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Clinical Trial Results:
Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic non small cell lung cancer.

Summary
EudraCT number	2013-001653-27
Trial protocol	FR
Global end of trial date	31 Dec 2023

Results information
Results version number	v1(current)
This version publication date	12 Jun 2025
First version publication date	12 Jun 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

UC_0105-1305_/_IFCT_1301

ISRCTN number

US NCT number

NCT02117167

WHO universal trial number (UTN)

Sponsor organisation name

UNICANCER

Sponsor organisation address

101 rue de Tolbiac, Paris, France, 75015

Public contact

Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr

Scientific contact

Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr

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

12 Oct 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Oct 2020

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2023

Was the trial ended prematurely?

Main objective of the trial

Safir 02 Lung was an open-label multicentric randomized phase II trial, using high throughput genome analysis as a therapeutic decision tool, aimed at comparing a targeted treatment administered according to identified molecular anomalies of the tumor with a standard maintenance as per guidelines (targeted substudy 1: Arm A1 and B1) as well as immunotherapy versus maintenance therapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2: Arm A2 and B2). The main objective was to evaluate whether treatment with targeted agents guided by high throughput molecular analyses (CGH array, next generation sequencing) improves overall progression-free survival as compared to standard maintenance therapy in patients with metastatic NSCLC ( (primary objective of substudy 1).

Protection of trial subjects

The clinical trial was conducted in accordance with: - the principles of ethics as stated in the last version in use of the Declaration of Helsinki, - the Good Clinical Practices (GCP) defined by the International Conference on Harmonization (ICH–E6, 17/07/96), - the European directive 2001/20/CE on the conduct of clinical trials, - Huriet’s law (n° 88-1138) of December 20th, 1988, relative to the protection of persons, participating in biomedical research and modified by the Public Health Law n°2004-806 of August 9th, 2004, - the law on ‘informatics and freedom’ (Informatique et Libertés n° 78-17) of January 6th,1978 modified by the law n° 2004-801 of August 6th, 2004 relative to the protection of persons with regard to the computerized processing of personal data, - the relevant principles of Décision du 24 novembre 2006 fixant les règles de bonnes pratiques cliniques pour les recherches biomédicales portant sur des médicaments à usage humain - Amended Law n° 2004-800 du 6 août 2004, relative to bioethics, - Regulation (EU) 2016/679 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data (General Data Protection Regulation)

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Apr 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

36 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 358

Worldwide total number of subjects

358

EEA total number of subjects

358

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)

242

From 65 to 84 years

116

85 years and over

Subject disposition

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Recruitment details

999 patients screened: 394 patients were eligible for substudy 1, among which 175 patients were randomized, N=116 patients were randomized in arm A1 and N=59 patients in arm B1. 365 patients were eligible for substudy 2, among which 183 patie

Screening details

Patients were considered as pre-eligible for randomisation in the substudy 1 when both following mandatory conditions were met : stable or responding disease was observed after 4 cycles of chemotherapy and targetable alteration was identified by the Molecular Tumor Board (MTB) Otherwise patients be oriented to the immunotherapy substudy 2

Period 1 title

Overall periode

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A1 : Planned targeted therapy

Arm description

Arm A1 / targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis. In arm A1, N=18 patients were treated with AZD2014, N=8 with AZD4547, N=9 with AZD5363, N=6 with AZD8931, N=4 with olaparib, N=1 with savotinib, N=65 with selumitinib, and N=5 with vandetanib.

Arm type

Experimental

Investigational medicinal product name

Vistusertib

Investigational medicinal product code

AZD2014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg bd, continuous dosing.

Investigational medicinal product name

AZD4547

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

80 mg bd, 2 weeks on/1 week off

Investigational medicinal product name

Capivasertib

Investigational medicinal product code

AZD5363

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

480 mg bd, 4 days on/3 days off

Investigational medicinal product name

AZD8931

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

40 mg bd, continuous dosing

Investigational medicinal product name

Olaparib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg bd continuous dosing

Investigational medicinal product name

Savolitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

600 mg od continuous dosing (400 mg od for patient with body weight less than 50 kg)

Investigational medicinal product name

Selumetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

75 mg bd, continuous dosing

Investigational medicinal product name

Vandetanib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg od, continuous dosing

Arm B1: Standard maintenance therapy

Arm description

Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In arm B1: 1 patient received erlotinib, 4 patients received Gemcitabin, and 54 patients received pemetrexed. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

Arm type

Active comparator

Investigational medicinal product name

Erlotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

25 mg, 100 mg and 150 mg erlotinib (as erlotinib hydrochloride) are used in this trial.

Investigational medicinal product name

Gemcitabin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Standard chemotherapies were prescribed as per usual practice and according to the product Summary of Product Characteristics (SmPC).

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

500 mg/m2, every 3 weeks

Arm A2: MEDI4736

Arm description

Planned immunotherapy; durvalumab

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

10 mg/kg, every 2 weeks.

Arm B2: Standard maintenance therapy

Arm description

Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In the Arm B2: 5 patients received Gemcitabin, 54 patients received Pemetrexed, 1 patient received Vinorelbine, and 2 patients did not receive treatment. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

Arm type

Active comparator

Investigational medicinal product name

Gemcitabin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Standard chemotherapies were prescribed as per usual practice and according to the product Summary of Product Characteristics (SmPC).

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

500 mg/m2, every 3 weeks

Investigational medicinal product name

Vinorelbine

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Treatment is left to the investigator’s decision as per local practice.

