0	0	1	0	0	0
Baseline score: 70%, Worst Postbaseline score: 70%	0	0	0	0	1	0	1	0
Baseline score: 90%, Worst Postbaseline score:100%	0	0	0	0	1	0	0	0
Baseline score: 100%, Worst Postbaseline score:70%	0	0	0	0	0	1	0	0
Baseline score: 80%, Worst Postbaseline score: 50%	0	0	0	0	1	0	0	0

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Karnofsky Performance Status (KPS) Scores

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Karnofsky Performance Status (KPS) Scores

End point description

KPS:compare effectiveness of medicine for disease and assess outcomes in subjects. KPS Scores:recorded on 11point scale(0,10, 20,30,40,50,60,70,80,90 and 100%),where 0=Dead;10=moribund,fatal processes progressing rapidly;20=very sick,hospital admission necessary,active supportive treatment necessary;30=severely disabled,hospital admission is indicated although death not imminent;40=disabled,requires special care/assistance;50=requires considerable assistance/frequent medical care;60=requires occasional assistance,but is able to care for personal needs;70=cares for self,unable to carry normal activity or active work;80=normal activity with effort,some signs of disease; 90=able to carry on normal activity,minor signs of disease;100=normal no complaints,no evidence of disease.Lower score,worse survival for most serious illnesses.Safety Analysis Set:all subjects who received drug,had at least 1 postbaseline safety evaluation.Number of subjects analysed=subjects evaluable for endpoint.

End point type

Secondary

End point timeframe

Baseline up to approximately 4 years 7 months

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	1	1	0 ^[15]	1	12	3	1	9
Units: subjects
Baseline score: 100%, Worst Postbaseline score:80%	1	0		0	2	0	0	2
Baseline score: 100%, Worst Postbaseline score:90%	0	1		0	2	1	0	2
Baseline score: 70%, Worst Postbaseline score: 70%	0	0		0	1	0	1	0
Baseline score: 90%, Worst Postbaseline score: 70%	0	0		0	1	0	0	0
Baseline score: 80%, Worst Postbaseline score: 80%	0	0		0	1	0	0	0
Baseline score: 90%, Worst Postbaseline score: 60%	0	0		0	0	1	0	0
Baseline score:100%, Worst Postbaseline score:100%	0	0		1	1	1	0	1
Baseline score: 100%, Worst Postbaseline score:70%	0	0		0	0	0	0	2
Baseline score: 90%, Worst Postbaseline score: 80%	0	0		0	1	0	0	1
Baseline score: 90%, Worst Postbaseline score: 90%	0	0		0	3	0	0	1

Notes
[15] - Here "number of subjects analysed" signifies subjects who were analysed for this endpoint.

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Most Frequent Treatment-emergent Adverse Events Related to Lenvatinib Exposure

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Most Frequent Treatment-emergent Adverse Events Related to Lenvatinib Exposure

End point description

Safety analysis set included all subjects who received any study drug and had at least one post-baseline safety evaluation.

End point type

Secondary

End point timeframe

From the date of first dose of study drug up to 30 days after the last dose of study drug (up to approximately 4 years 7 months)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	5	11	7	1	31	11	11	20
Units: subjects
Hypothyroidism	3	6	3	0	13	5	6	6
Abdominal pain	2	2	1	1	5	6	5	6
Diarrhea	3	5	3	1	8	5	5	12
Nausea	1	2	3	0	8	7	8	13
Vomiting	1	6	3	0	7	5	6	12
Asthenia	2	1	0	0	8	0	0	7
Fatigue	0	2	3	0	8	2	4	3
Alanine aminotransferase increased increased	0	2	1	0	1	3	1	4
Blood thyroid stimulating hormone increased	3	0	0	0	9	3	0	5
Weight decreased	3	4	1	0	6	5	3	4
Decreased appetite	0	5	1	0	13	4	2	5
Arthralgia	1	2	1	0	1	2	4	1
Myalgia	0	2	0	0	1	0	0	0
Pain in extremity	0	2	1	0	0	3	1	0
Headache	0	1	1	0	5	2	4	4
Proteinuria	0	3	3	0	7	2	5	8
Dysphonia	1	0	0	0	5	0	0	0
Erythema	1	1	1	0	0	0	0	0
Hair color changes	2	1	1	0	2	0	0	0
Palmar-plantar erythrodysaesthesia	0	2	0	0	1	1	2	0
Hypertension	0	3	4	1	10	1	4	3
Haematuria	0	0	0	0	0	4	1	4
Hypokalaemia	0	0	0	0	0	4	1	2
Hypophosphataemia	0	0	0	0	0	3	2	2
Platelet count decreased	0	0	0	0	0	2	3	11
Back pain	0	0	0	0	0	2	2	2
Dry skin	0	0	0	0	0	2	2	0
Oral pain	0	0	0	0	0	2	2	1
Pneumothorax	0	0	0	0	0	2	2	1
Dehydration	0	0	0	0	0	2	1	4
Hypoalbuminaemia	0	0	0	0	0	2	1	0
Lethargy	0	0	0	0	0	2	1	2
Leukopenia	0	0	0	0	0	1	2	3
Neutrophil count decreased	0	0	0	0	0	2	1	9
Oral dysaesthesia	0	0	0	0	0	2	1	0
Oropharyngeal pain	0	0	0	0	0	1	2	1
Proctalgia	0	0	0	0	0	2	1	0
Toxic encephalopathy	0	0	0	0	0	1	2	0
Lymphocyte count decreased	0	0	0	0	0	2	0	4
Abdominal pain upper	0	0	0	0	0	1	0	4
Hyperuricemia	0	0	0	1	0	0	0	0
Insomnia	0	0	0	1	0	0	0	0
Anaemia	0	0	0	0	0	9	7	15
Neutropenia	0	0	0	0	0	6	6	8
Epistaxis	0	0	0	0	0	5	4	4
Thrombocytopenia	0	0	0	0	0	5	4	5
Febrile neutropenia	0	0	0	0	0	5	3	2
Stomatitis	0	0	0	0	0	4	4	4
Constipation	0	0	0	0	0	5	2	2
White blood cell count decreased	0	0	0	0	0	4	3	12
Lymphopenia	0	0	0	0	0	2	0	0
Haematochezia	0	0	0	0	0	0	2	0
Pyrexia	0	0	0	0	0	2	0	0
Wound dehiscence	0	0	0	0	0	0	2	0
Hypocalcaemia	0	0	0	0	0	2	0	0
Dizziness	0	0	0	0	0	0	2	0
Dyspnoea	0	0	0	0	0	2	0	0
Hyperhidrosis	0	0	0	0	0	0	2	0

