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Clinical Trial Results:
SAPROCAN: Saracatinib (AZD0530) and docetaxel in metastatic, castrate-refractory prostate cancer: a phase I/randomised phase II study by the UK NCRI Prostate Clinical Studies Group

Summary
EudraCT number	2010-021447-41
Trial protocol	GB
Global end of trial date	31 Dec 2017

Results information
Results version number	v2(current)
This version publication date	06 Apr 2022
First version publication date	21 Aug 2020
Other versions	v1
Version creation reason	Correction of full data set Following publication of the final approved results on to the EudraCT database, whilst drafting a manuscript for a peer-reviewed journal, an issue was identified with one patient’s death data and the corresponding derived values for the survival endpoints. The necessary corrections were made and the analyses were re-run. The conclusions of the study remained the same. This update is a correction.

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

SAPROCAN2011

ISRCTN number

ISRCTN22566729

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

NHS Greater Glasgow and Clyde

Sponsor organisation address

Ward 11, Dykebar Hospital, Paisley, United Kingdom, PA2 7DE

Public contact

Carol Evans, Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, 0141 301 7189, carol.evans@glasgow.ac.uk

Scientific contact

Carol Evans, Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, 0141 301 7189, carol.evans@glasgow.ac.uk

Sponsor organisation name

University of Glasgow

Sponsor organisation address

Room 327 Wolfson Medical School Building, Glasgow, United Kingdom, G12 8QQ

Public contact

Carol Evans, Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, 0141 301 7189, carol.evans@glasgow.ac.uk

Scientific contact

Carol Evans, Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, 0141 301 7189, carol.evans@glasgow.ac.uk

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

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Dec 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

For the first part of the study (phase I), the primary objective is to find a safe and tolerable dose for saracatinib (AZD0530) given in combination with standard chemotherapy treatment (docetaxel and prednisolone) for patients with metastic castrate-refractory prostate cancer. For the second part of the study (phase II), the primary objective is to investigate whether we can improve the benefits of chemotherapy cancer treatment for patients with metastic castrate-refractory prostate cancer by adding a new drug, saracatinib (AZD0530).

Protection of trial subjects

Patients were required to attend for visits and investigations that were considered additional to standard of care. The number and type of visits and assessments were fully explained verbally and in a Patient Information Sheet which patients were given time to read and discuss with family and the research team prior to consent. All staff involved in delivering the study were fully GCP trained. In the dose escalation phase (Phase I), patients were reviewed weekly for Dose Limiting Toxicities, and a Safety Review Committee met at the completion of each dose cohort to review the patient details and confirm the escalation to the next dose level where appropriate. For the Phase II component of the study, patients were made aware that half of the participants would receive study drug and half would receive a placebo, but that the treatment assigned would be unknown to the patient and the study team unless emergency unblinding was required.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Mar 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 152

Worldwide total number of subjects

152

EEA total number of subjects

152

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

116

85 years and over

Subject disposition

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Recruitment details

Phase I opened to recruitment in March 2012. 10 patients were recruited into 3 cohorts; 9 were evaluable. Phase II opened to recruitment in October 2013 and was closed to recruitment in March 2016; 142 patients were randomised.

Screening details

Following consent, all patients underwent screening to determine eligibility, including confirmation of disease progression, physical exam, blood tests (including testosterone), review of prior treatment (prior cytotoxic chemotherapy excluded, washout of >30 days for other IMP required)

Period 1 title

Phase I & Phase II

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase I Cohort 1

Arm description

Saracatinib (AZD0530) 50mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression), Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on Day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days.

Arm type

Experimental

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Saracatinib (AZD0530) 50mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression). After cycle 1, dispensed in 21 day cycles.

Phase I Cohort 2

Arm description

Saracatinib (AZD0530) 125mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression), Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on Day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days

Arm type

Experimental

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Saracatinib (AZD0530) 125mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression). After cycle 1, dispensed in 21 day cycles.

Phase I Cohort 3

Arm description

Saracatinib (AZD0530) 175mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression), Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days

Arm type

Experimental

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Saracatinib (AZD0530) 175mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression). After cycle 1, dispensed in 21 day cycles.

Phase II Active

Arm description

Saracatinib (AZD0530) 175mg orally once daily continuously, starting 7 days prior to 1st cycle of docetaxel i.e. Day -7 and continuing until disease progression, Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on Day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days after 7 day run-in period with Saracatinib.

Arm type

Active comparator

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Saracatinib (AZD0530) 175mg orally once daily continuously, starting 7 days prior to 1st cycle of docetaxel i.e. Day -7 and continuing until disease progression. Each cycle is 21 days after 7 day run-in period with Saracatinib.

Phase II Placebo

Arm description

Placebo orally once daily continuously, starting 7 days prior to 1st cycle of docetaxel i.e. Day -7 and continuing until disease progression, Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on Day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days after 7 day run-in period with placebo.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo orally once daily continuously, starting 7 days prior to 1st cycle of docetaxel i.e. Day -7 and continuing until disease progression. Each cycle is 21 days after 7 day run-in period with placebo.

