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Clinical Trial Results:
A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Summary
EudraCT number	2011-001123-20
Trial protocol	IT GB Outside EU/EEA
Global end of trial date

Results information
Results version number	v1
This version publication date	10 Jun 2018
First version publication date	10 Jun 2018
Other versions	v2

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

CA180-372

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000567-PIP09-05

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

Interim

Date of interim/final analysis

28 May 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 May 2017

Global end of trial reached?

Main objective of the trial

To compare the 3-year efficacy based on EFS of dasatinib plus chemotherapy with external historical controls, in hierarchical order, as follows: - Superiority over chemotherapy alone of AIEOP-BFM 2000 - Non-inferiority to continuous imatinib plus chemotherapy of the amended EsPhALL trial - Superiority over continuous imatinib plus chemotherapy of the amended EsPhALL trial

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Apr 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 3

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Italy: 13

Country: Number of subjects enrolled

United States: 78

Worldwide total number of subjects

109

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

Screening details

A total of 109 subjects were enrolled and 106 subjects were treated with dasatinib (82 subjects received dasatinib in the tablet form exclusively and 24 subjects received either tablet and/or PFOS).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Tablet Only

Arm description

For children and adolescents capable of swallowing tablets, dasatinib tablets in strengths of 5 mg, 20 mg, and 50 mg, were given to cover the anticipated dose range.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablets in strengths of 5 mg, 20 mg, and 50 mg, were given to cover the anticipated dose range of 60 mg/m2 daily.

PFOS Used

Arm description

If necessary for administration in young children not able to swallow tablets, dasatinib was dispersed as Powder For Oral Suspension (PFOS) at a dose of 60 mg/m2 daily in 100% preservative-free juice.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

Powder for Oral Solution dispersed at dose of 60 mg/m2 daily. The PFOS bottle was constituted with 77 mL purified water or Sterile Water for Injection to give a total volume of 99 mL with a 10 mg/mL suspension.

Number of subjects in period 1 ^[1]	Tablet Only	PFOS Used
Started	82	24
Completed	78	22
Not completed	4	2
Death	4	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: A total of 109 subjects were enrolled and 106 subjects were treated with dasatinib (82 subjects received dasatinib in the tablet form exclusively and 24 subjects received either tablet and/or PFOS).

Baseline characteristics

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Reporting group title

Tablet Only

Reporting group description

For children and adolescents capable of swallowing tablets, dasatinib tablets in strengths of 5 mg, 20 mg, and 50 mg, were given to cover the anticipated dose range.

Reporting group title

PFOS Used

Reporting group description

Reporting group values	Tablet Only	PFOS Used	Total
Number of subjects	82	24	106
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	4	4
Children (2-11 years)	48	19	67
Adolescents (12-17 years)	34	1	35
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	10.33 ( 4.160 )	5.73 ( 3.612 )	-
Sex: Female, Male
Units: Subjects
Female	37	12	49
Male	45	12	57
Race
Units: Subjects
White	66	19	85
Black or African American	9	4	13
Asian	5	0	5
American Indian or Alaska Native	0	1	1
Native Hawaiian or Other Pacific Islander	1	0	1
Other	1	0	1
BCR-ABL Transcript
Units: Subjects
P190	60	15	75
P210	11	5	16
Not Available	11	4	15

Subject analysis set title

All Treated Subjects

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects receiving at least one dose of study treatment (tablet or PFOS)

Subject analysis sets values	All Treated Subjects
Number of subjects	106
Age categorical
Units: Subjects
In utero	0
Preterm newborn infants (gestational age < 37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	4
Children (2-11 years)	67
Adolescents (12-17 years)	35
Adults (18-64 years)	0
From 65-84 years	0
85 years and over	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	5.73 ( 3.612 )
Sex: Female, Male
Units: Subjects
Female
Male
Race
Units: Subjects
White
Black or African American
Asian
American Indian or Alaska Native
Native Hawaiian or Other Pacific Islander
Other
BCR-ABL Transcript
Units: Subjects
P190
P210
Not Available

End points

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Reporting group title

Tablet Only

Reporting group description

For children and adolescents capable of swallowing tablets, dasatinib tablets in strengths of 5 mg, 20 mg, and 50 mg, were given to cover the anticipated dose range.

Reporting group title

PFOS Used

Reporting group description

Subject analysis set title

All Treated Subjects

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects receiving at least one dose of study treatment (tablet or PFOS)

Primary: 3-year Event-free survival (EFS) Rate

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End point title

3-year Event-free survival (EFS) Rate

End point description

EFS is defined as the time from the starting date of dasatinib until an event. In the primary analysis, the 3-year EFS response rate is defined as the number of subjects without event after 3 years since the start of dasatinib divided by the number of treated subjects and expressed as a percentage. Events for EFS are defined as ANY first one of the following: · Lack of complete response in bone marrowa · Relapse at any site · Development of second malignant neoplasm · Death from any cause

End point type

Primary

End point timeframe

3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: Percentage
number (confidence interval 90%)	65.9 (56.3 to 74.5)	66.7 (47.9 to 82.2)	66.0 (57.7 to 73.7)

Binomial EFS rate difference vs. AIEOP-BFM 2000

Statistical analysis description

Difference in 3-year binomial EFS rate in all treated subjects (dasatinib plus chemotherapy) vs. chemotherapy alone in AIEOP-BFM 2000 historical control

Comparison groups

Tablet Only v PFOS Used

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.032 ^[1]

Method

Chi-squared

Parameter type

Estimate of Difference

Point estimate

16.86

Confidence interval

level

90%

sides

2-sided

lower limit

3.9

upper limit

29.8

Notes
[1] - Superiority test versus AIEOP-BFM 2000

Binomial EFS rate difference vs. EsPhALL Trial

Statistical analysis description

Difference in 3-year binomial EFS rate for all treated subjects (dasatinib plus chemotherapy) vs. continuous imatinib plus chemotherapy in the Amended EsPhALL Trial Historical Control