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib

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End point title

Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib

End point description

Duration of each cycle for Cohorts 1, 2A, 2B is 28 days. Duration of each cycle for Cohorts 3A, 3B is 21 days. Pharmacokinetic (PK) Analysis Set included all subjects who had received any study drug and had evaluable PK data. Here “subjects analysed” signifies subjects who were evaluable for this endpoint at given time points. Here, 99999 indicates standard deviation could not be calculated because only one subject was available for analysis.

End point type

Secondary

End point timeframe

Cohorts 1, 2A, 2B: Cycle(C)1 Day(D)1: 0.5-4 hours (h), 6-10 h post-dose, C1D15: pre-dose, 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose; Cohorts 3A, 3B: C1D1: 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	5	11	7	1	31	11	11	20
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1: 0.5-4 hours(n=5,11,7,1,29,11,11,20)	295.6 ± 214.01	134.8 ± 145.83	52.5 ± 81.40	11.1 ± 99999	177.4 ± 191.03	105.2 ± 131.54	111.4 ± 131.47	209.7 ± 197.66
Cycle 1 Day 1: 6-10 hours(n=5,11,7,1,30,11,11,20)	212.7 ± 185.98	281.9 ± 137.39	238.0 ± 135.87	188 ± 99999	289.4 ± 200.09	191.9 ± 100.69	148.5 ± 122.41	164.8 ± 73.59
Cycle 1 Day 15: Pre-dose(n=4,9,6,1,29,0,0,0)	46.9 ± 11.01	59.1 ± 29.19	96.9 ± 66.10	56.2 ± 99999	67.0 ± 53.78	0 ± 0	0 ± 0	0 ± 0
Cycle 1 Day 15: 0.5-4 hours(n=4,8,6,1,28,0,0,0)	133.4 ± 163.37	226.6 ± 204.61	191.8 ± 190.22	124 ± 99999	168.3 ± 157.67	0 ± 0	0 ± 0	0 ± 0
Cycle 1 Day 15: 6-10 hours(n=4,8,6,1,29,0,0,0)	351.8 ± 157.15	375.8 ± 121.21	413.0 ± 221.47	247 ± 99999	322.9 ± 138.87	0 ± 0	0 ± 0	0 ± 0
Cycle 2 Day 1: Pre-dose(n=5,8,7,1,27,11,8,17)	58.1 ± 19.58	61.6 ± 60.61	97.9 ± 77.08	59.8 ± 99999	66.8 ± 62.50	51.7 ± 44.23	76.1 ± 63.25	50.4 ± 65.10
Cycle 2 Day 1: 2-12 hours(n=5,7,7,1,28,11,9,18)	502.4 ± 360.71	440.7 ± 229.29	339.2 ± 212.44	102 ± 99999	382.4 ± 217.49	205.6 ± 134.66	237.4 ± 124.82	275.3 ± 135.73

No statistical analyses for this end point

Secondary: Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level

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End point title

Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level

End point description

Serum biomarkers included Fibroblast Growth Factor (FGF) 19, FGF 21, Vascular Endothelial Growth Factor (VEGF). In this outcome measure, percent change from baseline in serum biomarkers level per "PFS-4, Yes" and "PFS-4, No" have been reported. As per assessment of investigator based on RECIST v1.1, "PFS-4, Yes"= subjects evaluable for PFS-4 month and alive and without PD at 4 months from the first dose, "PFS-4, No"=subjects evaluable for PFS-4 month and not alive or with PD at 4 months from the first dose. PFS-4 evaluable set: all subjects treated with study drug for at least 4 months or those who died or radiologically progressed within 4 months after first dose or received anticancer treatment within 4 months after first dose. Here “number of subjects analysed” signifies subjects who were evaluable for this endpoint. "n" signifies subjects who were evaluable for this endpoint for specified categories.

End point type

Secondary

End point timeframe

Cohort 2B: Baseline, Cycle 2-3 Day 1 (Duration of each cycle=28 days); Cohort 3B: Baseline, Cycle 2 Day 1, Cycle 4 Day 1

End point values	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	18	9
Units: percent change
arithmetic mean (standard deviation)
C2D1: FGF 19 (PFS-4, Yes) (n=8, 9)	48.7 ± 110.78	172.1 ± 211.86
C2D1: FGF 19 (PFS-4, No) (n=18, 4)	109.9 ± 139.19	78.3 ± 203.30
C3D1: FGF 19 (PFS-4, Yes) (n=9, 0)	47.3 ± 130.42	0 ± 0
C3D1: FGF 19 (PFS-4, No) (n=8, 0)	194.5 ± 180.71	0 ± 0
C4D1: FGF 19 (PFS-4, Yes) (n=0, 9)	0 ± 0	237.7 ± 204.94
C4D1: FGF 19 (PFS-4, No) (n=0, 1)	0 ± 0	91.9 ± 99999
C2D1: FGF 21 (PFS-4, Yes) (n=8, 9)	-14.9 ± 68.95	70.2 ± 138.90
C2D1: FGF 21 (PFS-4, No) (n=18, 4)	134.3 ± 203.81	7.2 ± 48.64
C3D1: FGF 21 (PFS-4, Yes) (n=9, 0)	55.0 ± 125.51	0 ± 0
C3D1: FGF 21 (PFS-4, No) (n=8, 0)	17.0 ± 88.92	0 ± 0
C4D1: FGF 21 (PFS-4, Yes) (n=0, 9)	0 ± 0	256.2 ± 323.34
C4D1: FGF 21 (PFS-4, No) (n=0, 1)	0 ± 0	-1.5 ± 99999
C2D1: VEGF (PFS-4, Yes) (n=7, 9)	119.9 ± 309.01	87.9 ± 105.60
C2D1: VEGF (PFS-4, No) (n=18, 4)	124.2 ± 212.18	95.8 ± 92.53
C3D1: VEGF (PFS-4, Yes) (n=8, 0)	64.3 ± 153.50	0 ± 0
C3D1: VEGF (PFS-4, No) (n=8, 0)	23.2 ± 69.67	0 ± 0
C4D1: VEGF (PFS-4, Yes) (n=0, 9)	0 ± 0	84.3 ± 97.85
C4D1: VEGF (PFS-4, No) (n=0, 0)	0 ± 0	0 ± 0