Number of subjects in period 1	Phase I Cohort 1	Phase I Cohort 2	Phase I Cohort 3	Phase II Active	Phase II Placebo
Started	3	3	4	71	71
Completed	3	3	4	71	71

Period 2 title

Phase I

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase I Cohort 1

Arm description

Saracatinib (AZD0530) 50mg orally once daily continuously, starting on Day 11 of 1st cycle of docetaxel (continuing until disease progression), Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on Day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days .

Arm type

Experimental

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Saracatinib (AZD0530) 50mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression). After cycle 1, dispensed in 21 day cycles.

Phase I Cohort 2

Arm description

Saracatinib (AZD0530) 125mg orally once daily continuously, starting on Day 11 of 1st cycle of docetaxel (continuing until disease progression), Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on Day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days .

Arm type

Experimental

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Saracatinib (AZD0530) 125mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression). After cycle 1, dispensed in 21 day cycles.

Phase I Cohort 3

Arm description

Saracatinib (AZD0530) 175mg orally once daily continuously, starting on Day 11 of 1st cycle of docetaxel (continuing until disease progression), Docetaxel 75mg/m2 intravenously on Day 1 every 3 weeks (up to a maximum of 10 cycles), Prednisolone 5mg orally twice daily continuously starting on Day 1 of 1st cycle of docetaxel (continuing for 21 days after last dose of docetaxel or beyond at Investigator's discretion). Both docetaxel and prednisolone are regarded as nIMPs within the study. Each cycle is 21 days .

Arm type

Experimental

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Saracatinib (AZD0530) 175mg orally once daily continuously, starting on day 11 of 1st cycle of docetaxel (continuing until disease progression). After cycle 1, dispensed in 21 day cycles.

Phase II Patients

Arm description

Only required to overrule system error that requires the same number or fewer patients in a subsequent period: no summaries or analysis will be provided

Arm type

Required only for issue with system

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Phase I Cohort 1	Phase I Cohort 2	Phase I Cohort 3	Phase II Patients
Started	3	3	4	142
Completed	3	3	3	142
Not completed	0	0	1	0
Unevaluable (insufficient treatment taken)	-	-	1	-

Period 3 title

Phase II

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Blinding implementation details

Placebo-controlled. Packaging, labelling and preparation of the trial drug and placebo were performed in a way that ensured blinding throughout this part of the trial.

Are arms mutually exclusive

Yes

Phase II Active

Arm description

Arm type

Experimental

Investigational medicinal product name

Saracatinib

Investigational medicinal product code

AZD0530

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Phase II Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 3 ^[1]	Phase II Active	Phase II Placebo
Started	71	71
Completed	70	69
Not completed	1	2
Consent withdrawn by subject	1	2

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Phase I was a dose finding component and Phase II was an RCT. These were conducted separately on different populations and the numbers were not intended to be the same in this study.

Baseline characteristics

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Reporting group title

Phase I Cohort 1

Reporting group description

Reporting group title

Phase I Cohort 2

Reporting group description

Reporting group title

Phase I Cohort 3

Reporting group description

Reporting group title

Phase II Active

Reporting group description

Reporting group title

Phase II Placebo

Reporting group description

Reporting group values	Phase I Cohort 1	Phase I Cohort 2	Phase I Cohort 3	Phase II Active	Phase II Placebo	Total
Number of subjects	3	3	4	71	71	152
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	0	1	1	17	17	36
From 65-84 years	3	2	3	54	54	116
85 years and over	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	0	0	0	0	0	0
Male	3	3	4	71	71	152
Phase II stratification factor: Presence of bone metastases
Only applicable to Phase II patients
Units: Subjects
Yes	0	0	0	64	63	127
No	0	0	0	7	8	15
Not applicable	3	3	4	0	0	10
Phase II stratification factor: Presence of visceral (non-lymph node) disease
Only applicable to Phase II patients
Units: Subjects
Yes	0	0	0	15	16	31
No	0	0	0	56	55	111
Not applicable	3	3	4	0	0	10
Baseline PSA
Units: ng/mL
median (inter-quartile range (Q1-Q3))	53.00 (9.00 to 90.00)	75.00 (15.00 to 179.60)	61.00 (53.00 to 273.70)	68.45 (29.50 to 173.90)	87.80 (20.50 to 287.10)	-

Subject analysis set title

Phase I Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Phase I patients with one or more dose of study medication

Subject analysis set title

Phase I Evaluable Study Population

Subject analysis set type

Full analysis

Subject analysis set description

* Any patient who has experienced a DLT * Any patient who has received two doses of docetaxel (with no more than 14 days delay in administration of the second dose) * Any patient who has received at least 80% of scheduled doses of saracatinib within 42 days of first dose of docetaxel

Subject analysis set title

Phase II ITT Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients randomised on to the study

Subject analysis set title

Phase II Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Patients randomised on to the study with one or more dose of chemotherapy or study medication