Number of subjects in period 1	Arm A1 : Planned targeted therapy	Arm B1: Standard maintenance therapy	Arm A2: MEDI4736	Arm B2: Standard maintenance therapy
Started	116	59	121	62
Completed	1	1	10	0
Not completed	115	58	111	62
Clinical progression	2	3	1	3
Physician decision	1	1	4	4
Consent withdrawn by subject	2	1	1	4
Adverse event, non-fatal	15	8	12	7
Death	1	1	1	3
Other	1	-	1	-
Progressive disease	90	42	84	40
Sponsor decision	3	2	1	1
Alive/End Of Protocol (Completed)	-	-	6	-

Baseline characteristics

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Reporting group title

Arm A1 : Planned targeted therapy

Reporting group description

Reporting group title

Arm B1: Standard maintenance therapy

Reporting group description

Reporting group title

Arm A2: MEDI4736

Reporting group description

Planned immunotherapy; durvalumab

Reporting group title

Arm B2: Standard maintenance therapy

Reporting group description

Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In the Arm B2: 5 patients received Gemcitabin, 54 patients received Pemetrexed, 1 patient received Vinorelbine, and 2 patients did not receive treatment. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

Reporting group values	Arm A1 : Planned targeted therapy	Arm B1: Standard maintenance therapy	Arm A2: MEDI4736	Arm B2: Standard maintenance therapy	Total
Number of subjects	116	59	121	62	358
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	88	41	78	35	242
From 65-84 years	27	18	43	27	115
85 years and over	1	0	0	0	1
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	60 (55 to 64)	59 (52 to 66)	62 (53 to 67)	62 (52 to 68)	-
Gender categorical
Units: Subjects
Female	46	25	48	21	140
Male	70	34	73	41	218
ECOG
Units: Subjects
ECOG 0	45	32	48	19	144
ECOG 1	71	27	73	43	214
Histological type
Units: Subjects
Non Small Cell Lung Cancer	116	59	119	62	356
Small Cell Lung Cancer	0	0	2	0	2
Histological subtype
Units: Subjects
Adenocarcinoma	102	51	107	55	315
Large Cell Carcinoma	0	1	5	1	7
Squamous Cell Carcinoma	14	6	8	5	33
Other	0	1	1	1	3
Metastatic disease
Units: Subjects
No	4	3	6	3	16
Yes	112	56	115	59	342
Number of metastatic sites at screening
Units: Number
arithmetic mean (standard deviation)	2.9 ( 1.3 )	3.0 ( 1.6 )	2.8 ( 1.41 )	2.6 ( 1.1 )	-
The median time between initial diagnosis and randomization
Units: Months
median (inter-quartile range (Q1-Q3))	4 (4 to 5)	4 (4 to 5)	4.3 (4 to 5)	4.6 (4 to 5)	-

End points

Top of page

Reporting group title

Arm A1 : Planned targeted therapy

Reporting group description

Reporting group title

Arm B1: Standard maintenance therapy

Reporting group description

Reporting group title

Arm A2: MEDI4736

Reporting group description

Planned immunotherapy; durvalumab

Reporting group title

Arm B2: Standard maintenance therapy

Reporting group description

Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In the Arm B2: 5 patients received Gemcitabin, 54 patients received Pemetrexed, 1 patient received Vinorelbine, and 2 patients did not receive treatment. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

Primary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

Progression-free survival in the targeted drug arm compared to standard maintenance therapy arm. PFS was defined as the time from randomization to the first documented progression of disease or death, whatever the cause. Patients still alive at the time of analysis without documented progression (including lost of follow-up) were censored at the last known alive date (primary endpoint of substudy 1).

End point type

Primary

End point timeframe

from randomization to disease progression or death from any cause, whichever comes first, up to 16 months.

End point values	Arm A1 : Planned targeted therapy	Arm B1: Standard maintenance therapy	Arm A2: MEDI4736	Arm B2: Standard maintenance therapy
Number of subjects analysed	116	59	121	62
Units: Months
number (confidence interval 95%)	2.7 (1.6 to 2.9)	2.7 (1.6 to 4.1)	3.0 (2.3 to 4.4)	3.0 (2.0 to 5.1)

PFS analysis (substudy 1)

Statistical analysis description

The Cox regression analysis was then adjusted for the factors used as stratification variables in the randomization. There was no difference between arm A1 and arm B1 according to treatment, histological subtype, disease status at randomization, smoking status, and molecular alteration category.

Comparison groups

Arm A1 : Planned targeted therapy v Arm B1: Standard maintenance therapy

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.8691

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.36

PFS analysis (substudy 2)

Statistical analysis description

The Cox regression analysis was then adjusted for the factors used as stratification variables in the randomization. The results showed a difference base on histological subtypes (squamous vs non-squamous; p=8.5e-05) but no difference was observed between arm A2 and arm B2 according to treatment, disease status at randomization, and smoking status.

Comparison groups

Arm A2: MEDI4736 v Arm B2: Standard maintenance therapy

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.379

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

1.2

Secondary: Overall survival (OS) in both arms

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End point title

Overall survival (OS) in both arms

End point description

OS in each substudy. OS was defined as the time from randomization to death due to any cause. Patients still alive at the time of analysis (including lost of follow-up) were censored at the last known alive date.

End point type

Secondary

End point timeframe

from randomization to death (any cause), up to 16 months.

End point values	Arm A1 : Planned targeted therapy	Arm B1: Standard maintenance therapy	Arm A2: MEDI4736	Arm B2: Standard maintenance therapy
Number of subjects analysed	116	59	121	62
Units: Months
median (confidence interval 95%)	14.3 (11.0 to 18.3)	14.1 (8.0 to 30.9)	17.0 (12.1 to 19.5)	14.9 (10.5 to 22.0)

OS analysis (Substudy 1)

Statistical analysis description

There was no difference in OS based on treatments, histological subtypes, smoking status, and molecular alterations. There was a difference according to disease status at randomization (p=0.0325).

Comparison groups

Arm A1 : Planned targeted therapy v Arm B1: Standard maintenance therapy

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.8719

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.55

OS analysis (Substudy 2)

Statistical analysis description

There were no overall survival differences based on treatments, disease status at randomization, and smoking status. There was a difference according to histological subtypes (squamous vs non-squamous; p=0.007).