Comparison groups

Tablet Only v PFOS Used

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

^[2]

P-value

= 0.271 ^[3]

Method

Chi-squared

Parameter type

Estimate of difference

Point estimate

6.91

Confidence interval

level

90%

sides

2-sided

lower limit

-3.3

upper limit

17.2

Notes
[2] - non-inferiority margin = 5%. One-sided type I error rate of 0.05
[3] - Superiority test versus EsPhALL

Secondary: 3-year EFS rate (K-M estimate)

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End point title

3-year EFS rate (K-M estimate)

End point description

Overall estimation of the EFS of dasatinib plus chemotherapy was performed utilizing the Kaplan-Meier (KM) Product Limit method. The 3-year EFS rates were computed with the corresponding 95% CI's using Greenwood's formula. Analyses of EFS included KM plots with number of patients at risk. Subjects who neither relapse nor die or who are lost to follow-up were censored on the date of their last bone marrow, CSF assessment or physical exam, whichever occurred last.

End point type

Secondary

End point timeframe

3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: Percentage
number (confidence interval 95%)	65.1 (53.6 to 74.4)	66.7 (44.3 to 81.7)	65.5 (55.5 to 73.7)

No statistical analyses for this end point

Secondary: Overall Survival (K-M Estimate) Rate at 3 years

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End point title

Overall Survival (K-M Estimate) Rate at 3 years

End point description

Overall survival is defined as time from the first day of dasatinib treatment until the time of death. Subjects who have not died or who are lost to follow-up will be censored on the last date the subject is known to be alive. The rate of OS at 3 years was expressed as a percentage of all treated subjects.

End point type

Secondary

End point timeframe

3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: percentage
number (confidence interval 95%)	92.6 (84.3 to 96.6)	87.5 (66.1 to 95.8)	91.5 (84.2 to 95.5)

No statistical analyses for this end point

Secondary: Complete Remission Rate

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End point title

Complete Remission Rate

End point description

CR rate is defined as the proportion of subjects achieving a complete remission, i.e. < 5% lymphoblasts in bone marrow and in CSF, with no evidence of other extramedullary disease, and expressed as a percentage. Complete remission will be assessed at the end of Induction IA, end of induction IB and end of HR3 for all treated subjects.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: percentage
number (not applicable)
End of Induction period (period IA)\|	64.6	66.7	65.1
End of Induction period (period IB)\|	87.8	91.7	88.7
End of Consolidation period\|	93.9	91.7	93.4

No statistical analyses for this end point

Secondary: Percentage of subjects with Minimal Residual Disease based on Ig/TCR method

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End point title

Percentage of subjects with Minimal Residual Disease based on Ig/TCR method

End point description

The number of subjects with MRD at the end of the Induction 1B and Consolidation periods was divided by the number of treated subjects and expressed as a percentage.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: percentage
number (confidence interval 95%)
MRD-negative, end of Induction IB period\|	53.7 (42.30 to 64.75)	50.0 (29.12 to 70.88)	52.8 (42.89 to 62.60)
MRD-negative, end of Consolidation\|	74.4 (63.56 to 83.40)	62.5 (40.59 to 81.20)	71.7 (62.12 to 80.02)

No statistical analyses for this end point

Secondary: Number of subjects with AEs or drug related death

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End point title

Number of subjects with AEs or drug related death

End point description

The number of subjects with any AE or with study drug-related death was reported for each arm.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: subjects
AEs\|	82	24	106
Drug Related Death\|	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with BCR-ABL Mutations at time of disease progression

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End point title

Number of subjects with BCR-ABL Mutations at time of disease progression

End point description

The number of Ph+ ALL subjects with BCR-ABL Mutations at Disease Progression or Relapse was reported for each arm.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	25	6	106
Units: subjects
Number of subjects with mutations	2	0	2
Number of subjects with no mutations	17	3	20
Not Reported	6	3	9

No statistical analyses for this end point

Secondary: Number of subjects with Grade 3-4 hematology laboratory abnormalities

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End point title

Number of subjects with Grade 3-4 hematology laboratory abnormalities

End point description

The number of subjects experiencing Grade 3 or 4 hematology laboratory abnormalities was reported by arm.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: subjects
Leukocytes	77	23	100
Absolute Neutrophil Count	79	24	103
Platelet Count	72	21	93
Hemoglobin	67	21	88

No statistical analyses for this end point

Secondary: Number of subjects with Grade 3-4 liver function laboratory abnormalities

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End point title

Number of subjects with Grade 3-4 liver function laboratory abnormalities

End point description

The number of subjects experiencing Grade 3 or 4 liver function laboratory abnormalities was reported by arm.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: subjects
ALT\|	38	15	53
AST\|	21	7	28
Total bilirubin\|	9	0	9

No statistical analyses for this end point

Secondary: Number of subjects with Grade 3-4 kidney function abnormalities

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End point title

Number of subjects with Grade 3-4 kidney function abnormalities

End point description

The number of subjects experiencing Grade 3 or 4 kidney function laboratory abnormalities was reported by arm.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: subjects
BUN/Urea >ULN\|	33	7	40
Serum Creatinine\|	2	0	2

No statistical analyses for this end point

Secondary: Number of subjects with Grade 3-4 serum chemistry abnormalities

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End point title

Number of subjects with Grade 3-4 serum chemistry abnormalities

End point description

The number of subjects with grade 3-4 serum chemistry laboratory abnormalities was presented for each arm.