Subject analysis sets values	Phase I Safety Population	Phase I Evaluable Study Population	Phase II ITT Population	Phase II Safety Population
Number of subjects	10	9	142	140
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	2	2	34	33
From 65-84 years	8	7	108	107
85 years and over	0	0	0	0
Age continuous
Units:
	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female	0	0	0	0
Male	10	9	142	140
Phase II stratification factor: Presence of bone metastases
Only applicable to Phase II patients
Units: Subjects
Yes
No
Not applicable
Phase II stratification factor: Presence of visceral (non-lymph node) disease
Only applicable to Phase II patients
Units: Subjects
Yes
No
Not applicable
Baseline PSA
Units: ng/mL
median (inter-quartile range (Q1-Q3))

End points

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Reporting group title

Phase I Cohort 1

Reporting group description

Reporting group title

Phase I Cohort 2

Reporting group description

Reporting group title

Phase I Cohort 3

Reporting group description

Reporting group title

Phase II Active

Reporting group description

Reporting group title

Phase II Placebo

Reporting group description

Reporting group title

Phase I Cohort 1

Reporting group description

Reporting group title

Phase I Cohort 2

Reporting group description

Reporting group title

Phase I Cohort 3

Reporting group description

Reporting group title

Phase II Patients

Reporting group description

Only required to overrule system error that requires the same number or fewer patients in a subsequent period: no summaries or analysis will be provided

Reporting group title

Phase II Active

Reporting group description

Reporting group title

Phase II Placebo

Reporting group description

Subject analysis set title

Phase I Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Phase I patients with one or more dose of study medication

Subject analysis set title

Phase I Evaluable Study Population

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Phase II ITT Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients randomised on to the study

Subject analysis set title

Phase II Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Patients randomised on to the study with one or more dose of chemotherapy or study medication

Primary: Incidence of dose-limiting toxicities

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End point title

Incidence of dose-limiting toxicities ^[1] ^[2]

End point description

Any of the following events occurring between the first administration of saracatinib and day 42 of first dose of study medication, if, in the opinion of the investigator, the event was due to the combination of saracatinib, docetaxel and prednisolone: * Greater than 14-day delay in administration of second dose of docetaxel due to drug toxicity * Grade 4 neutropenia >= 7 days duration * Grade 3 – 4 neutropenia associated with an oral temperature >=38.5C * Grade 3 – 4 neutropenia associated with bacteriologically proven sepsis * Any grade 4 thrombocytopenia * Grade 3 thrombocytopenia associated with non-traumatic bleeding (except where this can be explained by therapeutic anticoagulation * Any other clinically significant grade 3 or above toxicity except nausea or vomiting

End point type

Primary

End point timeframe

Within 42 days of the first administration of saracatinib

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: Incidence of DLTs is reported using summary statistics only; no statistical analyses were performed on these data.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Incidence of DLTs is only relevant to the Phase I component of the study.

End point values	Phase I Cohort 1	Phase I Cohort 2	Phase I Cohort 3	Phase I Evaluable Study Population
Number of subjects analysed	3	3	3	9
Units: Patients
Patients	0	0	0	0

No statistical analyses for this end point

Primary: Primary analysis: Progression-free survival

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End point title

Primary analysis: Progression-free survival

End point description

End point type

Primary

End point timeframe

The primary endpoint is PFS, defined as the time from registration onto the study to progression (radiological progression or biochemical progression as defined by the PCWG21 criteria) or death from any cause, whichever occurs first.

End point values	Phase II Active	Phase II Placebo
Number of subjects analysed	71	71
Units: Weeks
median (confidence interval 80%)	19 (18 to 25)	29 (20 to 32)

Cox regression analysis

Statistical analysis description

A Cox regression model was fitted to the PFS data incorporating terms for study arm and the stratification factors used in the minimisation algorithm (presence of bone metastases, presence of visceral disease and site, which was reparameterised into sites reporting up to and including 10 patients versus those reporting more than 10 patients).

Comparison groups

Phase II Active v Phase II Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.942 ^[3]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.323

Confidence interval

level

80%

sides

2-sided

lower limit

1.053

upper limit

1.661

Notes
[3] - One-sided

Adverse events

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Timeframe for reporting adverse events

From consent until resolution, or for at least 30 days after discontinuation of study medication, whichever comes first or until toxicity has resolved to baseline or < Grade 1, or until the toxicity is considered to be irreversible.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Phase I Cohort 1