Comparison groups

Arm A2: MEDI4736 v Arm B2: Standard maintenance therapy

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.728

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.4

Secondary: ORR

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End point title

ORR

End point description

To compare overall response rates (ORR) and changes in tumor size in each substudy.

End point type

Secondary

End point timeframe

Tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months

End point values	Arm A1 : Planned targeted therapy	Arm B1: Standard maintenance therapy	Arm A2: MEDI4736	Arm B2: Standard maintenance therapy
Number of subjects analysed	116	59	121	62
Units: percent
number (not applicable)
CR/PR	5.3	10.5	14.3	3.6
PD/SD	94.7	89.5	85.7	96.4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Toxicities will be assessed during the whole treatment period (4 months expected in average) followed by a 1-year post-treatment follow-up period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Arm A1

Reporting group description

Reporting group title

Arm B1

Reporting group description

Reporting group title

Arm A2

Reporting group description

Reporting group title

Arm B2

Reporting group description

Serious adverse events	Arm A1	Arm B1	Arm A2	Arm B2
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 175 (12.00%)	14 / 59 (23.73%)	19 / 121 (15.70%)	13 / 62 (20.97%)
number of deaths (all causes)	78	37	72	35
number of deaths resulting from adverse events	1		1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Superficial basal cell carcinoma
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Intracardiac thrombus
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischemic stroke
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial disease
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thromboembolic event
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Aplasia
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Catheter site extravasation
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fever
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flu-like symptoms
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Hyperthermia
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Sudden death, cause unknown
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
Thoracic pain
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Interstitial lung disease
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest tightness
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnea
subjects affected / exposed	4 / 175 (2.29%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hemoptysis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Interstitial lung disease
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pleural effusion
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pneumonitis
subjects affected / exposed	4 / 175 (2.29%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pneumopathy
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Investigations
Liver function test increased
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fracture of scapula
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myopericarditis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial tamponade
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Confusional state
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stroke
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia aggravated
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aplasia bone marrow
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile aplasia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	0 / 175 (0.00%)	2 / 59 (3.39%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Eye disorders
Central retinal vein occlusion
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhea
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sigmoiditis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Acute calculous cholecystitis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Toxicodermia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Macroscopic hematuria
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	0 / 175 (0.00%)	2 / 59 (3.39%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Costal pain
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Rheumatoid arthritis flare up
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemophilus pneumonia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Perineal abscess
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal pneumonia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary infection
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatremia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anorexia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Arm A1	Arm B1	Arm A2	Arm B2
Total subjects affected by non serious adverse events
subjects affected / exposed	113 / 175 (64.57%)	53 / 59 (89.83%)	112 / 121 (92.56%)	55 / 62 (88.71%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Atypical Fibroxanthoma
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	3	0
Metastases To Meninges
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Metastatic Pain
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Thyroid Neoplasm
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Vascular disorders
Capillary Fragility
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0
Deep Vein Thrombosis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Hot Flush
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	4	0	0
Hypertension
subjects affected / exposed	12 / 175 (6.86%)	2 / 59 (3.39%)	4 / 121 (3.31%)	0 / 62 (0.00%)
occurrences all number	21	3	6	0
Phlebitis
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Thrombosis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	0	1	0
Collateral Circulation
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	3	0
Embolism
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Haematoma
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Hypotension
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Intermittent Claudication
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	4	0
Lymphoedema
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	3	0
Peripheral Arterial Occlusive Disease
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Superior Vena Cava Syndrome
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Vascular Pain
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	2
Venous Insufficiency
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Surgical and medical procedures
Nutritional
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Tooth Extraction
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	1	0	2	0
Prophylaxis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	40 / 175 (22.86%)	17 / 59 (28.81%)	45 / 121 (37.19%)	33 / 62 (53.23%)
occurrences all number	126	58	191	73
Chest Pain
subjects affected / exposed	12 / 175 (6.86%)	8 / 59 (13.56%)	22 / 121 (18.18%)	9 / 62 (14.52%)
occurrences all number	25	12	61	19
Chills
subjects affected / exposed	4 / 175 (2.29%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	6	0	1	1
Crepitations
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Face Oedema
subjects affected / exposed	9 / 175 (5.14%)	2 / 59 (3.39%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	13	8	1	0
Fatigue
subjects affected / exposed	20 / 175 (11.43%)	12 / 59 (20.34%)	16 / 121 (13.22%)	15 / 62 (24.19%)
occurrences all number	43	33	57	39
Feeling Cold
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
General Physical Health deterioration
subjects affected / exposed	0 / 175 (0.00%)	2 / 59 (3.39%)	1 / 121 (0.83%)	3 / 62 (4.84%)
occurrences all number	0	2	1	3
Generalised Oedema
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Hyperthermia
subjects affected / exposed	1 / 175 (0.57%)	2 / 59 (3.39%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	1	3	1	0