No statistical analyses for this end point

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Overall Palatability and Acceptability Questionnaire Score for Suspension of Lenvatinib

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End point title

Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Overall Palatability and Acceptability Questionnaire Score for Suspension of Lenvatinib

End point description

The palatability and acceptability was assessed using a questionnaire for suspension of lenvatinib questionnaire based on following domains: taste, appearance, smell, how does it feel in the mouth and overall acceptability. Overall palatability and acceptability was assessed on a 7-point Hedonic scale which is a Visual Analog Scale (VAS) graded as follows: 1=super bad, 2=really bad, 3=bad, 4=may be good or may be bad, 5=good, 6=really good, 7=super good. In this measure, number of subjects per grading for overall palatability and acceptability has been reported. Palatability analysis set included all subjects who received oral suspension of lenvatinib and answered at least 1 question in the palatability questionnaire case report form.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Cycle length=28 days for Cohorts 1, 2A, 2B; Cycle length=21 days for Cohorts 3A, 3B)

End point values	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2
Number of subjects analysed	0 ^[16]	2	1	0 ^[17]	1	0 ^[18]	1	4
Units: subjects
Good		1	0		1		1	1
May be Good or May be Bad		0	0		0		0	1
Bad		0	0		0		0	1
Really Bad		1	0		0		0	1
Super Bad		0	1		0		0	0

Notes
[16] - Here "subject analysed" signifies subjects who were evaluable for this endpoint.
[17] - Here "subject analysed" signifies subjects who were evaluable for this endpoint.
[18] - Here "subject analysed" signifies subjects who were evaluable for this endpoint.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the date of first dose of study drug up to 30 days after the last dose (up to approximately 7 years)

Adverse event reporting additional description

Safety analysis set included all subjects who received any study drug and had at least one post-baseline safety evaluation.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2

Reporting group description

Subjects (of age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 11 mg/m^2 (administered perbody surface area[BSA]) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallowcapsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity,subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by subject at any time, or studytermination by the sponsor, whichever occurred first. Eligible subjects of age group 2 to <6 years first underwent a 21-day run-in period with 5 mg/m^2lenvatinib before receiving lenvatinib 11 mg/m^2 in Cycle 1 in Cohort 1. Duration of each treatment cycle in Cohort1=28 days. After determining RD in Cohort1, subjects were enrolled in Cohorts 2A,2B and 3A.

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2

Reporting group description

Subjects (of age group 2 to <6 years and 6 to <18 years) with relapsed or refractory solid malignant tumors received lenvatinib 14 mg/m^2 (administered perBSA) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given assuspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliancewith safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by subject at any time, or study termination by thesponsor, whichever occurred first. Eligible subjects of age group 2 to <6 years first underwent a 21-day run-in period with 5 mg/m^2 lenvatinib beforereceiving lenvatinib 14 mg/m^2 in Cycle 1 in Cohort 1. Duration of each cycle in Cohort 1=28 days. After determining RD in Cohort 1, subjects were enrolled in Cohorts 2A, 2B and 3A.

Reporting group title

Lenvatinib 5 mg /m^2

Reporting group description

Eligible subjects of age group 2 to <6 years first underwent a 21-day run-in period with 5 mg/m^2 lenvatinib before receiving lenvatinib 11 mg/m^2 or 14 mg/m^2 in Cohort 1 (Single-agent Dose-finding) Cycle 1.

Reporting group title

Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2

Reporting group description

Subjects (of age group 6 to <18 years) with relapsed or refractory solid malignant tumors received dose of lenvatinib 17 mg/m^2 (administered per BSA) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension),orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety orefficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever occurred first. Duration of each cycle in Cohort 1=28 days. After determining the RD in Cohort 1, subjects were enrolled in Cohorts 2A, 2B and 3A.

Reporting group title

Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2

Reporting group description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24 mg/day) as capsule orsuspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally, oncedaily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity, subject noncompliance with safety or efficacyassessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whicheveroccurred first. Duration of each treatment cycle in Cohort 2B=28 days.

Reporting group title

Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2

Reporting group description

Subjects with 131 iodine-refractory differentiated thyroid cancer (DTC) received lenvatinib 14 mg/m^2 (administered per BSA with daily dose capped at 24milligram per day [mg/day]) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallowcapsules and given as suspension), orally, once daily on Days 1 to 28 of each treatment cycle as a single agent until disease progression, intolerable toxicity,subject noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, orstudy termination by the sponsor, whichever occurred first. Duration of each cycle=28 days.

Reporting group title

Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2

Reporting group description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsulesor suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally,once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/dayintravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3B=21 days.

Reporting group title

Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2

Reporting group description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 14 mg/m^2 (administrated per BSA with daily dose capped at 24 mg/day) as capsulesor suspension (lenvatinib capsules were dissolved in water or apple juice for subjects who were unable to swallow capsules and given as suspension), orally,once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000 mg/m^2/day intravenously and etoposide 100 mg/m^2/dayintravenously on Days 1 to 3 of each treatment cycle for up to a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, subjects were enrolled in Cohort 3B.