End point type

Secondary

End point timeframe

Approximately 3 years

End point values	Tablet Only	PFOS Used	All Treated Subjects
Number of subjects analysed	82	24	106
Units: subjects
HC03<LLN (All Grade)\|	27	11	38
HC03>ULN (All Grade)\|	24	1	25
LDH>ULN (All Grade)\|	63	18	81
Sodium\|	15	3	18
Potassium\|	33	10	43
Chloride (low) < LLN\|	20	2	22
Chloride(high) > ULN\|	29	11	40
Magnesium (low)\|	1	0	1
Phosphorus\|	9	4	13
Calcium (low)\|	15	3	18
Uric Acid\|	0	1	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All serious and non-serious adverse events were reported from first dose up to 30 days after last dose

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Tablet Only

Reporting group description

Subjects who were capable of swallowing tablets received treatment orally Dasatinib 60 milligram per meter square (mg/m2) once daily and subjects who were not able to swallow tablets received treatment as dispersed tablets in 100 percent (%) preservative free juice up to 27 months along with Associazione Italiana di Ematologia Pediatrica-Berlin-Frankfurt-Muenster Acute Lymphoblastic Leukemia (AIEOP-BFM ALL) 2000 chemotherapy regimen.

Reporting group title

PFOS Used

Reporting group description

Total of 24 subjects, 16 received Dasatinib 60 mg/m2 once daily orally as both the tablet and as a suspension from Powder for oral suspension (PFOS), 8 subjects who were not able to swallow tablets received the treatment as PFOS only up to 27 months along with AIEOP-BFM ALL 2000 chemotherapy regimen.