Impaired Healing
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Influenza Like Illness
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	5 / 121 (4.13%)	1 / 62 (1.61%)
occurrences all number	0	1	7	1
Malaise
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Mucosal Inflammation
subjects affected / exposed	16 / 175 (9.14%)	1 / 59 (1.69%)	3 / 121 (2.48%)	1 / 62 (1.61%)
occurrences all number	21	2	3	1
Mucosal Toxicity
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Oedema
subjects affected / exposed	31 / 175 (17.71%)	12 / 59 (20.34%)	6 / 121 (4.96%)	12 / 62 (19.35%)
occurrences all number	126	26	17	22
Oedema Peripheral
subjects affected / exposed	17 / 175 (9.71%)	7 / 59 (11.86%)	4 / 121 (3.31%)	5 / 62 (8.06%)
occurrences all number	41	16	13	19
Pain
subjects affected / exposed	15 / 175 (8.57%)	6 / 59 (10.17%)	17 / 121 (14.05%)	9 / 62 (14.52%)
occurrences all number	23	32	37	10
Peripheral Swelling
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Pyrexia
subjects affected / exposed	12 / 175 (6.86%)	3 / 59 (5.08%)	14 / 121 (11.57%)	3 / 62 (4.84%)
occurrences all number	16	3	16	4
Sudden Death
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Xerosis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	0	1	0
Chest Discomfort
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Facial pain
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	2	0	0	1
Sarcoidosis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	7	0
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Erectile Dysfunction
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Balanoposthitis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Cough
subjects affected / exposed	24 / 175 (13.71%)	7 / 59 (11.86%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	40	11	0	0
Dysphonia
subjects affected / exposed	5 / 175 (2.86%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	8	0	0	0
Dyspnoea
subjects affected / exposed	32 / 175 (18.29%)	12 / 59 (20.34%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	59	19	0	0
Epistaxis
subjects affected / exposed	6 / 175 (3.43%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	7	1	0	0
Haemoptysis
subjects affected / exposed	3 / 175 (1.71%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	1	0	0
Hypoxia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Lung Disorder
subjects affected / exposed	3 / 175 (1.71%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	1	0	0
Nasal Dryness
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Pleuritic Pain
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Pneumonitis
subjects affected / exposed	5 / 175 (2.86%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	7	1	0	0
Productive Cough
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0
Pulmonary Embolism
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	1	0	0
Pulmonary Haemorrhage
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Pulmonary Pneumatocele
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Rhinitis Allergic
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	12	1	0	0
Rhinorrhoea
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	1	0	0
Wheezing
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Anxiety
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	4 / 121 (3.31%)	1 / 62 (1.61%)
occurrences all number	4	1	7	1
Confusional State
subjects affected / exposed	0 / 175 (0.00%)	2 / 59 (3.39%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Delirium
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Depression
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	2 / 121 (1.65%)	1 / 62 (1.61%)
occurrences all number	1	0	2	4
Hallucination
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Insomnia
subjects affected / exposed	6 / 175 (3.43%)	2 / 59 (3.39%)	4 / 121 (3.31%)	3 / 62 (4.84%)
occurrences all number	11	12	10	8
Irritability
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Libido Decreased
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0
Sleep Disorder
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Logorrhoea
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Nightmare
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	15	0
Investigations
Alanine Aminotransferase increased
subjects affected / exposed	5 / 175 (2.86%)	8 / 59 (13.56%)	2 / 121 (1.65%)	3 / 62 (4.84%)
occurrences all number	17	8	9	4
Aspartate Aminotransferase
subjects affected / exposed	6 / 175 (3.43%)	6 / 59 (10.17%)	4 / 121 (3.31%)	3 / 62 (4.84%)
occurrences all number	22	6	6	5
Blood Alkaline Phosphatase
subjects affected / exposed	2 / 175 (1.14%)	2 / 59 (3.39%)	0 / 121 (0.00%)	2 / 62 (3.23%)
occurrences all number	3	6	0	2
Blood Cholesterol
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Blood Creatine
subjects affected / exposed	5 / 175 (2.86%)	0 / 59 (0.00%)	3 / 121 (2.48%)	0 / 62 (0.00%)
occurrences all number	11	0	4	0
Blood Creatinine Increased
subjects affected / exposed	6 / 175 (3.43%)	2 / 59 (3.39%)	10 / 121 (8.26%)	2 / 62 (3.23%)
occurrences all number	11	3	16	9
Blood Lactate
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	2 / 121 (1.65%)	1 / 62 (1.61%)
occurrences all number	4	1	3	1
Blood Phosphorus
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	6	0	0	0
Blood Pressure Increased
subjects affected / exposed	4 / 175 (2.29%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	6	0	10	9
Blood Urea Increased
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Creatinine Renal Clearance
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	1	1	0
Electrocardiogram Qt
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Hepatic Enzyme Increased
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Intestinal Transit Time
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Lipase Increased
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	6 / 121 (4.96%)	0 / 62 (0.00%)
occurrences all number	0	1	24	0
Platelet Count Decreased
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	1	1	1	1
Platelet Count Increased
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	1	0	1
Protein Total Decreased
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Transaminases Increased
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Troponin
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Weight Decreased
subjects affected / exposed	3 / 175 (1.71%)	3 / 59 (5.08%)	5 / 121 (4.13%)	3 / 62 (4.84%)
occurrences all number	3	3	6	3
Weight Increased
subjects affected / exposed	4 / 175 (2.29%)	1 / 59 (1.69%)	5 / 121 (4.13%)	1 / 62 (1.61%)
occurrences all number	5	2	10	1
Amino Acid Level Increased
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Amylase Increased
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	10 / 121 (8.26%)	0 / 62 (0.00%)
occurrences all number	0	0	34	0
Blood Thyroid Stimulating Hormone
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	0	5	0
Breath Sounds Abnormal
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	8	0
Cardiac Murmur
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	3	0
Eosinophil Count Increased
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Gamma-Glutamyltransferase
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	6 / 121 (4.96%)	6 / 62 (9.68%)
occurrences all number	0	0	18	10
Haemoglobin Decreased
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
High Density Lipoprotein Increased
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Thyroxine Increased
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Vitamin D Decreased
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Frostbite
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Eye Burns
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Fall
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Fracture
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Ligament Sprain
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Limb Injury