Reporting group title

Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2

Reporting group description

Subjects with relapsed or refractory osteosarcoma received lenvatinib 11 mg/m^2 (20 percent [%] lower than the recommended dose from Cohort 1;administered per BSA with daily dose capped at 24 mg/day) as capsules or suspension (lenvatinib capsules were dissolved in water or apple juice for subjectswho were unable to swallow capsules and given as suspension), orally, once daily on Days 1 to 21 of each treatment cycle in combination with ifosfamide 3000milligram per square meter per day (mg/m^2/day) intravenously and etoposide 100 mg/m^2/day intravenously on Days 1 to 3 of each treatment cycle for upto a total of 5 cycles as a combination therapy. Duration of each treatment cycle in Cohort 3A=21 days. After determining the RD in Cohort 3A, subjects were enrolled in Cohort 3B.

Serious adverse events	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Lenvatinib 5 mg /m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 5 (60.00%)	7 / 11 (63.64%)	0 / 2 (0.00%)	5 / 7 (71.43%)	21 / 31 (67.74%)	1 / 1 (100.00%)	16 / 20 (80.00%)	9 / 11 (81.82%)	7 / 11 (63.64%)
number of deaths (all causes)	1	3	0	1	4	0	2	0	2
number of deaths resulting from adverse events	1	3	0	1	4	0	2	0	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 5 (0.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	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	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arterial thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Venoocclusive disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	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	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Pneumothorax
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	4 / 31 (12.90%)	0 / 1 (0.00%)	3 / 20 (15.00%)	2 / 11 (18.18%)	2 / 11 (18.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	4 / 7	0 / 0	4 / 4	2 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0
Investigations
Amylase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Blood pressure increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	4 / 20 (20.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	4 / 5	0 / 0	12 / 12	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	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	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	4 / 20 (20.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	18 / 18	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	5 / 20 (25.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	16 / 16	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Post procedural haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Allergic transfusion reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Nervous system disorders
Depressed level of consciousness
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Brain injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Toxic encephalopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysmetria
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Blood and lymphatic system disorders
Disseminated intravascular coagulation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	5 / 5	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	3 / 11 (27.27%)	5 / 11 (45.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	5 / 5	4 / 4	8 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	4 / 4	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gingival bleeding
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Renal and urinary disorders
Renal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	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	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	4 / 31 (12.90%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	1 / 4	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	2 / 7 (28.57%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	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	0 / 0	0 / 0
Intervertebral disc compression
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection bacterial
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vulvitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Transfusion related complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1, Single-agent Dose-finding: Lenvatinib 11 mg/m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 14 mg/m^2	Lenvatinib 5 mg /m^2	Cohort 1, Single-agent Dose-finding: Lenvatinib 17 mg/m^2	Cohort2B,Single-agentExpansion,Osteosarcoma:Lenvatinib14mg/m^2	Cohort 2A, Single-agent Expansion, DTC: Lenvatinib 14 mg/m^2	Cohort 3B, Combination Expansion: Lenvatinib 14 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 14 mg/m^2	Cohort 3A, Combination Dose-finding: Lenvatinib 11 mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	11 / 11 (100.00%)	2 / 2 (100.00%)	7 / 7 (100.00%)	29 / 31 (93.55%)	1 / 1 (100.00%)	20 / 20 (100.00%)	11 / 11 (100.00%)	11 / 11 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	2 / 5 (40.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	2	2	0	0	5	0	1	0	1
Malignant pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Pericardial effusion malignant
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Tumour pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	3 / 31 (9.68%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	4	0	0	0	0
Myelodysplastic syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Flushing
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Haematoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0
Hot flush
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	3	0	0
Hypertension
subjects affected / exposed	2 / 5 (40.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	4 / 7 (57.14%)	10 / 31 (32.26%)	1 / 1 (100.00%)	5 / 20 (25.00%)	5 / 11 (45.45%)	3 / 11 (27.27%)
occurrences all number	2	3	0	12	13	2	6	10	4
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Lymphoedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Superior vena cava syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 5 (40.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	10 / 31 (32.26%)	0 / 1 (0.00%)	8 / 20 (40.00%)	2 / 11 (18.18%)	1 / 11 (9.09%)
occurrences all number	4	1	0	0	13	0	28	3	9
Axillary pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Catheter site bruise
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Catheter site dermatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Catheter site pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	1	2	0
Catheter site swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Chills
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Device related thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Face oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Fatigue
subjects affected / exposed	2 / 5 (40.00%)	3 / 11 (27.27%)	1 / 2 (50.00%)	3 / 7 (42.86%)	9 / 31 (29.03%)	0 / 1 (0.00%)	4 / 20 (20.00%)	6 / 11 (54.55%)	4 / 11 (36.36%)
occurrences all number	4	4	1	7	15	0	4	9	8
Inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Influenza like illness
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Infusion site irritation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Localised oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Malaise
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0
Non-cardiac chest pain
subjects affected / exposed	2 / 5 (40.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	3 / 11 (27.27%)	1 / 11 (9.09%)
occurrences all number	6	0	0	0	1	0	3	4	1
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	3 / 31 (9.68%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	3	0	0	0	0
Pain
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	4 / 31 (12.90%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	5	0	1	4	0	1	0	1
Pyrexia
subjects affected / exposed	2 / 5 (40.00%)	4 / 11 (36.36%)	1 / 2 (50.00%)	4 / 7 (57.14%)	11 / 31 (35.48%)	1 / 1 (100.00%)	6 / 20 (30.00%)	3 / 11 (27.27%)	6 / 11 (54.55%)
occurrences all number	8	9	1	10	17	1	9	5	6
Swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Injection site mass
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Sensation of foreign body
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Genital pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Menstruation irregular
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	2	0	0	2	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Vulvovaginal pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Amenorrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Genital lesion
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Perineal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Premature menopause
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 5 (40.00%)	3 / 11 (27.27%)	1 / 2 (50.00%)	2 / 7 (28.57%)	9 / 31 (29.03%)	0 / 1 (0.00%)	6 / 20 (30.00%)	4 / 11 (36.36%)	4 / 11 (36.36%)
occurrences all number	3	3	1	2	10	0	6	5	4
Dysaesthesia pharynx
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dysphonia
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	6 / 31 (19.35%)	0 / 1 (0.00%)	1 / 20 (5.00%)	2 / 11 (18.18%)	1 / 11 (9.09%)
occurrences all number	2	0	0	0	10	0	2	3	2
Dyspnoea