Reporting group description

Reporting group title

Phase I Cohort 2

Reporting group description

Reporting group title

Phase I Cohort 3

Reporting group description

Reporting group title

Phase II Active

Reporting group description

Reporting group title

Phase II Placebo

Reporting group description

Serious adverse events	Phase I Cohort 1	Phase I Cohort 2	Phase I Cohort 3	Phase II Active	Phase II Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 4 (50.00%)	47 / 69 (68.12%)	38 / 71 (53.52%)
number of deaths (all causes)	0	0	0	6	4
number of deaths resulting from adverse events	0	0	0	3	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
Additional description: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Vascular disorders
HYPERTENSION
Additional description: HYPERTENSION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
THROMBOEMBOLIC EVENT
Additional description: THROMBOEMBOLIC EVENT
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 69 (5.80%)	6 / 71 (8.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 4	4 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOTENSION
Additional description: HYPOTENSION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VASCULAR DISORDERS - OTHER, SPECIFY
Additional description: VASCULAR DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
General disorders and administration site conditions
EDEMA LIMBS
Additional description: EDEMA LIMBS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 69 (1.45%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FATIGUE
Additional description: FATIGUE
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEVER
Additional description: FEVER
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	7 / 69 (10.14%)	8 / 71 (11.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	4 / 7	7 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FLU LIKE SYMPTOMS
Additional description: FLU LIKE SYMPTOMS
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
Additional description: GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFUSION SITE EXTRAVASATION
Additional description: INFUSION SITE EXTRAVASATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
MALAISE
Additional description: MALAISE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
NON-CARDIAC CHEST PAIN
Additional description: NON-CARDIAC CHEST PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
PAIN
Additional description: PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
PELVIC PAIN
Additional description: PELVIC PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
DYSPNEA
Additional description: DYSPNEA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
Additional description: PLEURAL EFFUSION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
EPISTAXIS
Additional description: EPISTAXIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
PLEURITIC PAIN
Additional description: PLEURITIC PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
PNEUMONITIS
Additional description: PNEUMONITIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
PRODUCTIVE COUGH
Additional description: PRODUCTIVE COUGH
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
Additional description: RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Psychiatric disorders
DELIRIUM
Additional description: DELIRIUM
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
INSOMNIA
Additional description: INSOMNIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Investigations
ALANINE AMINOTRANSFERASE INCREASED
Additional description: ALANINE AMINOTRANSFERASE INCREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
BLOOD BILIRUBIN INCREASED
Additional description: BLOOD BILIRUBIN INCREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
LYMPHOCYTE COUNT DECREASED
Additional description: LYMPHOCYTE COUNT DECREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
PLATELET COUNT DECREASED
Additional description: PLATELET COUNT DECREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
NEUTROPHIL COUNT DECREASED
Additional description: NEUTROPHIL COUNT DECREASED
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	16 / 69 (23.19%)	7 / 71 (9.86%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 2	17 / 17	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
HIP FRACTURE
Additional description: HIP FRACTURE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
Cardiac disorders
ATRIAL FIBRILLATION
Additional description: ATRIAL FIBRILLATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHEST PAIN - CARDIAC
Additional description: CHEST PAIN - CARDIAC
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
HEART FAILURE
Additional description: HEART FAILURE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
MYOCARDIAL INFARCTION
Additional description: MYOCARDIAL INFARCTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
PALPITATIONS
Additional description: PALPITATIONS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
SINUS TACHYCARDIA
Additional description: SINUS TACHYCARDIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
ATAXIA
Additional description: ATAXIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
DEPRESSED LEVEL OF CONSCIOUSNESS
Additional description: DEPRESSED LEVEL OF CONSCIOUSNESS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
HEADACHE
Additional description: HEADACHE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
Additional description: NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LETHARGY
Additional description: LETHARGY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
PARESTHESIA
Additional description: PARESTHESIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
PERIPHERAL MOTOR NEUROPATHY
Additional description: PERIPHERAL MOTOR NEUROPATHY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
PERIPHERAL SENSORY NEUROPATHY
Additional description: PERIPHERAL SENSORY NEUROPATHY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
SYNCOPE
Additional description: SYNCOPE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 69 (0.00%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANEMIA
Additional description: ANEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
Additional description: FEBRILE NEUTROPENIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	10 / 69 (14.49%)	7 / 71 (9.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	10 / 11	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Gastrointestinal disorders
ABDOMINAL DISTENSION
Additional description: ABDOMINAL DISTENSION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
ABDOMINAL PAIN
Additional description: ABDOMINAL PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COLONIC PERFORATION
Additional description: COLONIC PERFORATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
CONSTIPATION
Additional description: CONSTIPATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	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
DIARRHEA
Additional description: DIARRHEA
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	10 / 69 (14.49%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	13 / 13	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC ULCER
Additional description: GASTRIC ULCER
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
ILEAL OBSTRUCTION
Additional description: ILEAL OBSTRUCTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
NAUSEA
Additional description: NAUSEA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	3 / 69 (4.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANCREATITIS
Additional description: PANCREATITIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
RECTAL HEMORRHAGE
Additional description: RECTAL HEMORRHAGE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