Serious adverse events	Tablet Only	PFOS Used
Total subjects affected by serious adverse events
subjects affected / exposed	79 / 82 (96.34%)	22 / 24 (91.67%)
number of deaths (all causes)	3	2
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Astrocytoma
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukaemia recurrent
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Embolism
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	4 / 82 (4.88%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	15 / 82 (18.29%)	7 / 24 (29.17%)
occurrences causally related to treatment / all	1 / 20	1 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chills
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related thrombosis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Localised oedema
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	11 / 82 (13.41%)	7 / 24 (29.17%)
occurrences causally related to treatment / all	2 / 14	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Non-Cardiac chest pain
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 82 (1.22%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	39 / 82 (47.56%)	13 / 24 (54.17%)
occurrences causally related to treatment / all	8 / 104	6 / 26
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	7 / 82 (8.54%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	6 / 82 (7.32%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Oedema genital
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chylothorax
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	4 / 82 (4.88%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	5 / 82 (6.10%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	8 / 82 (9.76%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	3 / 9	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stridor
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Personality change
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	2 / 82 (2.44%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	2 / 82 (2.44%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	1 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	7 / 82 (8.54%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood culture positive
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug clearance decreased
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterovirus test positive
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	8 / 82 (9.76%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	7 / 11	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	7 / 82 (8.54%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin i increased
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urine output decreased
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral test
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	5 / 82 (6.10%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count increased
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactic transfusion reaction
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access complication
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral ischaemia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 6	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukoencephalopathy
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Posterior reversible encephalopathy syndrome
subjects affected / exposed	3 / 82 (3.66%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	4 / 82 (4.88%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	12 / 82 (14.63%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	5 / 18	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	61 / 82 (74.39%)	20 / 24 (83.33%)
occurrences causally related to treatment / all	33 / 217	8 / 60
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	3 / 82 (3.66%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	4 / 5	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphatic disorder
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	20 / 82 (24.39%)	5 / 24 (20.83%)
occurrences causally related to treatment / all	12 / 33	6 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	9 / 82 (10.98%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	7 / 15	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Photophobia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vision blurred
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	10 / 82 (12.20%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	1 / 13	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	8 / 82 (9.76%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	5 / 10	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 82 (2.44%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	15 / 82 (18.29%)	6 / 24 (25.00%)
occurrences causally related to treatment / all	5 / 24	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea haemorrhagic
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Enterocolitis
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal ulcer
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	3 / 82 (3.66%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	2 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	4 / 82 (4.88%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	2 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	6 / 82 (7.32%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proctitis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	14 / 82 (17.07%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 17	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	13 / 82 (15.85%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	2 / 18	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venoocclusive liver disease
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash macular
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash generalised
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	9 / 82 (10.98%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	1 / 9	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder spasm
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis noninfective
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	2 / 82 (2.44%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myalgia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	4 / 82 (4.88%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in jaw
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	11 / 82 (13.41%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	0 / 18	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 82 (1.22%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchitis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida infection
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida pneumonia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis of male external genital organ
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridial infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	6 / 82 (7.32%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	2 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	6 / 82 (7.32%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coccidioidomycosis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Conjunctivitis