subjects affected / exposed	2 / 5 (40.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	6 / 31 (19.35%)	0 / 1 (0.00%)	2 / 20 (10.00%)	2 / 11 (18.18%)	3 / 11 (27.27%)
occurrences all number	3	0	0	2	8	0	3	3	3
Dyspnoea exertional
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Epistaxis
subjects affected / exposed	2 / 5 (40.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	2 / 7 (28.57%)	4 / 31 (12.90%)	1 / 1 (100.00%)	7 / 20 (35.00%)	6 / 11 (54.55%)	5 / 11 (45.45%)
occurrences all number	3	3	0	2	7	1	15	8	10
Hypoxia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	4 / 20 (20.00%)	4 / 11 (36.36%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	1	0	8	4	2
Pharyngeal inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0
Pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	1	1	0
Pleuritic pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	2
Pneumonitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pneumothorax
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	1 / 20 (5.00%)	2 / 11 (18.18%)	1 / 11 (9.09%)
occurrences all number	6	0	0	0	4	0	1	2	1
Productive cough
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	1	0	0	0	0	0	0	1
Respiratory distress
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Rhinorrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	1	1	0
Haemoptysis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Anxiety
subjects affected / exposed	2 / 5 (40.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	3 / 31 (9.68%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	3 / 11 (27.27%)
occurrences all number	2	1	0	1	3	0	2	1	8
Confusional state
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Depressed mood
subjects affected / exposed	2 / 5 (40.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Depression
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	1	0	0
Insomnia
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	3 / 11 (27.27%)
occurrences all number	1	0	0	0	0	2	0	1	7
Irritability
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Nightmare
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Sleep disorder
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Major depression
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Mood altered
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	4 / 11 (36.36%)	0 / 2 (0.00%)	2 / 7 (28.57%)	1 / 31 (3.23%)	1 / 1 (100.00%)	5 / 20 (25.00%)	1 / 11 (9.09%)	3 / 11 (27.27%)
occurrences all number	0	6	0	4	1	1	13	2	3
Amylase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	2 / 7 (28.57%)	2 / 31 (6.45%)	1 / 1 (100.00%)	3 / 20 (15.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	3	0	6	2	1	13	3	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	2	0	0	4	0	0	0	1
Blood bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	1	0	0	0	0	3	0	3
Blood calcium decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	2 / 11 (18.18%)
occurrences all number	0	0	0	1	1	0	1	1	2
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	2	0	0	1	1
Blood magnesium decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	10
Blood phosphorus decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Blood phosphorus increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Blood potassium decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	5	0	2
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	9 / 31 (29.03%)	1 / 1 (100.00%)	5 / 20 (25.00%)	0 / 11 (0.00%)	3 / 11 (27.27%)
occurrences all number	0	0	0	0	13	1	8	0	4
Blood urea increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	1	0	0	1	0
Blood uric acid decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
C-reactive protein increased
subjects affected / exposed	0 / 5 (0.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	1 / 7 (14.29%)	4 / 31 (12.90%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	3	0	1	4	0	2	0	0
Culture stool positive
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Ejection fraction decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	2	0	0	1	2
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	2	2	0	2	1	1
Full blood count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	1	0	2	5	0	4	4	1
Haemoglobin decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Lipase decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Lipase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	2	2	0
Lymphocyte count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	6 / 20 (30.00%)	2 / 11 (18.18%)	4 / 11 (36.36%)
occurrences all number	0	0	0	0	2	0	15	5	19
Neutrophil count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	10 / 20 (50.00%)	2 / 11 (18.18%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	0	0	46	5	2
Neutrophil count increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	2 / 7 (28.57%)	2 / 31 (6.45%)	0 / 1 (0.00%)	11 / 20 (55.00%)	4 / 11 (36.36%)	2 / 11 (18.18%)
occurrences all number	0	0	0	3	14	0	86	16	12
Red blood cell sedimentation rate increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Thyroglobulin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Thyroxine decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Urine output decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Weight decreased
subjects affected / exposed	3 / 5 (60.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	3 / 7 (42.86%)	11 / 31 (35.48%)	0 / 1 (0.00%)	5 / 20 (25.00%)	3 / 11 (27.27%)	6 / 11 (54.55%)
occurrences all number	13	6	0	5	17	0	9	7	8
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	13 / 20 (65.00%)	4 / 11 (36.36%)	5 / 11 (45.45%)
occurrences all number	0	0	0	0	0	0	88	11	8
Coronavirus test positive
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Electrocardiogram PR prolongation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Occult blood positive
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0	0
Thyroxine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Weight increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
White blood cell count increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Brain natriuretic peptide increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	0	0	1	0	2
Contusion
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	1	1	0	0	1	0	1	0	2
Fall
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	2	6
Ligament sprain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Limb injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	0	1
Procedural pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	2	2	0
Wound
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Wound complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Wound dehiscence
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	2	0
Anaemia postoperative
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Ankle fracture
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Post procedural complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Vaccination complication
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	5	0	0	0	0	0	0	0	0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	4	0	0
Left ventricular dysfunction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Sinus bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	4 / 11 (36.36%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	4	0
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	2	0
Ventricular dysfunction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	5	0	0
Cardiac dysfunction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Cardiotoxicity
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Bundle branch block right
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Systolic dysfunction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Nervous system disorders
Amputation stump pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Cranial nerve paralysis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	1 / 1 (100.00%)	2 / 20 (10.00%)	3 / 11 (27.27%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	3	1	2	5	1
Dysaesthesia
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Headache
subjects affected / exposed	1 / 5 (20.00%)	6 / 11 (54.55%)	0 / 2 (0.00%)	3 / 7 (42.86%)	15 / 31 (48.39%)	0 / 1 (0.00%)	6 / 20 (30.00%)	7 / 11 (63.64%)	4 / 11 (36.36%)
occurrences all number	2	9	0	6	20	0	10	13	5
Hypoaesthesia
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	2	0	0
Lethargy
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	2 / 11 (18.18%)
occurrences all number	1	0	0	0	2	0	2	1	2
Migraine
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	1	0	0	0	8
Monoparesis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Muscle contractions involuntary
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	3	2	0
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Phantom pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0
Presyncope
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Pyramidal tract syndrome
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0
Sensory disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Somnolence
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	4 / 31 (12.90%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	5	0	0	0	1
Syncope
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1	0	1