VOMITING
Additional description: VOMITING
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 69 (5.80%)	5 / 71 (7.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	5 / 6	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
SKIN ULCERATION
Additional description: SKIN ULCERATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
ACUTE KIDNEY INJURY
Additional description: ACUTE KIDNEY INJURY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	6 / 69 (8.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	5 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
HEMATURIA
Additional description: HEMATURIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL AND URINARY DISORDERS - OTHER, SPECIFY
Additional description: RENAL AND URINARY DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
URINARY INCONTINENCE
Additional description: URINARY INCONTINENCE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
ARTHRALGIA
Additional description: ARTHRALGIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
AVASCULAR NECROSIS
Additional description: AVASCULAR NECROSIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
BACK PAIN
Additional description: BACK PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHEST WALL PAIN
Additional description: CHEST WALL PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
Additional description: MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	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
MYALGIA
Additional description: MYALGIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
BRONCHIAL INFECTION
Additional description: BRONCHIAL INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
Additional description: INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	5 / 69 (7.25%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 5	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
JOINT INFECTION
Additional description: JOINT INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
LUNG INFECTION
Additional description: LUNG INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	8 / 69 (11.59%)	4 / 71 (5.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	7 / 8	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
SEPSIS
Additional description: SEPSIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	4 / 69 (5.80%)	5 / 71 (7.04%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	4 / 4	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2
UPPER RESPIRATORY INFECTION
Additional description: UPPER RESPIRATORY INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SKIN INFECTION
Additional description: SKIN INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
Additional description: URINARY TRACT INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
WOUND INFECTION
Additional description: WOUND INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
ACIDOSIS
Additional description: ACIDOSIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
ANOREXIA
Additional description: ANOREXIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEHYDRATION
Additional description: DEHYDRATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERGLYCEMIA
Additional description: HYPERGLYCEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
HYPOCALCEMIA
Additional description: HYPOCALCEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
HYPERKALEMIA
Additional description: HYPERKALEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
HYPOGLYCEMIA
Additional description: HYPOGLYCEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	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
METABOLISM AND NUTRITION DISORDERS - OTHER, SPECIFY
Additional description: METABOLISM AND NUTRITION DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase I Cohort 1	Phase I Cohort 2	Phase I Cohort 3	Phase II Active	Phase II Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	61 / 69 (88.41%)	68 / 71 (95.77%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
Additional description: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
Vascular disorders
HOT FLASHES
Additional description: HOT FLASHES
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	2 / 71 (2.82%)
occurrences all number	0	0	0	8	3
HYPERTENSION
Additional description: HYPERTENSION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 69 (5.80%)	4 / 71 (5.63%)
occurrences all number	0	0	0	10	16
HYPOTENSION
Additional description: HYPOTENSION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
PHLEBITIS
Additional description: PHLEBITIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	3	0	0	0
LYMPHEDEMA
Additional description: LYMPHEDEMA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
THROMBOEMBOLIC EVENT
Additional description: THROMBOEMBOLIC EVENT
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	1 / 71 (1.41%)
occurrences all number	0	0	0	3	1
General disorders and administration site conditions
EDEMA FACE
Additional description: EDEMA FACE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
CHILLS
Additional description: CHILLS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	1	1	0
EDEMA LIMBS
Additional description: EDEMA LIMBS
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	2 / 71 (2.82%)
occurrences all number	2	0	0	8	4
FATIGUE
Additional description: FATIGUE
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 3 (100.00%)	2 / 3 (66.67%)	4 / 4 (100.00%)	49 / 69 (71.01%)	54 / 71 (76.06%)
occurrences all number	12	6	17	238	292
FEVER
Additional description: FEVER
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	6 / 69 (8.70%)	4 / 71 (5.63%)
occurrences all number	0	0	1	7	4
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
Additional description: GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	3 / 4 (75.00%)	28 / 69 (40.58%)	26 / 71 (36.62%)
occurrences all number	2	1	6	77	65
FLU LIKE SYMPTOMS
Additional description: FLU LIKE SYMPTOMS
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	1	0	0	1	0
MALAISE
Additional description: MALAISE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
NON-CARDIAC CHEST PAIN
Additional description: NON-CARDIAC CHEST PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences all number	0	0	0	2	1
PAIN
Additional description: PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	5 / 69 (7.25%)	8 / 71 (11.27%)
occurrences all number	0	0	2	17	15
Immune system disorders
ALLERGIC REACTION
Additional description: ALLERGIC REACTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences all number	0	0	0	2	0
Reproductive system and breast disorders
PELVIC PAIN
Additional description: PELVIC PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
COUGH
Additional description: COUGH
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	10 / 69 (14.49%)	4 / 71 (5.63%)
occurrences all number	3	0	0	23	12
DYSPNEA
Additional description: DYSPNEA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	11 / 69 (15.94%)	6 / 71 (8.45%)
occurrences all number	0	0	0	28	13
EPISTAXIS
Additional description: EPISTAXIS
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	6 / 69 (8.70%)	3 / 71 (4.23%)
occurrences all number	1	0	0	14	9
PNEUMONITIS
Additional description: PNEUMONITIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences all number	0	0	0	4	0
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
Additional description: RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	8 / 69 (11.59%)	7 / 71 (9.86%)
occurrences all number	0	0	0	24	17
SINUS DISORDER
Additional description: SINUS DISORDER
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0	0
SORE THROAT
Additional description: SORE THROAT
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 69 (5.80%)	3 / 71 (4.23%)