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Scapula Fracture
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	4	0
Skin Injury
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Congenital, familial and genetic disorders
Aplasia
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Ichthyosis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0
Cardiac disorders
Angina Pectoris
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	2	0	1	0
Atrial Fibrillation
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Bradycardia
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Coronary Artery Disease
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Extrasystoles
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	0	1	0
Pericardial Effusion
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	2	0	3	0
Tachycardia
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	1	2	0
Atrioventricular Block First Degree
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Cardiac Arrest
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Myocardial Infarction
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Myocarditis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Nervous system disorders
Ageusia
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	4	0	0	1
Ataxia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Balance Disorder
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	3	0	0	2
Carpal Tunnel Syndrome
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	5	0	0	0
Dizziness
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	2 / 121 (1.65%)	2 / 62 (3.23%)
occurrences all number	2	1	2	2
Dysaesthesia
subjects affected / exposed	1 / 175 (0.57%)	2 / 59 (3.39%)	0 / 121 (0.00%)	2 / 62 (3.23%)
occurrences all number	1	2	0	3
Dysarthria
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Dysgeusia
subjects affected / exposed	7 / 175 (4.00%)	2 / 59 (3.39%)	1 / 121 (0.83%)	3 / 62 (4.84%)
occurrences all number	33	3	1	4
Dyskinesia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Facial Paralysis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Headache
subjects affected / exposed	10 / 175 (5.71%)	0 / 59 (0.00%)	16 / 121 (13.22%)	4 / 62 (6.45%)
occurrences all number	17	0	59	4
Ischaemic Stroke
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Language Disorder
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Nervous System Disorder
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Neuralgia
subjects affected / exposed	0 / 175 (0.00%)	2 / 59 (3.39%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	14	2	0
Neuropathy Peripheral
subjects affected / exposed	6 / 175 (3.43%)	5 / 59 (8.47%)	7 / 121 (5.79%)	2 / 62 (3.23%)
occurrences all number	19	24	27	2
Paraesthesia
subjects affected / exposed	8 / 175 (4.57%)	7 / 59 (11.86%)	9 / 121 (7.44%)	5 / 62 (8.06%)
occurrences all number	31	17	16	21
Peripheral Sensory
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Restless Legs Syndrome
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0
Sciatica
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	3 / 121 (2.48%)	1 / 62 (1.61%)
occurrences all number	4	2	5	1
Tremor
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	2 / 62 (3.23%)
occurrences all number	2	0	1	2
Allodynia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Aphonia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Convulsion
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Dropped Head Syndrome
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Hypoaesthesia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	0	0	4	2
Olfactory Nerve Disorder
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Syncope
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	0	0	1	1
Viith Nerve Paralysis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	20 / 175 (11.43%)	20 / 59 (33.90%)	18 / 121 (14.88%)	16 / 62 (25.81%)
occurrences all number	52	57	48	45
Bicytopenia
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Bone Marrow Failure
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Eosinophilia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	9	0	0	0
Febrile Neutropenia
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	1	0	1
Leukopenia
subjects affected / exposed	1 / 175 (0.57%)	3 / 59 (5.08%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	3	0	0
Lymphopenia
subjects affected / exposed	0 / 175 (0.00%)	2 / 59 (3.39%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	2	5	0
Neutropenia
subjects affected / exposed	1 / 175 (0.57%)	8 / 59 (13.56%)	2 / 121 (1.65%)	3 / 62 (4.84%)
occurrences all number	2	15	6	3
Thrombocytopenia
subjects affected / exposed	1 / 175 (0.57%)	6 / 59 (10.17%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	1	8	2	0
Thrombocytosis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	2 / 121 (1.65%)	1 / 62 (1.61%)
occurrences all number	22	0	4	1
Ear Pain
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	2	0	0
Hypoacusis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Tinnitus
subjects affected / exposed	7 / 175 (4.00%)	1 / 59 (1.69%)	2 / 121 (1.65%)	2 / 62 (3.23%)
occurrences all number	46	2	2	8
Vertigo
subjects affected / exposed	4 / 175 (2.29%)	0 / 59 (0.00%)	6 / 121 (4.96%)	0 / 62 (0.00%)
occurrences all number	4	0	12	0
Eye disorders
Chorioretinopathy
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0
Conjunctival Haemorrhage
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Dry Eye
subjects affected / exposed	5 / 175 (2.86%)	3 / 59 (5.08%)	1 / 121 (0.83%)	2 / 62 (3.23%)
occurrences all number	11	9	1	2
Eye Disorder
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Eye Pain
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Eye Swelling
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	1	0	0	1
Eyelid Oedema
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	6	0	0	2
Lacrimation Increased
subjects affected / exposed	3 / 175 (1.71%)	3 / 59 (5.08%)	0 / 121 (0.00%)	10 / 62 (16.13%)
occurrences all number	11	6	0	42
Ocular Hypertension
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Periorbital Oedema
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	2 / 62 (3.23%)
occurrences all number	2	0	0	9
Photopsia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0
Retinal Detachment
subjects affected / exposed	4 / 175 (2.29%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	10	0	0	0
Retinal Vein Occlusion
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Retinopathy
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Serous Retinal
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Vsion Blurred
subjects affected / exposed	6 / 175 (3.43%)	0 / 59 (0.00%)	3 / 121 (2.48%)	0 / 62 (0.00%)
occurrences all number	10	0	3	0
Visual Acuity Reduced
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Visual Impairment
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	2	1	3	0
Xerophthalmia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Blindness
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	0	0	1	2
Diplopia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	9	0
Eye Irritation
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Eye Oedema
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	5
Eyelid Skin Dryness
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	3 / 121 (2.48%)	0 / 62 (0.00%)
occurrences all number	0	0	4	0
Vitreous Floaters
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	0	1	0
Abdominal Pain
subjects affected / exposed	11 / 175 (6.29%)	3 / 59 (5.08%)	8 / 121 (6.61%)	3 / 62 (4.84%)
occurrences all number	17	3	17	3
Abdominal Pain Upper
subjects affected / exposed	9 / 175 (5.14%)	5 / 59 (8.47%)	5 / 121 (4.13%)	4 / 62 (6.45%)
occurrences all number	24	18	7	8
Anal Haemorrhage
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Constipation
subjects affected / exposed	17 / 175 (9.71%)	8 / 59 (13.56%)	16 / 121 (13.22%)	9 / 62 (14.52%)
occurrences all number	30	12	37	18
Diarrhoea