Toxic encephalopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	1	1
Tremor
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	1	1
Dysgeusia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Blood and lymphatic system disorders
Acquired antithrombin III deficiency
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Anaemia
subjects affected / exposed	1 / 5 (20.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	1 / 7 (14.29%)	5 / 31 (16.13%)	0 / 1 (0.00%)	15 / 20 (75.00%)	7 / 11 (63.64%)	9 / 11 (81.82%)
occurrences all number	2	2	0	1	7	0	77	29	43
Febrile neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1	0	1
Leukopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	3 / 20 (15.00%)	2 / 11 (18.18%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	20	21	4
Lymphopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	4	0	0	3	0	8
Neutropenia
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	8 / 20 (40.00%)	6 / 11 (54.55%)	6 / 11 (54.55%)
occurrences all number	1	0	0	0	0	0	51	25	19
Polycythaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Thrombocytopenia
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	5 / 20 (25.00%)	4 / 11 (36.36%)	5 / 11 (45.45%)
occurrences all number	1	1	0	0	7	0	46	54	50
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Vertigo
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	0	2	3	0
Eye disorders
Diplopia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1	0	1
Dry eye
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Eye discharge
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Eye pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	0	0	1	0	2
Eye ulcer
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Eyelid oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	0	4
Ocular hyperaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Papilloedema
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Photophobia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Vision blurred
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	0	1
Abdominal pain
subjects affected / exposed	2 / 5 (40.00%)	7 / 11 (63.64%)	1 / 2 (50.00%)	2 / 7 (28.57%)	9 / 31 (29.03%)	1 / 1 (100.00%)	7 / 20 (35.00%)	6 / 11 (54.55%)	6 / 11 (54.55%)
occurrences all number	3	9	1	6	27	1	23	18	20
Abdominal pain upper
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	4 / 31 (12.90%)	0 / 1 (0.00%)	4 / 20 (20.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	1	0	1	9	0	8	1	0
Anal fissure
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	2 / 20 (10.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	5	0	2	2	0
Anal fistula
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Anal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Anal incontinence
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Anal inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1	1	1
Anal pruritus
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Anal skin tags
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Aphthous ulcer
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0
Constipation
subjects affected / exposed	1 / 5 (20.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	1 / 7 (14.29%)	10 / 31 (32.26%)	0 / 1 (0.00%)	7 / 20 (35.00%)	5 / 11 (45.45%)	6 / 11 (54.55%)
occurrences all number	1	2	0	1	14	0	10	8	11
Diarrhoea
subjects affected / exposed	4 / 5 (80.00%)	5 / 11 (45.45%)	1 / 2 (50.00%)	4 / 7 (57.14%)	12 / 31 (38.71%)	1 / 1 (100.00%)	13 / 20 (65.00%)	6 / 11 (54.55%)	8 / 11 (72.73%)
occurrences all number	5	9	1	8	29	12	72	14	24
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dry mouth
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Dyschezia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Dyspepsia
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	5 / 31 (16.13%)	0 / 1 (0.00%)	4 / 20 (20.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	5	0	7	0	0
Eructation
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	2	0	0	0	1
Flatulence
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	1	0	0	0	1
Gastritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	4	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1	0	0	1
Gingival pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Glossitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Haematemesis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Haematochezia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	3 / 11 (27.27%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	4	3	0
Haemorrhoids
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	0	1
Hypoaesthesia oral
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Mouth ulceration
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	2 / 11 (18.18%)	1 / 11 (9.09%)
occurrences all number	2	0	0	1	1	0	0	2	1
Nausea
subjects affected / exposed	3 / 5 (60.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	3 / 7 (42.86%)	12 / 31 (38.71%)	0 / 1 (0.00%)	14 / 20 (70.00%)	8 / 11 (72.73%)	8 / 11 (72.73%)
occurrences all number	8	4	0	3	16	0	45	28	28
Noninfective gingivitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Odynophagia
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	2 / 20 (10.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	3	0	2	2	0
Oesophageal obstruction
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Oral discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Oral dysaesthesia
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	2 / 11 (18.18%)
occurrences all number	2	6	0	0	0	0	0	1	3
Oral pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	3 / 11 (27.27%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	0	0	1	3	2
Pancreatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Perianal erythema
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0
Proctalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	2 / 11 (18.18%)	3 / 11 (27.27%)
occurrences all number	0	0	0	2	0	0	1	2	5
Proctitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Rectal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	0	0	3	0	2
Stomatitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	4 / 31 (12.90%)	0 / 1 (0.00%)	4 / 20 (20.00%)	3 / 11 (27.27%)	5 / 11 (45.45%)
occurrences all number	2	0	0	0	5	0	8	4	7
Toothache
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	2	0
Vomiting
subjects affected / exposed	1 / 5 (20.00%)	7 / 11 (63.64%)	0 / 2 (0.00%)	4 / 7 (57.14%)	14 / 31 (45.16%)	0 / 1 (0.00%)	12 / 20 (60.00%)	8 / 11 (72.73%)	9 / 11 (81.82%)
occurrences all number	9	20	0	5	41	0	58	20	28
Anal fissure haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Gastrointestinal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Gingival bleeding
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0
Mouth haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Paraesthesia oral
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	10	0	0	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	0
Alopecia
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	1	1	0	0	0	0	2	1	1
Dermatitis acneiform
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Dermatitis allergic
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Dermatitis bullous
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Dry skin
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	1 / 2 (50.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	3 / 11 (27.27%)	3 / 11 (27.27%)
occurrences all number	1	1	1	1	2	0	0	3	4
Eczema
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0
Erythema
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	1 / 2 (50.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	1	1	1	1	0	0	0	2
Hair colour changes
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	1	2	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	0	2	0
Hyperkeratosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Night sweats
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Onychalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pain of skin
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	2 / 5 (40.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	1 / 1 (100.00%)	0 / 20 (0.00%)	3 / 11 (27.27%)	1 / 11 (9.09%)
occurrences all number	4	2	0	0	2	2	0	12	1
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	1 / 20 (5.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	4	0	1	2	0	1	3	0
Rash
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	3 / 11 (27.27%)	3 / 11 (27.27%)
occurrences all number	1	0	0	0	1	0	4	7	3
Rash generalised
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Rash macular
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	2	0	3	0
Rash papular
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Scab
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Skin exfoliation
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Skin ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0
Spider naevus
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Decubitus ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	4	0	0	0	0
Ecchymosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Itching scar
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Palmar erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Scar pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Umbilical discharge
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Purpura
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Rash erythematous
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	1	0	1	0	1
Bladder pain
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Cystitis noninfective
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	1 / 20 (5.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)
occurrences all number	0	2	0	1	2	0	2	3	0
Glycosuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	2	0	1
Haematuria
subjects affected / exposed	0 / 5 (0.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	4 / 20 (20.00%)	1 / 11 (9.09%)	5 / 11 (45.45%)
occurrences all number	0	3	0	1	2	0	12	2	6
Hydronephrosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Leukocyturia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	9	0	0
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 5 (0.00%)	3 / 11 (27.27%)	0 / 2 (0.00%)	3 / 7 (42.86%)	13 / 31 (41.94%)	0 / 1 (0.00%)	9 / 20 (45.00%)	5 / 11 (45.45%)	3 / 11 (27.27%)
occurrences all number	0	16	0	8	27	0	44	13	5
Renal failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Renal impairment
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Renal tubular disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1	0	1
Urine flow decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Albuminuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Nephropathy toxic
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	2	0	0	0	1
Hypothyroidism
subjects affected / exposed	3 / 5 (60.00%)	6 / 11 (54.55%)	1 / 2 (50.00%)	3 / 7 (42.86%)	13 / 31 (41.94%)	0 / 1 (0.00%)	6 / 20 (30.00%)	8 / 11 (72.73%)	6 / 11 (54.55%)
occurrences all number	5	10	1	3	17	0	8	11	7
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	1 / 7 (14.29%)	10 / 31 (32.26%)	0 / 1 (0.00%)	3 / 20 (15.00%)	6 / 11 (54.55%)	6 / 11 (54.55%)
occurrences all number	0	2	0	2	17	0	8	8	7
Back pain
subjects affected / exposed	1 / 5 (20.00%)	4 / 11 (36.36%)	0 / 2 (0.00%)	2 / 7 (28.57%)	10 / 31 (32.26%)	1 / 1 (100.00%)	5 / 20 (25.00%)	4 / 11 (36.36%)	6 / 11 (54.55%)
occurrences all number	2	8	0	2	15	2	5	6	7
Bone pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	3 / 20 (15.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	3	0	3	0	3
Coccydynia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Flank pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Groin pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	0	2
Joint swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Limb mass
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Muscle spasms
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	1	1	0
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	2	0	1	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	6 / 31 (19.35%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	6	0	1	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	10 / 31 (32.26%)	0 / 1 (0.00%)	3 / 20 (15.00%)	1 / 11 (9.09%)	2 / 11 (18.18%)
occurrences all number	1	1	0	2	14	0	5	1	3
Myalgia
subjects affected / exposed	2 / 5 (40.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	2 / 11 (18.18%)	1 / 11 (9.09%)
occurrences all number	12	2	0	0	2	0	3	3	1
Neck pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	1 / 1 (100.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	3	1	0	1	1
Pain in extremity
subjects affected / exposed	2 / 5 (40.00%)	4 / 11 (36.36%)	0 / 2 (0.00%)	3 / 7 (42.86%)	9 / 31 (29.03%)	0 / 1 (0.00%)	3 / 20 (15.00%)	5 / 11 (45.45%)	6 / 11 (54.55%)
occurrences all number	4	10	0	5	10	0	4	11	16
Pain in jaw
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0
Periostitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	1	1
Spinal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Muscle atrophy
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Muscle rigidity
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Clostridium difficile infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	2
Cystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Device related infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	0	1
Ear infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Eye infection bacterial
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Eyelid infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Folliculitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Gastroenteritis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	0	0	0	0	1
Gastrointestinal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Gingivitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Influenza
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	1 / 2 (50.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0	0
Localised infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	1	0	0	0	2
Nasopharyngitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0	0
Oesophageal candidiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0
Oral candidiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	1	0	1	0	1
Oral herpes
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	2	1	0
Osteomyelitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Paronychia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	1	1
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pseudomonas infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Rash pustular
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	2	1	1
Rhinitis
subjects affected / exposed	1 / 5 (20.00%)	2 / 11 (18.18%)	2 / 2 (100.00%)	3 / 7 (42.86%)	3 / 31 (9.68%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	2	3	2	3	3	0	2	1	1
Sepsis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Sinusitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	0	0	0	0	1
Staphylococcal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	2
Staphylococcal sepsis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	3 / 31 (9.68%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	4	0	0	1	1
Urinary tract infection
subjects affected / exposed	1 / 5 (20.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	2	1	0	3	1	0	2	0	2
Vaginal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0
Vascular device infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Viral infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Vulvovaginal candidiasis
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Abscess limb
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Anal fungal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Angular cheilitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Catheter site infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Genital candidiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Genital infection fungal
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Tonsillitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Cachexia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Decreased appetite
subjects affected / exposed	4 / 5 (80.00%)	5 / 11 (45.45%)	0 / 2 (0.00%)	3 / 7 (42.86%)	15 / 31 (48.39%)	0 / 1 (0.00%)	7 / 20 (35.00%)	3 / 11 (27.27%)	5 / 11 (45.45%)
occurrences all number	14	9	0	5	26	0	12	3	8
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	1	0	2	4	2
Electrolyte imbalance
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	4	0
Fluid retention
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Hyperkalaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	1	2	0
Hypermagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	0	1
Hyperphosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0	0
Hypertriglyceridaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	8	0	0	0
Hyperuricaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	1 / 1 (100.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	2	1	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 11 (18.18%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	2 / 11 (18.18%)
occurrences all number	0	4	0	0	2	0	5	1	4
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	3	0	0	0	3
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	1 / 31 (3.23%)	0 / 1 (0.00%)	3 / 20 (15.00%)	1 / 11 (9.09%)	4 / 11 (36.36%)
occurrences all number	0	0	0	2	2	0	10	4	8
Hypomagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	1 / 7 (14.29%)	2 / 31 (6.45%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	1	2	0	0	0	4
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 11 (9.09%)	0 / 2 (0.00%)	1 / 7 (14.29%)	3 / 31 (9.68%)	0 / 1 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	3	0	1	1	1
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	4 / 20 (20.00%)	2 / 11 (18.18%)	3 / 11 (27.27%)
occurrences all number	0	0	0	0	1	0	12	13	8
Hypoproteinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Metabolic acidosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	0	0	1
Vitamin D deficiency
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	0 / 1 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Hyperamylasaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Hypercholesterolaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	0 / 31 (0.00%)	1 / 1 (100.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Hypochloraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 11 (0.00%)	0 / 2 (0.00%)	0 / 7 (0.00%)	1 / 31 (3.23%)	0 / 1 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Sep 2014