occurrences all number	0	0	0	5	5
Psychiatric disorders
ANXIETY
Additional description: ANXIETY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
INSOMNIA
Additional description: INSOMNIA
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	9 / 69 (13.04%)	3 / 71 (4.23%)
occurrences all number	2	0	0	25	16
DEPRESSION
Additional description: DEPRESSION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1	1
PSYCHIATRIC DISORDERS - OTHER, SPECIFY
Additional description: PSYCHIATRIC DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	4
PERSONALITY CHANGE
Additional description: PERSONALITY CHANGE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED
Additional description: ALANINE AMINOTRANSFERASE INCREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences all number	0	0	0	3	1
ALKALINE PHOSPHATASE INCREASED
Additional description: ALKALINE PHOSPHATASE INCREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
ASPARTATE AMINOTRANSFERASE INCREASED
Additional description: ASPARTATE AMINOTRANSFERASE INCREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences all number	0	0	0	3	0
WEIGHT GAIN
Additional description: WEIGHT GAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	2
NEUTROPHIL COUNT DECREASED
Additional description: NEUTROPHIL COUNT DECREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	6 / 69 (8.70%)	2 / 71 (2.82%)
occurrences all number	0	0	0	8	2
WHITE BLOOD CELL DECREASED
Additional description: WHITE BLOOD CELL DECREASED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	0	1	0	0
WEIGHT LOSS
Additional description: WEIGHT LOSS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	2 / 71 (2.82%)
occurrences all number	0	0	0	3	2
Injury, poisoning and procedural complications
BRUISING
Additional description: BRUISING
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	5 / 69 (7.25%)	6 / 71 (8.45%)
occurrences all number	0	0	0	22	17
FALL
Additional description: FALL
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
Cardiac disorders
CARDIAC DISORDERS - OTHER, SPECIFY
Additional description: CARDIAC DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
CHEST PAIN - CARDIAC
Additional description: CHEST PAIN - CARDIAC
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences all number	0	0	0	2	0
Nervous system disorders
COGNITIVE DISTURBANCE
Additional description: COGNITIVE DISTURBANCE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
CONCENTRATION IMPAIRMENT
Additional description: CONCENTRATION IMPAIRMENT
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	2	1
DIZZINESS
Additional description: DIZZINESS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	5 / 69 (7.25%)	5 / 71 (7.04%)
occurrences all number	0	1	0	11	10
HEADACHE
Additional description: HEADACHE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	5 / 69 (7.25%)	4 / 71 (5.63%)
occurrences all number	0	0	0	6	7
DYSGEUSIA
Additional description: DYSGEUSIA
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	27 / 69 (39.13%)	23 / 71 (32.39%)
occurrences all number	3	2	1	94	78
LETHARGY
Additional description: LETHARGY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	4 / 69 (5.80%)	2 / 71 (2.82%)
occurrences all number	0	0	2	4	2
MEMORY IMPAIRMENT
Additional description: MEMORY IMPAIRMENT
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	3
NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
Additional description: NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	1	0	0	1	1
PARESTHESIA
Additional description: PARESTHESIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	3 / 71 (4.23%)
occurrences all number	0	0	0	2	4
PERIPHERAL MOTOR NEUROPATHY
Additional description: PERIPHERAL MOTOR NEUROPATHY
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	6 / 69 (8.70%)	10 / 71 (14.08%)
occurrences all number	1	0	1	9	13
PERIPHERAL SENSORY NEUROPATHY
Additional description: PERIPHERAL SENSORY NEUROPATHY
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 4 (25.00%)	23 / 69 (33.33%)	29 / 71 (40.85%)
occurrences all number	7	2	3	80	147
Blood and lymphatic system disorders
ANEMIA
Additional description: ANEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	6 / 69 (8.70%)	4 / 71 (5.63%)
occurrences all number	0	0	0	14	16
BLOOD AND LYMPHATIC SYSTEM DISORDERS - OTHER, SPECIFY
Additional description: BLOOD AND LYMPHATIC SYSTEM DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 69 (2.90%)	3 / 71 (4.23%)
occurrences all number	0	1	0	2	12
FEBRILE NEUTROPENIA
Additional description: FEBRILE NEUTROPENIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
LEUKOCYTOSIS
Additional description: LEUKOCYTOSIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
THROMBOTIC THROMBOCYTOPENIC PURPURA
Additional description: THROMBOTIC THROMBOCYTOPENIC PURPURA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
Ear and labyrinth disorders
HEARING IMPAIRED
Additional description: HEARING IMPAIRED
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
TINNITUS
Additional description: TINNITUS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
VESTIBULAR DISORDER
Additional description: VESTIBULAR DISORDER
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
Eye disorders
BLURRED VISION
Additional description: BLURRED VISION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	5	2
CONJUNCTIVITIS
Additional description: CONJUNCTIVITIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences all number	0	0	0	0	2
DRY EYE
Additional description: DRY EYE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	3 / 71 (4.23%)
occurrences all number	0	0	0	2	10
EXTRAOCULAR MUSCLE PARESIS
Additional description: EXTRAOCULAR MUSCLE PARESIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
EYE DISORDERS - OTHER, SPECIFY
Additional description: EYE DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences all number	0	0	0	0	4
EYE PAIN
Additional description: EYE PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences all number	0	0	0	5	0
WATERING EYES
Additional description: WATERING EYES
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	5 / 71 (7.04%)
occurrences all number	0	0	0	9	23
Gastrointestinal disorders
ABDOMINAL PAIN
Additional description: ABDOMINAL PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences all number	0	0	1	3	1
BLOATING
Additional description: BLOATING
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	5
CHEILITIS
Additional description: CHEILITIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	3
CONSTIPATION
Additional description: CONSTIPATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	11 / 69 (15.94%)	5 / 71 (7.04%)
occurrences all number	0	0	2	27	11
DIARRHEA
Additional description: DIARRHEA
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 4 (100.00%)	35 / 69 (50.72%)	36 / 71 (50.70%)
occurrences all number	1	1	12	104	87
DYSPEPSIA
Additional description: DYSPEPSIA
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	6 / 69 (8.70%)	11 / 71 (15.49%)
occurrences all number	2	2	0	10	29
DRY MOUTH
Additional description: DRY MOUTH
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	5 / 69 (7.25%)	2 / 71 (2.82%)
occurrences all number	0	0	1	21	9
FLATULENCE
Additional description: FLATULENCE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences all number	0	0	0	2	0
FECAL INCONTINENCE
Additional description: FECAL INCONTINENCE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
GASTRITIS
Additional description: GASTRITIS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
GASTROESOPHAGEAL REFLUX DISEASE
Additional description: GASTROESOPHAGEAL REFLUX DISEASE
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences all number	2	0	0	0	0
GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
Additional description: GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	4 / 69 (5.80%)	4 / 71 (5.63%)