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	13 / 82 (15.85%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	1 / 14	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Empyema
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis bacterial
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal sepsis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	2 / 82 (2.44%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	6 / 82 (7.32%)	4 / 24 (16.67%)
occurrences causally related to treatment / all	0 / 6	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Mucosal infection
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nail bed infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nail infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media
subjects affected / exposed	3 / 82 (3.66%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pasteurella infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Perineal cellulitis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	7 / 82 (8.54%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	1 / 8	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonal bacteraemia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash pustular
subjects affected / exposed	1 / 82 (1.22%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	17 / 82 (20.73%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	6 / 26	1 / 5
deaths causally related to treatment / all	0 / 1	0 / 0
Septic embolus
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	5 / 82 (6.10%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	2 / 82 (2.44%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	4 / 82 (4.88%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	2 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic candida
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic mycosis
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral diarrhoea
subjects affected / exposed	0 / 82 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	8 / 82 (9.76%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	3 / 14	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertriglyceridaemia
subjects affected / exposed	1 / 82 (1.22%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	3 / 82 (3.66%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	7 / 82 (8.54%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	2 / 7	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	7 / 82 (8.54%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	2 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	2 / 82 (2.44%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Tablet Only	PFOS Used
Total subjects affected by non serious adverse events
subjects affected / exposed	82 / 82 (100.00%)	24 / 24 (100.00%)
Vascular disorders
Flushing
subjects affected / exposed	9 / 82 (10.98%)	1 / 24 (4.17%)
occurrences all number	12	1
Haematoma
subjects affected / exposed	4 / 82 (4.88%)	2 / 24 (8.33%)
occurrences all number	6	2
Hypertension
subjects affected / exposed	35 / 82 (42.68%)	6 / 24 (25.00%)
occurrences all number	65	13
Hypotension
subjects affected / exposed	23 / 82 (28.05%)	5 / 24 (20.83%)
occurrences all number	37	6
Pallor
subjects affected / exposed	7 / 82 (8.54%)	4 / 24 (16.67%)
occurrences all number	13	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	11 / 82 (13.41%)	0 / 24 (0.00%)
occurrences all number	19	0
Catheter site bruise
subjects affected / exposed	0 / 82 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	3
Catheter site erythema
subjects affected / exposed	3 / 82 (3.66%)	3 / 24 (12.50%)
occurrences all number	3	4
Catheter site pain
subjects affected / exposed	10 / 82 (12.20%)	4 / 24 (16.67%)
occurrences all number	13	5
Face oedema
subjects affected / exposed	7 / 82 (8.54%)	1 / 24 (4.17%)
occurrences all number	10	1
Chills
subjects affected / exposed	16 / 82 (19.51%)	4 / 24 (16.67%)
occurrences all number	29	8
Fatigue
subjects affected / exposed	45 / 82 (54.88%)	13 / 24 (54.17%)
occurrences all number	121	26
Gait disturbance
subjects affected / exposed	6 / 82 (7.32%)	4 / 24 (16.67%)
occurrences all number	7	8
Influenza like illness
subjects affected / exposed	6 / 82 (7.32%)	0 / 24 (0.00%)
occurrences all number	7	0
Malaise
subjects affected / exposed	7 / 82 (8.54%)	0 / 24 (0.00%)
occurrences all number	8	0
Mucosal inflammation
subjects affected / exposed	43 / 82 (52.44%)	8 / 24 (33.33%)
occurrences all number	68	13
Non-Cardiac chest pain
subjects affected / exposed	15 / 82 (18.29%)	3 / 24 (12.50%)
occurrences all number	23	7
Oedema
subjects affected / exposed	9 / 82 (10.98%)	1 / 24 (4.17%)
occurrences all number	9	1
Oedema peripheral
subjects affected / exposed	16 / 82 (19.51%)	1 / 24 (4.17%)
occurrences all number	31	1
Pain
subjects affected / exposed	25 / 82 (30.49%)	3 / 24 (12.50%)
occurrences all number	38	7
Pyrexia
subjects affected / exposed	58 / 82 (70.73%)	21 / 24 (87.50%)
occurrences all number	234	55
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 82 (1.22%)	3 / 24 (12.50%)
occurrences all number	1	3
Drug hypersensitivity
subjects affected / exposed	14 / 82 (17.07%)	3 / 24 (12.50%)
occurrences all number	18	3
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	5 / 82 (6.10%)	3 / 24 (12.50%)
occurrences all number	6	3
Dyspnoea
subjects affected / exposed	14 / 82 (17.07%)	4 / 24 (16.67%)
occurrences all number	22	4
Cough
subjects affected / exposed	63 / 82 (76.83%)	15 / 24 (62.50%)
occurrences all number	197	40
Epistaxis
subjects affected / exposed	24 / 82 (29.27%)	3 / 24 (12.50%)
occurrences all number	42	5
Hypoxia
subjects affected / exposed	11 / 82 (13.41%)	4 / 24 (16.67%)
occurrences all number	12	8
Nasal congestion
subjects affected / exposed	24 / 82 (29.27%)	4 / 24 (16.67%)
occurrences all number	48	4
Oropharyngeal pain
subjects affected / exposed	31 / 82 (37.80%)	4 / 24 (16.67%)
occurrences all number	55	11
Pleural effusion
subjects affected / exposed	13 / 82 (15.85%)	3 / 24 (12.50%)
occurrences all number	15	3
Productive cough
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences all number	11	2
Respiratory tract congestion
subjects affected / exposed	8 / 82 (9.76%)	2 / 24 (8.33%)
occurrences all number	13	3
Rhinitis allergic
subjects affected / exposed	8 / 82 (9.76%)	0 / 24 (0.00%)
occurrences all number	9	0
Rhinorrhoea
subjects affected / exposed	24 / 82 (29.27%)	13 / 24 (54.17%)
occurrences all number	56	18
Tachypnoea
subjects affected / exposed	9 / 82 (10.98%)	2 / 24 (8.33%)
occurrences all number	10	3
Sneezing
subjects affected / exposed	5 / 82 (6.10%)	2 / 24 (8.33%)
occurrences all number	5	2
Wheezing
subjects affected / exposed	12 / 82 (14.63%)	1 / 24 (4.17%)
occurrences all number	14	2
Psychiatric disorders
Anxiety
subjects affected / exposed	11 / 82 (13.41%)	4 / 24 (16.67%)
occurrences all number	15	12
Agitation
subjects affected / exposed	6 / 82 (7.32%)	4 / 24 (16.67%)
occurrences all number	7	13
Depression
subjects affected / exposed	13 / 82 (15.85%)	3 / 24 (12.50%)
occurrences all number	16	3
Insomnia
subjects affected / exposed	13 / 82 (15.85%)	3 / 24 (12.50%)
occurrences all number	17	3
Hallucination
subjects affected / exposed	2 / 82 (2.44%)	2 / 24 (8.33%)
occurrences all number	2	2
Irritability
subjects affected / exposed	7 / 82 (8.54%)	5 / 24 (20.83%)