subjects affected / exposed	35 / 175 (20.00%)	7 / 59 (11.86%)	20 / 121 (16.53%)	8 / 62 (12.90%)
occurrences all number	95	8	45	13
Dry Mouth
subjects affected / exposed	7 / 175 (4.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	1 / 62 (1.61%)
occurrences all number	11	0	2	1
Dyspepsia
subjects affected / exposed	6 / 175 (3.43%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	8	0	1	0
Dysphagia
subjects affected / exposed	2 / 175 (1.14%)	2 / 59 (3.39%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	5	2	5	0
Functional
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal Disorder
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal Motility
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Gastrooesophageal Reflux
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	3 / 121 (2.48%)	0 / 62 (0.00%)
occurrences all number	8	0	4	0
Haemorrhoids
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	0	1	0
Mouth Ulceration
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	3	0	1	0
Nausea
subjects affected / exposed	30 / 175 (17.14%)	17 / 59 (28.81%)	14 / 121 (11.57%)	17 / 62 (27.42%)
occurrences all number	55	31	31	33
Noninfective Gingivitis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Odynophagia
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	4	0	1	0
Oesophagitis
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	5	0	0	1
Reflux Gastritis
subjects affected / exposed	3 / 175 (1.71%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	16	1	0	0
Salivary Hypersecretion
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Stomatitis
subjects affected / exposed	4 / 175 (2.29%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	7	0	0	0
Vomiting
subjects affected / exposed	19 / 175 (10.86%)	6 / 59 (10.17%)	5 / 121 (4.13%)	9 / 62 (14.52%)
occurrences all number	28	10	8	19
Aerophagia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Anal Fissure
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	3
Colitis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Gastrointestinal Pain
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Inguinal Hernia
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Rectal Haemorrhage
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Subileus
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Tongue Oedema
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Toothache
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	2 / 62 (3.23%)
occurrences all number	0	0	1	3
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	4 / 121 (3.31%)	0 / 62 (0.00%)
occurrences all number	1	0	7	0
Hepatocellular Injury
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	3 / 121 (2.48%)	3 / 62 (4.84%)
occurrences all number	11	1	4	8
Hyperbilirubinaemia
subjects affected / exposed	0 / 175 (0.00%)	3 / 59 (5.08%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	3	0	0
Cholecystitis Acute
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Hepatomegaly
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	5 / 175 (2.86%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	14	0	0	0
Alopecia
subjects affected / exposed	7 / 175 (4.00%)	2 / 59 (3.39%)	4 / 121 (3.31%)	1 / 62 (1.61%)
occurrences all number	18	2	4	9
Dermatitis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Dermatitis Acneiform
subjects affected / exposed	13 / 175 (7.43%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	31	0	1	0
Dry Skin
subjects affected / exposed	25 / 175 (14.29%)	3 / 59 (5.08%)	13 / 121 (10.74%)	3 / 62 (4.84%)
occurrences all number	71	4	34	6
Eczema
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	2 / 121 (1.65%)	1 / 62 (1.61%)
occurrences all number	3	0	4	1
Erythema
subjects affected / exposed	12 / 175 (6.86%)	1 / 59 (1.69%)	4 / 121 (3.31%)	2 / 62 (3.23%)
occurrences all number	45	1	6	2
Hypertrichosis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0
Ichthyosis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0
Lividity
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Nail Discolouration
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Nail Disorder
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	10	0	6	0
Nail Ridging
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Nail Toxicity
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	7	0	1	0
Night Sweats
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	5 / 121 (4.13%)	0 / 62 (0.00%)
occurrences all number	3	0	9	0
Onychoclasis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Onycholysis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	6	0	0	0
Palmar-Plantar
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	6	0	0	0
Photosensitivity Reaction
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	1	0	0
Pruritus
subjects affected / exposed	14 / 175 (8.00%)	1 / 59 (1.69%)	18 / 121 (14.88%)	1 / 62 (1.61%)
occurrences all number	19	1	66	1
Rash
subjects affected / exposed	48 / 175 (27.43%)	3 / 59 (5.08%)	10 / 121 (8.26%)	7 / 62 (11.29%)
occurrences all number	167	5	44	9
Rash Follicular
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	18	0	0	0
Rash Macular
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0
Rash Maculo-Papular
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	7	0	1	0
Rash Pruritic
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Skin Fissures
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	5	0	0	0
Skin Lesion
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	5	0	1	0
Skin Toxicity
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Stasis Dermatitis
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Actinic Keratosis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Cutaneous Sarcoidosis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	8	0
Intertrigo
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Macule
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	2
Pigmentation Disorder
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Rash Erythematous
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	2	0
Rash Papular
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Skin Exfoliation
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Skin Induration
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Skin Mass
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	0	4	0
Vitiligo
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	11	0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Dysuria
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Haematuria
subjects affected / exposed	4 / 175 (2.29%)	2 / 59 (3.39%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	8	2	1	1
Proteinuria
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	3	0	0	1
Renal Failure
subjects affected / exposed	5 / 175 (2.86%)	3 / 59 (5.08%)	2 / 121 (1.65%)	4 / 62 (6.45%)
occurrences all number	8	4	2	8
Renal Impairment
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	1	0	0
Renal Pain
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Ureteral Disorder
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Urinary Incontinence
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Pollakiuria
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	0	4	0
Urinary Retention
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	3
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	8 / 121 (6.61%)	0 / 62 (0.00%)
occurrences all number	1	0	19	0
Hyperthyroidism
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	9 / 121 (7.44%)	1 / 62 (1.61%)
occurrences all number	0	0	24	1
Thyroid Disorder
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	9	0
Thyroiditis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	5	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 175 (6.29%)	3 / 59 (5.08%)	18 / 121 (14.88%)	5 / 62 (8.06%)
occurrences all number	26	5	113	5
Back Pain
subjects affected / exposed	13 / 175 (7.43%)	3 / 59 (5.08%)	15 / 121 (12.40%)	7 / 62 (11.29%)
occurrences all number	23	4	51	15
Bone Pain
subjects affected / exposed	2 / 175 (1.14%)	2 / 59 (3.39%)	9 / 121 (7.44%)	6 / 62 (9.68%)