occurrences all number	0	0	1	4	13
MUCOSITIS ORAL
Additional description: MUCOSITIS ORAL
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 3 (100.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	8 / 69 (11.59%)	11 / 71 (15.49%)
occurrences all number	7	0	1	22	25
NAUSEA
Additional description: NAUSEA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	23 / 69 (33.33%)	26 / 71 (36.62%)
occurrences all number	0	2	7	47	71
ORAL PAIN
Additional description: ORAL PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	7 / 71 (9.86%)
occurrences all number	0	0	0	3	21
ORAL HEMORRHAGE
Additional description: ORAL HEMORRHAGE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
SALIVARY DUCT INFLAMMATION
Additional description: SALIVARY DUCT INFLAMMATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0	0
RECTAL HEMORRHAGE
Additional description: RECTAL HEMORRHAGE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	5 / 69 (7.25%)	2 / 71 (2.82%)
occurrences all number	0	0	0	8	2
VOMITING
Additional description: VOMITING
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	8 / 69 (11.59%)	13 / 71 (18.31%)
occurrences all number	0	0	2	15	16
STOMACH PAIN
Additional description: STOMACH PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	2	0
Hepatobiliary disorders
HEPATOBILIARY DISORDERS - OTHER, SPECIFY
Additional description: HEPATOBILIARY DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	4	0
Skin and subcutaneous tissue disorders
ALOPECIA
Additional description: ALOPECIA
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 3 (100.00%)	1 / 3 (33.33%)	3 / 4 (75.00%)	24 / 69 (34.78%)	31 / 71 (43.66%)
occurrences all number	9	5	15	118	155
DRY SKIN
Additional description: DRY SKIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	3 / 69 (4.35%)	3 / 71 (4.23%)
occurrences all number	0	0	3	3	19
ERYTHEMA MULTIFORME
Additional description: ERYTHEMA MULTIFORME
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences all number	0	0	0	0	2
NAIL DISCOLORATION
Additional description: NAIL DISCOLORATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	8 / 69 (11.59%)	6 / 71 (8.45%)
occurrences all number	0	1	0	18	24
NAIL LOSS
Additional description: NAIL LOSS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	2 / 71 (2.82%)
occurrences all number	0	0	0	1	3
NAIL RIDGING
Additional description: NAIL RIDGING
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	9 / 71 (12.68%)
occurrences all number	0	0	0	5	43
PRURITUS
Additional description: PRURITUS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	2	0
PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
Additional description: PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	0 / 71 (0.00%)
occurrences all number	0	0	0	6	0
RASH MACULO-PAPULAR
Additional description: RASH MACULO-PAPULAR
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	6 / 69 (8.70%)	6 / 71 (8.45%)
occurrences all number	0	0	1	14	8
RASH ACNEIFORM
Additional description: RASH ACNEIFORM
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences all number	1	0	0	0	4
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
Additional description: SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	4 / 69 (5.80%)	6 / 71 (8.45%)
occurrences all number	0	0	4	7	7
Renal and urinary disorders
URINARY FREQUENCY
Additional description: URINARY FREQUENCY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1	1
HEMATURIA
Additional description: HEMATURIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
URINE DISCOLORATION
Additional description: URINE DISCOLORATION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	3	0
Endocrine disorders
CUSHINGOID
Additional description: CUSHINGOID
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
Additional description: ARTHRALGIA
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	2	0	0	1	1
BONE PAIN
Additional description: BONE PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
BACK PAIN
Additional description: BACK PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	2 / 71 (2.82%)
occurrences all number	2	0	0	1	3
GENERALIZED MUSCLE WEAKNESS
Additional description: GENERALIZED MUSCLE WEAKNESS
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	1 / 71 (1.41%)
occurrences all number	0	0	0	3	1
CHEST WALL PAIN
Additional description: CHEST WALL PAIN
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	2 / 71 (2.82%)
occurrences all number	0	0	0	2	2
MUSCLE WEAKNESS LOWER LIMB
Additional description: MUSCLE WEAKNESS LOWER LIMB
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)
occurrences all number	0	0	0	4	2
MUSCLE WEAKNESS UPPER LIMB
Additional description: MUSCLE WEAKNESS UPPER LIMB
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
MYALGIA
Additional description: MYALGIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	9 / 69 (13.04%)	10 / 71 (14.08%)
occurrences all number	0	0	0	12	27
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
Additional description: MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	4 / 71 (5.63%)
occurrences all number	0	0	0	2	12
PAIN IN EXTREMITY
Additional description: PAIN IN EXTREMITY
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)
occurrences all number	3	0	0	2	0
Infections and infestations
INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
Additional description: INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 4 (50.00%)	8 / 69 (11.59%)	8 / 71 (11.27%)
occurrences all number	2	0	3	9	10
MUCOSAL INFECTION
Additional description: MUCOSAL INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
NAIL INFECTION
Additional description: NAIL INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	6 / 71 (8.45%)
occurrences all number	0	0	0	0	7
PARONYCHIA
Additional description: PARONYCHIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)
occurrences all number	0	0	0	0	2
SKIN INFECTION
Additional description: SKIN INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
RHINITIS INFECTIVE
Additional description: RHINITIS INFECTIVE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1	1
TOOTH INFECTION
Additional description: TOOTH INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
UPPER RESPIRATORY INFECTION
Additional description: UPPER RESPIRATORY INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
URINARY TRACT INFECTION
Additional description: URINARY TRACT INFECTION
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
Metabolism and nutrition disorders
ANOREXIA
Additional description: ANOREXIA
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	2 / 4 (50.00%)	20 / 69 (28.99%)	17 / 71 (23.94%)
occurrences all number	3	1	3	35	43
GLUCOSE INTOLERANCE
Additional description: GLUCOSE INTOLERANCE
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1	2
HYPERCALCEMIA
Additional description: HYPERCALCEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
HYPERGLYCEMIA
Additional description: HYPERGLYCEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	3	0
HYPOCALCEMIA
Additional description: HYPOCALCEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)
occurrences all number	0	0	0	1	1
HYPOPHOSPHATEMIA
Additional description: HYPOPHOSPHATEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 69 (4.35%)	0 / 71 (0.00%)
occurrences all number	0	0	0	4	0
HYPOKALEMIA
Additional description: HYPOKALEMIA
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)
occurrences all number	0	0	0	1	0
METABOLISM AND NUTRITION DISORDERS - OTHER, SPECIFY
Additional description: METABOLISM AND NUTRITION DISORDERS - OTHER, SPECIFY
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	0	0	0	1
LOCALISED OEDEMA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 69 (2.90%)	8 / 71 (11.27%)
occurrences all number	0	0	0	5	36