occurrences all number	9	7
Investigations
Alanine aminotransferase increased
subjects affected / exposed	29 / 82 (35.37%)	13 / 24 (54.17%)
occurrences all number	88	32
Amylase increased
subjects affected / exposed	2 / 82 (2.44%)	2 / 24 (8.33%)
occurrences all number	6	2
Aspartate aminotransferase increased
subjects affected / exposed	23 / 82 (28.05%)	12 / 24 (50.00%)
occurrences all number	57	19
Blood bilirubin increased
subjects affected / exposed	11 / 82 (13.41%)	1 / 24 (4.17%)
occurrences all number	12	1
Blood creatinine increased
subjects affected / exposed	7 / 82 (8.54%)	2 / 24 (8.33%)
occurrences all number	10	2
Cardiac murmur
subjects affected / exposed	11 / 82 (13.41%)	1 / 24 (4.17%)
occurrences all number	25	1
Gamma-Glutamyltransferase increased
subjects affected / exposed	5 / 82 (6.10%)	2 / 24 (8.33%)
occurrences all number	8	3
Electrocardiogram qt prolonged
subjects affected / exposed	6 / 82 (7.32%)	0 / 24 (0.00%)
occurrences all number	14	0
Lipase increased
subjects affected / exposed	2 / 82 (2.44%)	2 / 24 (8.33%)
occurrences all number	2	3
Lymphocyte count decreased
subjects affected / exposed	5 / 82 (6.10%)	3 / 24 (12.50%)
occurrences all number	38	17
Neutrophil count decreased
subjects affected / exposed	31 / 82 (37.80%)	10 / 24 (41.67%)
occurrences all number	170	51
Platelet count decreased
subjects affected / exposed	29 / 82 (35.37%)	10 / 24 (41.67%)
occurrences all number	176	53
Weight increased
subjects affected / exposed	9 / 82 (10.98%)	2 / 24 (8.33%)
occurrences all number	21	2
Weight decreased
subjects affected / exposed	22 / 82 (26.83%)	4 / 24 (16.67%)
occurrences all number	29	4
White blood cell count decreased
subjects affected / exposed	16 / 82 (19.51%)	5 / 24 (20.83%)
occurrences all number	79	40
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	10 / 82 (12.20%)	3 / 24 (12.50%)
occurrences all number	11	7
Anal injury
subjects affected / exposed	1 / 82 (1.22%)	2 / 24 (8.33%)
occurrences all number	1	2
Arthropod bite
subjects affected / exposed	4 / 82 (4.88%)	2 / 24 (8.33%)
occurrences all number	4	3
Contusion
subjects affected / exposed	24 / 82 (29.27%)	8 / 24 (33.33%)
occurrences all number	46	12
Skin abrasion
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences all number	8	2
Sunburn
subjects affected / exposed	5 / 82 (6.10%)	2 / 24 (8.33%)
occurrences all number	5	2
Transfusion reaction
subjects affected / exposed	6 / 82 (7.32%)	0 / 24 (0.00%)
occurrences all number	10	0
Cardiac disorders
Pericardial effusion
subjects affected / exposed	6 / 82 (7.32%)	0 / 24 (0.00%)
occurrences all number	6	0
Sinus bradycardia
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	6	0
Sinus tachycardia
subjects affected / exposed	16 / 82 (19.51%)	3 / 24 (12.50%)
occurrences all number	25	4
Tachycardia
subjects affected / exposed	25 / 82 (30.49%)	10 / 24 (41.67%)
occurrences all number	50	30
Nervous system disorders
Ataxia
subjects affected / exposed	2 / 82 (2.44%)	2 / 24 (8.33%)
occurrences all number	2	3
Dizziness
subjects affected / exposed	14 / 82 (17.07%)	0 / 24 (0.00%)
occurrences all number	30	0
Lethargy
subjects affected / exposed	6 / 82 (7.32%)	1 / 24 (4.17%)
occurrences all number	11	2
Headache
subjects affected / exposed	60 / 82 (73.17%)	10 / 24 (41.67%)
occurrences all number	218	24
Neuropathy peripheral
subjects affected / exposed	5 / 82 (6.10%)	1 / 24 (4.17%)
occurrences all number	10	2
Peripheral motor neuropathy
subjects affected / exposed	11 / 82 (13.41%)	1 / 24 (4.17%)
occurrences all number	16	1
Peripheral sensory neuropathy
subjects affected / exposed	12 / 82 (14.63%)	1 / 24 (4.17%)
occurrences all number	14	1
Somnolence
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	6	0
Tremor
subjects affected / exposed	7 / 82 (8.54%)	1 / 24 (4.17%)
occurrences all number	7	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	66 / 82 (80.49%)	17 / 24 (70.83%)
occurrences all number	556	131
Febrile neutropenia
subjects affected / exposed	30 / 82 (36.59%)	7 / 24 (29.17%)
occurrences all number	53	9
Leukopenia
subjects affected / exposed	9 / 82 (10.98%)	3 / 24 (12.50%)
occurrences all number	23	9
Neutropenia
subjects affected / exposed	35 / 82 (42.68%)	8 / 24 (33.33%)
occurrences all number	111	34
Thrombocytopenia
subjects affected / exposed	40 / 82 (48.78%)	10 / 24 (41.67%)
occurrences all number	281	47
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	21 / 82 (25.61%)	4 / 24 (16.67%)
occurrences all number	33	11
Eye disorders
Eye discharge
subjects affected / exposed	0 / 82 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	2
Eye pain
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences all number	7	2
Ocular hyperaemia
subjects affected / exposed	4 / 82 (4.88%)	3 / 24 (12.50%)
occurrences all number	4	4
Periorbital oedema
subjects affected / exposed	6 / 82 (7.32%)	3 / 24 (12.50%)
occurrences all number	9	3
Vision blurred
subjects affected / exposed	14 / 82 (17.07%)	1 / 24 (4.17%)
occurrences all number	17	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	8 / 82 (9.76%)	3 / 24 (12.50%)
occurrences all number	10	7
Abdominal pain
subjects affected / exposed	57 / 82 (69.51%)	16 / 24 (66.67%)
occurrences all number	188	41
Abdominal pain upper
subjects affected / exposed	17 / 82 (20.73%)	2 / 24 (8.33%)
occurrences all number	33	2
Anal fissure
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	5	0
Anal inflammation
subjects affected / exposed	4 / 82 (4.88%)	3 / 24 (12.50%)
occurrences all number	4	4
Ascites
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	7	0
Colitis
subjects affected / exposed	11 / 82 (13.41%)	2 / 24 (8.33%)
occurrences all number	15	2
Constipation
subjects affected / exposed	46 / 82 (56.10%)	12 / 24 (50.00%)
occurrences all number	105	24
Diarrhoea
subjects affected / exposed	62 / 82 (75.61%)	13 / 24 (54.17%)
occurrences all number	187	48
Dyspepsia
subjects affected / exposed	6 / 82 (7.32%)	1 / 24 (4.17%)
occurrences all number	9	1
Dyschezia
subjects affected / exposed	0 / 82 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	2
Enteritis
subjects affected / exposed	0 / 82 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	2
Haematochezia
subjects affected / exposed	12 / 82 (14.63%)	2 / 24 (8.33%)
occurrences all number	24	2
Mouth ulceration
subjects affected / exposed	5 / 82 (6.10%)	3 / 24 (12.50%)
occurrences all number	7	3
Nausea
subjects affected / exposed	69 / 82 (84.15%)	12 / 24 (50.00%)
occurrences all number	267	50
Oral pain
subjects affected / exposed	24 / 82 (29.27%)	3 / 24 (12.50%)
occurrences all number	35	5
Proctalgia
subjects affected / exposed	13 / 82 (15.85%)	2 / 24 (8.33%)
occurrences all number	18	3
Proctitis
subjects affected / exposed	3 / 82 (3.66%)	2 / 24 (8.33%)
occurrences all number	3	2
Rectal haemorrhage
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	7	0
Stomatitis
subjects affected / exposed	41 / 82 (50.00%)	8 / 24 (33.33%)
occurrences all number	86	13
Toothache
subjects affected / exposed	8 / 82 (9.76%)	1 / 24 (4.17%)
occurrences all number	11	1
Vomiting
subjects affected / exposed	66 / 82 (80.49%)	17 / 24 (70.83%)
occurrences all number	341	79
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	12	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	19 / 82 (23.17%)	2 / 24 (8.33%)
occurrences all number	20	3