Details added to define Grade 4 hypertension. Change in ANC level in inclusion criteria. Contraceptive period was extended in the inclusion criteria. Management of PRES added to Treatment section.

14 Apr 2015

Secondary objective of observing bone growth changed to assessing palatability and acceptability of study drug. Details added to dose escalation procedures for single-agent lenvatinib and combination therapy. Dose-escalation method changed from Continual-reassessment method (CRM) to Time-to-event continual-reassessment method (TiTE-CRM). Use of eastern cooperative oncology group performance status (ECOG PS) changed to karnofsky performance status (KPS). Previous treatment with ifosfamide and neurotoxicity added to exclusion criteria. Run-In Period added for subjects aged 2 to <6 years in Cohort 1. Details added for management of toxicity for subjects receiving combination therapy. Updates to study drug administration and permitted concomitant medications. Measurement of tibial growth plates and fecal occult blood tests added to baseline assessments.

01 Sep 2016

Different standards set for hematologic toxicity for subjects receiving combination therapy. RD for single-agent lenvatinib in Cohort 1 determined as 14 mg/m^2, with a maximum lenvatinib dosage of 24 mg daily. Procedures added for study drug administration when subject underwent surgery. Details added regarding frequency of tumor assessments. Exploratory endpoint of OS added. Estimated number of enrolled subjects with radioiodine-131 (I131)-refractory differentiated thyroid cancer (RR-DTC) reduced and subjects with osteosarcoma increased. Permitted enrollment of subjects with RR-DTC and osteosarcoma subjects in Cohort 2A and 2B, respectively, who had either measurable or evaluable disease (based on RECIST 1.1). Sites of tumor assessments were updated for subjects with RR-DTC and osteosarcoma as advised by the protocol steering committee (PSC), to align with the standard of care.

12 Nov 2019

OS changed from an exploratory to a secondary objective. Clarified the procedure for procurement of study drug for subjects continuing study treatment at the time of the data cutoff date for the primary analysis. Clarified the timing for collection of blood samples for pharmacodynamic and biomarker analysis for subjects ongoing after the data cutoff date for the primary analysis.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults with Osteosarcoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohort 1: Recommended Dose (RD) of Lenvatinib

Primary: Cohort 1: Recommended Dose (RD) of Lenvatinib

Primary: Cohort 2A: Number of Subjects With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)

Primary: Cohort 2A: Number of Subjects With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)

Primary: Cohort 2A: Number of Subjects With Best Overall Response (BOR)

Primary: Cohort 2A: Number of Subjects With Best Overall Response (BOR)

Primary: Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4

Primary: Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4

Primary: Cohort 3A: Recommended Dose of Lenvatinib When Given in Combination With Etoposide and Ifosfamide

Primary: Cohort 3A: Recommended Dose of Lenvatinib When Given in Combination With Etoposide and Ifosfamide

Secondary: Cohorts 1, 2B, 3A, and 3B: Number of Subjects With Best Overall Response (BOR)

Secondary: Cohorts 1, 2B, 3A, and 3B: Number of Subjects With Best Overall Response (BOR)

Secondary: Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR)

Secondary: Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Who Experienced Disease Control

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Who Experienced Disease Control

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Experienced Clinical Benefit

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects Experienced Clinical Benefit

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary: Cohorts 1, 2A, 2B, 3A, and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Measurements on Urine DipStick for Proteinuria

Secondary: Cohorts 1, 2A, 2B, 3A, and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Measurements on Urine DipStick for Proteinuria

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Lansky Performance Play Score

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Lansky Performance Play Score

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Karnofsky Performance Status (KPS) Scores

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Shift From Baseline to Worst Post Baseline Score in Karnofsky Performance Status (KPS) Scores

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Most Frequent Treatment-emergent Adverse Events Related to Lenvatinib Exposure

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Most Frequent Treatment-emergent Adverse Events Related to Lenvatinib Exposure

Secondary: Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib

Secondary: Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib

Secondary: Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level

Secondary: Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Overall Palatability and Acceptability Questionnaire Score for Suspension of Lenvatinib

Secondary: Cohorts 1, 2A, 2B, 3A and 3B: Number of Subjects With Overall Palatability and Acceptability Questionnaire Score for Suspension of Lenvatinib

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults with Osteosarcoma