occurrences all number	2	3	15	7
Flank Pain
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	5	0	0
Hypercreatinaemia
subjects affected / exposed	0 / 175 (0.00%)	3 / 59 (5.08%)	3 / 121 (2.48%)	0 / 62 (0.00%)
occurrences all number	0	3	19	0
Joint Stiffness
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Joint Swelling
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0
Muscle Spasms
subjects affected / exposed	5 / 175 (2.86%)	0 / 59 (0.00%)	4 / 121 (3.31%)	0 / 62 (0.00%)
occurrences all number	12	0	13	0
Muscular Weakness
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	2	1	2	0
Musculoskeletal Chest Pain
subjects affected / exposed	2 / 175 (1.14%)	2 / 59 (3.39%)	2 / 121 (1.65%)	1 / 62 (1.61%)
occurrences all number	4	2	2	1
Musculoskeletal Pain
subjects affected / exposed	3 / 175 (1.71%)	3 / 59 (5.08%)	13 / 121 (10.74%)	5 / 62 (8.06%)
occurrences all number	4	4	44	5
Myalgia
subjects affected / exposed	10 / 175 (5.71%)	1 / 59 (1.69%)	8 / 121 (6.61%)	3 / 62 (4.84%)
occurrences all number	22	1	16	5
Neck Pain
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	7 / 121 (5.79%)	2 / 62 (3.23%)
occurrences all number	0	1	31	2
Pain In Extremity
subjects affected / exposed	7 / 175 (4.00%)	3 / 59 (5.08%)	6 / 121 (4.96%)	2 / 62 (3.23%)
occurrences all number	17	5	10	2
Periarthritis
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	1	3	0
Rheumatoid Arthritis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Spinal Pain
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	4 / 121 (3.31%)	0 / 62 (0.00%)
occurrences all number	1	2	16	0
Musculoskeletal Stiffness
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Myositis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Nuchal Rigidity
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Osteoarthritis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	6	0
Tendonitis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	3
Torticollis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Infections and infestations
Arthritis Bacterial
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Bronchitis
subjects affected / exposed	7 / 175 (4.00%)	6 / 59 (10.17%)	10 / 121 (8.26%)	4 / 62 (6.45%)
occurrences all number	9	8	15	4
Candida Infection
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	0	1	0
Cellulitis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Conjunctivitis
subjects affected / exposed	4 / 175 (2.29%)	4 / 59 (6.78%)	7 / 121 (5.79%)	6 / 62 (9.68%)
occurrences all number	4	7	17	13
Device Related Infection
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Diverticulitis
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Ear Infection
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Eye Infection
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Folliculitis
subjects affected / exposed	12 / 175 (6.86%)	1 / 59 (1.69%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	47	2	2	0
Fungal Infection
subjects affected / exposed	4 / 175 (2.29%)	1 / 59 (1.69%)	2 / 121 (1.65%)	1 / 62 (1.61%)
occurrences all number	6	1	3	1
Gastroenteritis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	0	1	0
Gingival Abscess
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Herpes Zoster
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	3	0	1	0
Hordeolum
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Influenza
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	1	0	2	0
Lung Infection
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	1	1	1	0
Nail Infection
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Nasopharyngitis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	2	0	2	0
Onychomycosis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Oral Fungal Infection
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Oral Herpes
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Paronychia
subjects affected / exposed	9 / 175 (5.14%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	29	0	1	0
Periodontitis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Pharyngitis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	4	0	0	1
Pneumonia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	1	0	3	1
Pyelonephritis
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Rash Pustular
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Respiratory Tract Infection
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	2	0	0	1
Rhinitis
subjects affected / exposed	6 / 175 (3.43%)	3 / 59 (5.08%)	7 / 121 (5.79%)	2 / 62 (3.23%)
occurrences all number	8	4	7	2
Sinusitis
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	2	0	2	0
Skin Infection
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Tooth Abscess
subjects affected / exposed	2 / 175 (1.14%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	1	0	0
Urinary Tract Infection
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	3 / 121 (2.48%)	1 / 62 (1.61%)
occurrences all number	4	0	4	1
Vulvovaginal Candidiasis
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Vulvovaginal Mycotic
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	1	0	0
Abscess
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Laryngitis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	0	0	1	1
Periumbilical Abscess
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Sepsis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Spinal Cord Infection
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	0	0	1
Tracheitis
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	0	0	3	0
Viral Infection
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	1 / 175 (0.57%)	1 / 59 (1.69%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	1	0	0
Cell Death
subjects affected / exposed	4 / 175 (2.29%)	1 / 59 (1.69%)	4 / 121 (3.31%)	3 / 62 (4.84%)
occurrences all number	6	2	10	5
Decreased Appetite
subjects affected / exposed	21 / 175 (12.00%)	7 / 59 (11.86%)	20 / 121 (16.53%)	14 / 62 (22.58%)
occurrences all number	40	12	33	18
Dehydration
subjects affected / exposed	0 / 175 (0.00%)	1 / 59 (1.69%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	0	1	0	1
Hypercalcaemia
subjects affected / exposed	2 / 175 (1.14%)	0 / 59 (0.00%)	3 / 121 (2.48%)	0 / 62 (0.00%)
occurrences all number	2	0	4	0
Hypercholesterolaemia
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0
Hypercreatinaemia
subjects affected / exposed	0 / 175 (0.00%)	3 / 59 (5.08%)	6 / 121 (4.96%)	0 / 62 (0.00%)
occurrences all number	0	3	21	0
Hyperglycaemia
subjects affected / exposed	6 / 175 (3.43%)	1 / 59 (1.69%)	2 / 121 (1.65%)	0 / 62 (0.00%)
occurrences all number	10	1	4	0
Hyperkalaemia
subjects affected / exposed	3 / 175 (1.71%)	1 / 59 (1.69%)	4 / 121 (3.31%)	1 / 62 (1.61%)
occurrences all number	3	2	6	2
Hypermagnesaemia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Hyperphosphataemia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Hyperuricaemia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
Hypoalbuminaemia
subjects affected / exposed	4 / 175 (2.29%)	1 / 59 (1.69%)	1 / 121 (0.83%)	1 / 62 (1.61%)
occurrences all number	11	1	1	1
Hypoglycaemia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Hypokalaemia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	3 / 121 (2.48%)	0 / 62 (0.00%)
occurrences all number	1	0	14	0
Hypomagnesaemia
subjects affected / exposed	6 / 175 (3.43%)	0 / 59 (0.00%)	4 / 121 (3.31%)	1 / 62 (1.61%)
occurrences all number	10	0	5	2
Hyponatraemia
subjects affected / exposed	3 / 175 (1.71%)	0 / 59 (0.00%)	0 / 121 (0.00%)	1 / 62 (1.61%)
occurrences all number	3	0	0	1
Hypophosphataemia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Hypoproteinaemia
subjects affected / exposed	1 / 175 (0.57%)	0 / 59 (0.00%)	0 / 121 (0.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0
Malnutrition
subjects affected / exposed	0 / 175 (0.00%)	0 / 59 (0.00%)	1 / 121 (0.83%)	0 / 62 (0.00%)
occurrences all number	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

14 Feb 2014

- Modification of the investigators list.

25 Mar 2014

- Modification of the coordinating investigator’s contact details - Rephrasing of the primary objective - Addition of a secondary objective - Modifications of inclusion and non-inclusion criteria (precision on IC N°9, modification of NIC N°1 of the selection process, and modification of IC N°2, ICN°6, NIC N°3 and NIC N°6 of the randomization process). - Clarification on the population considered for the analysis of the primary endpoint - Precision on the duration of the cycle in figure 1 of the diagram of the study - Clarification on cross-over between study arms A and B - Modification of the stratification factors - Clarification on non-randomisation reasons and treatment accountancy - Modifications of administration and dose reduction recommendations in the event of toxicity - Modifications of concomitant treatments, in the follow-up and exams. - Addition of explanatory diagram (general organization of the tumor sample circuit / period between the end of the induction treatment and randomization) - Planification of an interim analysis after the randomisation of 60 patients in the SAFIR02 program - Modifications of toxicities regarding eyes and skin - Clarification on SAEs criteria - Clarification on the moment of Steering Committee and IDMC meet - Modifications on biopsy collection - Correction of typographic errors

24 Jul 2014

- Modification of the investigators list.

07 Jan 2015

- Modifications of IC and NIC (modification of ICN°3 and NIC N°11 of the selection process) - Modification of Figure 1 - Update of the protocol (Tables 5 et 13, section 11.1.3) and investigator’s brochures - Modification of section 7.7.2.4 (concomitant treatment administration) - Suppresssion of Section 10 (inclustion criteria previously listed) - Change of the CRB contact details - Modification of the stratification factors - Addition of an “other” category in Appendix 6 (Order of preference for treatment) - Clarification on Appendix 9 (Guidance on management of hepatotoxicity)

10 Jul 2015

- Modification of the investigators list

09 Sep 2015

- Modification of the study design with the addition of the substudy 2 to assess efficacy and toxicity of the antiPD-L1 MEDI4736 (Durvalumab). - Modification of IC and NIC (screening phase: IC N°7 and addition NIC N°3; Substudy 1: NIC N°6; NIC N°10; NIC N°12; NIC N°13). - Updates of the targeted therapies information. - Update of toxicity profiles of targeted therapies and toxicity management guidelines.

16 Nov 2015

- Modification of toxicity management of MEDI4736.

24 Mar 2016

- Modification study design and patients’ diaries (Targeted therapy / Immunotherapy / Standard Chimiotherapy)

19 Apr 2016

- Modification of the investigators list

09 Sep 2016

- Increase of the number of patients included during screening phase. - Modification molecular analysis method with use of Formalin-Fixed Paraffin-Embedded tissue and plasma to generate tumoral genomic profile. - Modification of maintenance treatment with withdrawal of Erlotinib in epidermal cancers - Introduction of MEDI4736 pseudo-progression management guidelines.

16 Nov 2016

- Modification of the investigators list

16 Jan 2017

- Modification of the investigators list

22 Mar 2017

- Modification of the investigators list

19 Sep 2018

- Replacement of Dr Claire LETHROSNE by Dr Laetitia RAJPAR as a principal investigator at the hospital Louis Pasteur at Chartres. - Modification of the investigators list

25 Mar 2019

- Ending of AZD8931 manufacture - Futility analyses - Addition of targeted therapies (Olaparib, Savolitinib, Cobimetinib, and Vemurafenib) - Reduction of the number of tumoral assessment following 6 months treatment - Update of the Durvalumab investigator’s brochure - Update of the Selumetinib investigator’s brochure - Update of the AZD2014 investigator’s brochure - Update of the AZD5363 investigator’s brochure - Addition of a place of release of treatment batches - Addition of the possibility to use cytoblocks - Extension of durvalumab administrations until progression - Change of coordinator

04 Jun 2019

- Recruitment stopped - Addition of a storage site, releases and deliveries of experimental products - Update of the Olaparib investigator’s brochure - Update of the Savolitinib investigator’s brochure - Update of the AZD5363 investigator’s brochure - Update of the Durvalumab investigator’s brochure - General Data Protection Regulation integration - Modification of the investigators list

01 May 2020

- Update of the Olaparib investigator’s brochure - Update of the Durvalumab investigator’s brochure

Were there any global interruptions to the trial? No

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

None reported

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Clinical Trial Results:
Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic non small cell lung cancer.

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Clinical Trial Results: Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic non small cell lung cancer.

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Baseline characteristics

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Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

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Secondary: Overall survival (OS) in both arms

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Clinical Trial Results:
Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic non small cell lung cancer.