Dermatitis diaper
subjects affected / exposed	1 / 82 (1.22%)	4 / 24 (16.67%)
occurrences all number	1	5
Dermatitis acneiform
subjects affected / exposed	9 / 82 (10.98%)	0 / 24 (0.00%)
occurrences all number	14	0
Dry skin
subjects affected / exposed	16 / 82 (19.51%)	3 / 24 (12.50%)
occurrences all number	23	3
Eczema
subjects affected / exposed	2 / 82 (2.44%)	2 / 24 (8.33%)
occurrences all number	2	2
Ecchymosis
subjects affected / exposed	4 / 82 (4.88%)	3 / 24 (12.50%)
occurrences all number	6	7
Erythema
subjects affected / exposed	18 / 82 (21.95%)	4 / 24 (16.67%)
occurrences all number	26	5
Hyperhidrosis
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	5	0
Ingrowing nail
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	5	0
Pain of skin
subjects affected / exposed	5 / 82 (6.10%)	1 / 24 (4.17%)
occurrences all number	5	1
Petechiae
subjects affected / exposed	14 / 82 (17.07%)	3 / 24 (12.50%)
occurrences all number	24	3
Pruritus
subjects affected / exposed	21 / 82 (25.61%)	6 / 24 (25.00%)
occurrences all number	28	11
Rash
subjects affected / exposed	37 / 82 (45.12%)	11 / 24 (45.83%)
occurrences all number	84	28
Rash papular
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences all number	6	2
Rash maculo-papular
subjects affected / exposed	16 / 82 (19.51%)	5 / 24 (20.83%)
occurrences all number	27	11
Swelling face
subjects affected / exposed	8 / 82 (9.76%)	1 / 24 (4.17%)
occurrences all number	8	1
Urticaria
subjects affected / exposed	7 / 82 (8.54%)	2 / 24 (8.33%)
occurrences all number	9	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	8 / 82 (9.76%)	4 / 24 (16.67%)
occurrences all number	10	6
Urinary retention
subjects affected / exposed	5 / 82 (6.10%)	1 / 24 (4.17%)
occurrences all number	8	1
Haematuria
subjects affected / exposed	11 / 82 (13.41%)	2 / 24 (8.33%)
occurrences all number	14	2
Urinary tract pain
subjects affected / exposed	1 / 82 (1.22%)	2 / 24 (8.33%)
occurrences all number	1	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	33 / 82 (40.24%)	5 / 24 (20.83%)
occurrences all number	73	18
Back pain
subjects affected / exposed	40 / 82 (48.78%)	8 / 24 (33.33%)
occurrences all number	97	18
Bone pain
subjects affected / exposed	18 / 82 (21.95%)	4 / 24 (16.67%)
occurrences all number	35	5
Muscle spasms
subjects affected / exposed	3 / 82 (3.66%)	2 / 24 (8.33%)
occurrences all number	3	2
Muscular weakness
subjects affected / exposed	14 / 82 (17.07%)	7 / 24 (29.17%)
occurrences all number	18	10
Musculoskeletal chest pain
subjects affected / exposed	8 / 82 (9.76%)	0 / 24 (0.00%)
occurrences all number	15	0
Musculoskeletal pain
subjects affected / exposed	13 / 82 (15.85%)	2 / 24 (8.33%)
occurrences all number	17	2
Myalgia
subjects affected / exposed	12 / 82 (14.63%)	3 / 24 (12.50%)
occurrences all number	23	6
Neck pain
subjects affected / exposed	8 / 82 (9.76%)	1 / 24 (4.17%)
occurrences all number	13	2
Osteonecrosis
subjects affected / exposed	7 / 82 (8.54%)	0 / 24 (0.00%)
occurrences all number	8	0
Pain in extremity
subjects affected / exposed	51 / 82 (62.20%)	12 / 24 (50.00%)
occurrences all number	151	25
Pain in jaw
subjects affected / exposed	17 / 82 (20.73%)	1 / 24 (4.17%)
occurrences all number	27	3
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 82 (2.44%)	2 / 24 (8.33%)
occurrences all number	3	2
Catheter site infection
subjects affected / exposed	1 / 82 (1.22%)	2 / 24 (8.33%)
occurrences all number	1	3
Candida infection
subjects affected / exposed	11 / 82 (13.41%)	0 / 24 (0.00%)
occurrences all number	18	0
Cellulitis
subjects affected / exposed	9 / 82 (10.98%)	1 / 24 (4.17%)
occurrences all number	9	1
Clostridium difficile colitis
subjects affected / exposed	9 / 82 (10.98%)	2 / 24 (8.33%)
occurrences all number	11	2
Conjunctivitis
subjects affected / exposed	12 / 82 (14.63%)	0 / 24 (0.00%)
occurrences all number	15	0
Clostridium difficile infection
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences all number	7	2
Device related infection
subjects affected / exposed	6 / 82 (7.32%)	1 / 24 (4.17%)
occurrences all number	7	1
Ear infection
subjects affected / exposed	7 / 82 (8.54%)	0 / 24 (0.00%)
occurrences all number	7	0
Enterocolitis bacterial
subjects affected / exposed	0 / 82 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	3
Enterocolitis infectious
subjects affected / exposed	9 / 82 (10.98%)	1 / 24 (4.17%)
occurrences all number	11	1
Influenza
subjects affected / exposed	7 / 82 (8.54%)	0 / 24 (0.00%)
occurrences all number	7	0
Lung infection
subjects affected / exposed	6 / 82 (7.32%)	2 / 24 (8.33%)
occurrences all number	6	2
Mucosal infection
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	5	0
Oral candidiasis
subjects affected / exposed	14 / 82 (17.07%)	0 / 24 (0.00%)
occurrences all number	22	0
Otitis media
subjects affected / exposed	10 / 82 (12.20%)	1 / 24 (4.17%)
occurrences all number	12	3
Paronychia
subjects affected / exposed	3 / 82 (3.66%)	2 / 24 (8.33%)
occurrences all number	4	3
Pharyngitis
subjects affected / exposed	9 / 82 (10.98%)	1 / 24 (4.17%)
occurrences all number	10	1
Pneumonia
subjects affected / exposed	5 / 82 (6.10%)	1 / 24 (4.17%)
occurrences all number	5	1
Rhinitis
subjects affected / exposed	11 / 82 (13.41%)	0 / 24 (0.00%)
occurrences all number	18	0
Rhinovirus infection
subjects affected / exposed	6 / 82 (7.32%)	1 / 24 (4.17%)
occurrences all number	6	1
Sepsis
subjects affected / exposed	5 / 82 (6.10%)	2 / 24 (8.33%)
occurrences all number	6	2
Skin infection
subjects affected / exposed	11 / 82 (13.41%)	1 / 24 (4.17%)
occurrences all number	13	2
Sinusitis
subjects affected / exposed	17 / 82 (20.73%)	1 / 24 (4.17%)
occurrences all number	25	1
Upper respiratory tract infection
subjects affected / exposed	29 / 82 (35.37%)	10 / 24 (41.67%)
occurrences all number	45	14
Urinary tract infection
subjects affected / exposed	12 / 82 (14.63%)	2 / 24 (8.33%)
occurrences all number	13	4
Viral upper respiratory tract infection
subjects affected / exposed	6 / 82 (7.32%)	3 / 24 (12.50%)
occurrences all number	7	4
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	12 / 82 (14.63%)	2 / 24 (8.33%)
occurrences all number	16	2
Decreased appetite
subjects affected / exposed	31 / 82 (37.80%)	9 / 24 (37.50%)
occurrences all number	65	22
Fluid overload
subjects affected / exposed	5 / 82 (6.10%)	0 / 24 (0.00%)
occurrences all number	5	0
Hyperglycaemia
subjects affected / exposed	17 / 82 (20.73%)	6 / 24 (25.00%)
occurrences all number	20	10
Hypertriglyceridaemia
subjects affected / exposed	3 / 82 (3.66%)	2 / 24 (8.33%)
occurrences all number	3	2
Hypoalbuminaemia
subjects affected / exposed	25 / 82 (30.49%)	9 / 24 (37.50%)
occurrences all number	38	10
Hypocalcaemia
subjects affected / exposed	25 / 82 (30.49%)	5 / 24 (20.83%)
occurrences all number	50	8
Hypoglycaemia
subjects affected / exposed	2 / 82 (2.44%)	2 / 24 (8.33%)
occurrences all number	3	2
Hypokalaemia
subjects affected / exposed	41 / 82 (50.00%)	9 / 24 (37.50%)
occurrences all number	118	22
Hyponatraemia
subjects affected / exposed	19 / 82 (23.17%)	4 / 24 (16.67%)
occurrences all number	26	9
Hypomagnesaemia
subjects affected / exposed	14 / 82 (17.07%)	5 / 24 (20.83%)
occurrences all number	26	10
Hypophosphataemia
subjects affected / exposed	17 / 82 (20.73%)	6 / 24 (25.00%)
occurrences all number	26	9