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Were there any global substantial amendments to the protocol? Yes

19 Aug 2014

As per the original study protocol, patients that are un-blinded should discontinue study treatment - this has been clarified in the amended protocol. Update on the information provided for emergency un-blinding of patients to highlight that sites will need log in details for the IVRS system. Information added on wash out periods for Abiraterone and Bicalutamide. Dose Reduction section made clearer at request of sites Updated PV section for clarity and to give further guidance on pregnancy of patients partners.

28 Jul 2017

Visit schedule during maintenance therapy updated to allow 6-weekly visits. Clarification of AE reporting requirements during follow-up. PV section updated in line with current CRUK CTU Glasgow template. Recruitment period changed to 30 months from 18 months to reflect actual time.

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:
SAPROCAN: Saracatinib (AZD0530) and docetaxel in metastatic, castrate-refractory prostate cancer: a phase I/randomised phase II study by the UK NCRI Prostate Clinical Studies Group

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of dose-limiting toxicities

Primary: Incidence of dose-limiting toxicities

Primary: Primary analysis: Progression-free survival

Primary: Primary analysis: Progression-free survival

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: SAPROCAN: Saracatinib (AZD0530) and docetaxel in metastatic, castrate-refractory prostate cancer: a phase I/randomised phase II study by the UK NCRI Prostate Clinical Studies Group

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of dose-limiting toxicities

Primary: Incidence of dose-limiting toxicities

Primary: Primary analysis: Progression-free survival

Primary: Primary analysis: Progression-free survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
SAPROCAN: Saracatinib (AZD0530) and docetaxel in metastatic, castrate-refractory prostate cancer: a phase I/randomised phase II study by the UK NCRI Prostate Clinical Studies Group