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Were there any global substantial amendments to the protocol? Yes

20 Sep 2011

The following amendment was developed to incorporate two key changes including: 1) Changing the statistical design of the trial to allow comparison to historical external controls. Specifically, the 3-year event free survival (EFS) of dasatinib plus chemotherapy will be compared to the 3-year EFS of chemotherapy alone from the Associazione Italiana di Ematologia Pediatrica - Berlin-Frankfurt-Muenster ALL 2000 (AIEOP BFM 2000) trial and the 3-year EFS of imatinib plus chemotherapy from the European intergroup Study on post induction treatment of Philadelphia positive Acute Lymphoblastic Leukemia (EsPhALL). This analysis will improve the ability to interpret the safety and efficacy of dasatinib added to chemotherapy among other treatment options for this pediatric leukemia. 2) Incorporating additional supportive care options for chemotherapy to accommodate the standard of care at sites in the United Kingdom (UK). Additionally, typographical errors were also corrected.

07 Dec 2012

The key purposes of this amendment are to incorporate the following key changes: 1) Introduce a new pediatric formulation of dasatinib. 2) Address lack of availability of native-asparaginase in the United States and allow use of Peg-Asparaginase upfront in such instances as well as provide more detailed instruction for dose modifications of the various asparaginase formulations. 3) Indicate that the BCR-ABL mutation status will be reported for baseline and at time of progression as a secondary objective instead of as an exploratory objective. 4) Allow Philadelphia chromosome positivity from peripheral blood to be acceptable for study entry. 5) Expand the window for screening activities to 21 days. 6) Modify the definition of high risk group and low/standard risk group in response to Induction 1A treatment. 7) Provides for clarifications, fixes inconsistencies across sections of the protocol and corrects various typographical errors.

31 Jul 2013

The key purposes of this amendment are to incorporate the following key changes: 1) Increase the number of treated subjects from 75 to at least 75 and up to 90. 2) Modify language regarding pregnancy prevention. 3) Incorporate recommendations for subject management and supportive care during High Risk (HR) Blocks 1-3. 4) Provides for clarifications, fixes inconsistencies across sections of the protocol and corrects various typographical errors.

28 Oct 2013

The key purposes of this amendment are to incorporate the following changes: 1) Add mandatory supportive care measures during the 3 High Risk Blocks 2) Provide updates to the WOCBP language to harmonize this language with the current BMS directives for WOCBP.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 3-year Event-free survival (EFS) Rate

Primary: 3-year Event-free survival (EFS) Rate

Secondary: 3-year EFS rate (K-M estimate)

Secondary: 3-year EFS rate (K-M estimate)

Secondary: Overall Survival (K-M Estimate) Rate at 3 years

Secondary: Overall Survival (K-M Estimate) Rate at 3 years

Secondary: Complete Remission Rate

Secondary: Complete Remission Rate

Secondary: Percentage of subjects with Minimal Residual Disease based on Ig/TCR method

Secondary: Percentage of subjects with Minimal Residual Disease based on Ig/TCR method

Secondary: Number of subjects with AEs or drug related death

Secondary: Number of subjects with AEs or drug related death

Secondary: Number of subjects with BCR-ABL Mutations at time of disease progression

Secondary: Number of subjects with BCR-ABL Mutations at time of disease progression

Secondary: Number of subjects with Grade 3-4 hematology laboratory abnormalities

Secondary: Number of subjects with Grade 3-4 hematology laboratory abnormalities

Secondary: Number of subjects with Grade 3-4 liver function laboratory abnormalities

Secondary: Number of subjects with Grade 3-4 liver function laboratory abnormalities

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Secondary: Number of subjects with Grade 3-4 kidney function abnormalities

Secondary: Number of subjects with Grade 3-4 serum chemistry abnormalities

Secondary: Number of subjects with Grade 3-4 serum chemistry abnormalities

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Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
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Clinical trials

Clinical Trial Results: A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 3-year Event-free survival (EFS) Rate

Primary: 3-year Event-free survival (EFS) Rate

Secondary: 3-year EFS rate (K-M estimate)

Secondary: 3-year EFS rate (K-M estimate)

Secondary: Overall Survival (K-M Estimate) Rate at 3 years

Secondary: Overall Survival (K-M Estimate) Rate at 3 years

Secondary: Complete Remission Rate

Secondary: Complete Remission Rate

Secondary: Percentage of subjects with Minimal Residual Disease based on Ig/TCR method

Secondary: Percentage of subjects with Minimal Residual Disease based on Ig/TCR method

Secondary: Number of subjects with AEs or drug related death

Secondary: Number of subjects with AEs or drug related death

Secondary: Number of subjects with BCR-ABL Mutations at time of disease progression

Secondary: Number of subjects with BCR-ABL Mutations at time of disease progression

Secondary: Number of subjects with Grade 3-4 hematology laboratory abnormalities

Secondary: Number of subjects with Grade 3-4 hematology laboratory abnormalities

Secondary: Number of subjects with Grade 3-4 liver function laboratory abnormalities

Secondary: Number of subjects with Grade 3-4 liver function laboratory abnormalities

Secondary: Number of subjects with Grade 3-4 kidney function abnormalities

Secondary: Number of subjects with Grade 3-4 kidney function abnormalities

Secondary: Number of subjects with Grade 3-4 serum chemistry abnormalities

Secondary: Number of subjects with Grade 3-4 serum chemistry abnormalities

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia