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Clinical Trial Results:
An Open-label, Multicenter, Randomized, Phase 2 Study of a Recombinant Human Anti-VEGFR-2 Monoclonal Antibody, IMC-1121B in Combination with Platinum-based Chemotherapy versus Platinum-based Chemotherapy Alone as First-line Treatment of Patients with Recurrent or Advanced Non-small Cell Lung Cancer (NSCLC)

Summary
EudraCT number	2009-016784-11
Trial protocol	DE GB BE
Global end of trial date	19 Apr 2018

Results information
Results version number	v1(current)
This version publication date	03 May 2019
First version publication date	03 May 2019
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

I4T-IE-JVBL

ISRCTN number

US NCT number

NCT01160744

WHO universal trial number (UTN)

Other trial identifiers

Trial Number: 13916

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Public contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,

Scientific contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,

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

19 Apr 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Apr 2018

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to determine if participants with Stage IV NSCLC have a better outcome when treated with IMC-1121B in combination with pemetrexed + carboplatin/cisplatin or gemcitabine + carboplatin/cisplatin than when treated with pemetrexed + carboplatin/cisplatin or gemcitabine + carboplatin/cisplatin alone.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Sep 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 223

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Poland: 16

Country: Number of subjects enrolled

Germany: 22

Country: Number of subjects enrolled

United Kingdom: 5

Worldwide total number of subjects

280

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

137

From 65 to 84 years

143

85 years and over

Subject disposition

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Recruitment details

No Text Available

Screening details

Participants who died (any cause) or had disease progression were considered to be study completers.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Pem + Carb or Cis (Non-Squamous)

Arm description

Pemetrexed (Pem): 500 milligrams/square meter (mg/m²) on Day 1 of every 21-day cycle. Carboplatin (Carb) [Area Under the Concentration Time Curve 6 (AUC 6)] : Day 1 of every 21-day cycle. Cisplatin (Cis): 75 mg/m² intravenous (IV) on Day 1 of every 21-day cycle. Participants were treated for up to 89 weeks.

Arm type

Experimental

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pemetrexed : 500 milligrams/square meter (mg/m²) on Day 1 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin [Area Under the Concentration Time Curve 6 (AUC 6)] : Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin: 75 mg/m² intravenous (IV) on Day 1 of every 21-day cycle. Participants were treated for up to 89 weeks.

Ram + Pem + Carb or Cis (Non-Squamous)

Arm description

Ramucirumab (Ram): 10 milligrams/kilogram (mg/kg) Day 1 of every 21-day cycle. Pem: 500 mg/m² on Day 1 of every 21-day cycle. Carb (AUC 6): Day 1 of every 21-day cycle. Cis: 75 mg/m² IV on Day 1 of every 21-day cycle. Participants were treated for up to 89 weeks.

Arm type

Active comparator

Investigational medicinal product name

Ramucirumab

Investigational medicinal product code

Other name

IMC-1121B, LY3009806

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ramucirumab : 10 milligrams/kilogram (mg/kg) Day 1 of every 21-day cycle.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pemetrexed: 500 mg/m² on Day 1 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin (AUC 6): Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin : 75 mg/m² IV on Day 1 of every 21-day cycle. Participants were treated for up to 89 weeks.

Gem + Carb or Cis (Squamous)

Arm description

Gemcitabine (Gem): 1000 mg/m² on Days 1 and 8 of every 21-day cycle. Carb [Area Under the Concentration Time Curve 5 (AUC 5)]: Day 1 of every 21-day cycle. Cis: 75 mg/m² IV on Day 1 of every 21-day cycle. Participants were treated for up to 89 weeks.

Arm type

Experimental

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine: 1000 mg/m² on Days 1 and 8 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin[Area Under the Concentration Time Curve 5 (AUC 5)]: Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin: 75 mg/m² IV on Day 1 of every 21-day cycle. Participants were treated for up to 89 weeks.

Ram + Gem + Carb or Cis (Squamous)

Arm description

Ram: 10 mg/kg on Day 1 of each every 21-day cycle. Gem: 1000 mg/m² on Days 1 and 8 of every 21-day cycle. Carb (AUC 5): Day 1 of every 21-day cycle. Cis: 75 mg/m² IV on Day 1 of each every 21-day cycle. Participants were treated for up to 89 weeks.

Arm type

Active comparator

Investigational medicinal product name

Ramucirumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ramucirumab: 10 mg/kg on Day 1 of each every 21-day cycle.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine: 1000 mg/m² on Days 1 and 8 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin (AUC 5): Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin : 75 mg/m² IV on Day 1 of each every 21-day cycle.

Number of subjects in period 1	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Started	71	69	69	71
Received Study Drug	69	67	63	71
Completed	60	64	62	67
Not completed	11	5	7	4
Consent withdrawn by subject	11	5	6	4
Not meet inclusion/exclusion criteria	-	-	1	-

Baseline characteristics

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Reporting group title

Pem + Carb or Cis (Non-Squamous)

Reporting group description

Reporting group title

Ram + Pem + Carb or Cis (Non-Squamous)

Reporting group description

Reporting group title

Gem + Carb or Cis (Squamous)

Reporting group description

Reporting group title

Ram + Gem + Carb or Cis (Squamous)

Reporting group description

Reporting group values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)	Total
Number of subjects	71	69	69	71	280
Age categorical
Units: Subjects
<=18 years	0	0	0	0	0
Between 18 and 65 years	37	37	27	34	135
>=65 years	34	32	40	37	143
Missing Data	0	0	2	0	2
Gender categorical
Units: Subjects
Female	26	33	26	16	101
Male	45	36	43	55	179
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	4	1	0	6
Not Hispanic or Latino	70	65	68	71	274
Unknown or Not Reported	0	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
White	65	60	65	67	257
Black	2	8	1	4	15
Asian	4	1	1	0	6
Other	0	0	2	0	2
Region of Enrollment
Units: Subjects
United States	71	69	42	41	223
Canada	0	0	4	1	5
Belgium	0	0	5	4	9
Poland	0	0	4	12	16
Germany	0	0	14	8	22
United Kingdom	0	0	0	5	5

End points

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Reporting group title

Pem + Carb or Cis (Non-Squamous)

Reporting group description

Reporting group title

Ram + Pem + Carb or Cis (Non-Squamous)

Reporting group description

Reporting group title

Gem + Carb or Cis (Squamous)

Reporting group description

Reporting group title

Ram + Gem + Carb or Cis (Squamous)

Reporting group description

Primary: Progression-Free survival (PFS)

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End point title

Progression-Free survival (PFS)

End point description

PFS was the time from randomization to the first objective progression as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1) or death from any cause, whichever occurred first. Progressive disease (PD) was defined as ≥20% increase in sum of diameter (SOD) of target lesions and short axes of target lymph nodes, taking as reference the smallest sum of the longest diameters recorded since treatment started and an absolute increase in sum diameter of ≥5 millimeters (mm); appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Participants alive and without disease progression were censored at the time of the last objective tumor assessment. Participants who did not progress and were lost to follow-up were censored at their last radiographic assessment. If no baseline or post baseline radiologic assessments were available, participants were censored at date of randomization.

End point type

Primary

End point timeframe

Randomization to PD or death (up to 24 months) Analysis Population Description (APD): Intent-to-Treat (ITT) Population: All randomized participants. Participants censored: Pem+Carb/Cis=14, Ram+Pem+Carb/Cis=13, Gem+Carb/Cis=14, Ram+Gem+Carb/Cis=18.

End point values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Number of subjects analysed	71	69	69	71
Units: months
median (confidence interval 90%)	5.6 (4.0 to 5.7)	7.2 (5.8 to 8.4)	5.4 (4.7 to 5.7)	5.6 (4.4 to 6.0)

Progression-Free survival (PFS)

Comparison groups

Ram + Pem + Carb or Cis (Non-Squamous) v Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1318

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.75

Confidence interval

level

90%

sides

2-sided

lower limit

0.55

upper limit

1.03

Progression-Free survival (PFS)

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5215

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

90%

sides

2-sided

lower limit

0.64

upper limit

1.22

Secondary: Percentage of Participants with Best overall Response of complete response (CR) or partial response (PR) [Objective Response Rate (ORR)]

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End point title

Percentage of Participants with Best overall Response of complete response (CR) or partial response (PR) [Objective Response Rate (ORR)]

End point description

Best overall response of CR or PR was defined using RECIST v 1.1 criteria. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was defined as ≥30% decrease in SOD of target lesions taking as reference the baseline sum diameter. PD was defined as ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference the smallest sum of the longest diameters recorded since treatment started and an absolute increase in sum diameter of ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR/total number of participants)*100. APD: ITT Population: All randomized participants.

End point type

Secondary

End point timeframe

Day 1, Cycle 1 (3-week cycles) and every 6 weeks thereafter to PD (up to 24 months)

End point values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Number of subjects analysed	71	69	69	71
Units: percentage of participants
number (not applicable)	38.0	49.3	24.6	46.5

Percentage of Participants with Best overall Resp

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1797

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.58

Confidence interval

level

90%

sides

2-sided

lower limit

0.9

upper limit

2.78

Percentage of Participants with Best overall Resp

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.007

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

2.66

Confidence interval

level

90%

sides

2-sided

lower limit

1.45

upper limit

4.86

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as the time from the date of randomization to the date of death from any cause. If the participant was alive at the end of the follow-up period or was lost to follow-up, OS was censored on the last date the participant was known to be alive. Analysis Population Description: ITT Population: All randomized participants. Participants censored: Pem+Carb/Cis=22, Ram+Pem+Carb/Cis=16, Gem+Carb/Cis=32, Ram+Gem+Carb/Cis=32.

End point type

Secondary

End point timeframe

Randomization to the date of death from any cause (up to 31.3 months)

End point values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Number of subjects analysed	71	69	69	71
Units: months
median (confidence interval 90%)	10.4 (8.2 to 15.9)	13.9 (10.0 to 17.8)	11.3 (9.7 to 13.3)	10.4 (7.8 to 14.8)

Overall Survival (OS)

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8916

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

90%

sides

2-sided

lower limit

0.74

upper limit

1.42

Overall Survival (OS)

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6847

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.93

Confidence interval

level

90%

sides

2-sided

lower limit

0.69

upper limit

1.27

Secondary: Duration of response (DOR)

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End point title

Duration of response (DOR)

End point description

DOR was measured from the time criteria were met for the first objectively recorded CR or PR until the first date criteria for PD were met or death. Response was defined using RECIST v 1.1 criteria. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker level of non-target lesions. PR was defined as ≥30% decrease SOD of target lesions taking as reference the baseline sum diameter. PD was defined as ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference the smallest sum of the longest diameters recorded since treatment started and an absolute increase in sum diameter of ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Participants who did not relapse were censored at the day of their last objective tumor assessment.

End point type

Secondary

End point timeframe

Time of first response (CR or PR) until PD or death (up to 24 months) APD:All randomized participants with a best overall response of CR or PR. Participants censored: Pem+Carb/Cis=44, Ram+Pem+Carb/Cis=35, Gem+Carb/Cis=50, Ram+Gem+Carb/Cis=37.

End point values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Number of subjects analysed	27	34	17	33
Units: months
median (confidence interval 90%)	4.5 (3.1 to 5.7)	5.5 (4.4 to 5.8)	4.3 (4.2 to 5.5)	4.3 (3.3 to 5.6)

No statistical analyses for this end point

Secondary: Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and who Died

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End point title

Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and who Died

End point description

Data presented are the number of participants with at least 1 treatment-emergent adverse event (TEAE) and treatment-emergent serious adverse event (SAE), as well as, the number of participants who died during the study. TEAEs were defined as serious and other non-serious AEs that occurred or worsened after study treatment (regardless of causality). A summary of SAEs and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. Analysis Population Description: All randomized participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Day 1, Cycle 1 (3-week cycles) Up To 3 Years

End point values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Number of subjects analysed	69	67	63	71
Units: participants
number (not applicable)
Treatment-Emergent SAE	38	44	29	39
Treatment-Emergent Adverse Event	68	67	63	71
Deaths	51	55	55	56

No statistical analyses for this end point

Other pre-specified: Percentage of Participants with CR, PR, or Stable Disease (SD) [Disease Control Rate (DCR)]

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End point title

Percentage of Participants with CR, PR, or Stable Disease (SD) [Disease Control Rate (DCR)]

End point description

DCR: percentage of participants with CR, PR, or SD using RECIST v 1.1 criteria. CR: disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR: ≥30% decrease in SOD of target lesions taking as reference baseline sum diameter. PD: ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference smallest sum of longest diameters recorded since treatment started and an absolute increase in sum diameter ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor increase to qualify for PD. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR+SD/total number of participants)*100.

End point type

Other pre-specified

End point timeframe

Day 1, Cycle 1 (3-week cycles) and every 6 weeks thereafter to PD (up to 24 months) Analysis Population Description: ITT Population: All randomized participants.

End point values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Number of subjects analysed	71	69	69	71
Units: percentage of participants
number (confidence interval 90%)	70.4 (61.5 to 79.3)	85.5 (78.5 to 92.5)	66.7 (57.3 to 76.0)	73.2 (64.6 to 81.9)

Percentage of Participants with CR, PR, or Stable

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0316

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

2.48

Confidence interval

level

90%

sides

2-sided

lower limit

1.22

upper limit

5.02

Percentage of Participants with CR, PR, or Stable

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3962

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.37

Confidence interval

level

90%

sides

2-sided

lower limit

0.74

upper limit

2.52

Other pre-specified: Change in Tumor Size (CTS)

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End point title

Change in Tumor Size (CTS)

End point description

CTS was defined as the log ratio of tumor size at 6 weeks to tumor size at baseline. CTS at 6 weeks=Log (Sum of Target Lesion Measurements at 6 Weeks)-Log (Sum of Target Lesion Measurements at Baseline). Analysis Population Description: All randomized participants with results at baseline and 6 weeks.

End point type

Other pre-specified

End point timeframe

Baseline, 6 weeks

End point values	Pem + Carb or Cis (Non-Squamous)	Ram + Pem + Carb or Cis (Non-Squamous)	Gem + Carb or Cis (Squamous)	Ram + Gem + Carb or Cis (Squamous)
Number of subjects analysed	53	58	50	53
Units: log ratio
arithmetic mean (standard deviation)	-0.2 ± 0.23	-0.2 ± 0.22	-0.3 ± 0.31	-0.4 ± 0.39

Change in Tumor Size (CTS)

Comparison groups

Ram + Pem + Carb or Cis (Non-Squamous) v Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1571

Method

t-test, 2-sided

Confidence interval

sides

2-sided

lower limit

upper limit

Change in Tumor Size (CTS)

Comparison groups

Pem + Carb or Cis (Non-Squamous) v Ram + Pem + Carb or Cis (Non-Squamous)

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1597

Method

t-test, 2-sided

Confidence interval

sides

2-sided

lower limit

upper limit

Adverse events

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Timeframe for reporting adverse events

Entire Study

Adverse event reporting additional description

I4T-IE-JVBL

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Carb/Cis+Pem+Ram (non-SQ)

Reporting group description

Reporting group title

Carb/Cis+Pem (non-SQ)

Reporting group description

Reporting group title

Carb/Cis+Gem+Ram (SQ)

Reporting group description

Reporting group title

Carb/Cis+Gem (SQ)

Reporting group description

Serious adverse events	Carb/Cis+Pem+Ram (non-SQ)	Carb/Cis+Pem (non-SQ)	Carb/Cis+Gem+Ram (SQ)	Carb/Cis+Gem (SQ)
Total subjects affected by serious adverse events
subjects affected / exposed	44 / 67 (65.67%)	38 / 69 (55.07%)	39 / 71 (54.93%)	29 / 63 (46.03%)
number of deaths (all causes)	4	6	3	4
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignant pleural effusion
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
neoplasm progression
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
Vascular disorders
air embolism
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
deep vein thrombosis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	3 / 71 (4.23%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
embolism
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)	0 / 63 (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
femoral artery occlusion
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
haematoma
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
hypertension
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	2 / 71 (2.82%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
hypotension
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	2 / 69 (2.90%)	2 / 71 (2.82%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
orthostatic hypotension
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
venous thrombosis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
General disorders and administration site conditions
asthenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
chest pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
death
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
fatigue
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	2 / 69 (2.90%)	2 / 71 (2.82%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
general physical health deterioration
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
malaise
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	2 / 71 (2.82%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
multi-organ failure
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
non-cardiac chest pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
oedema peripheral
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pyrexia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
sudden death
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
Immune system disorders
hypersensitivity
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
Respiratory, thoracic and mediastinal disorders
acute respiratory failure
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
asphyxia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
chronic obstructive pulmonary disease
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
dyspnoea
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	1 / 69 (1.45%)	6 / 71 (8.45%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
epistaxis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
haemoptysis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
haemothorax
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
hiccups
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
oesophagobronchial fistula
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
pleural effusion
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pneumothorax
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
pulmonary embolism
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
respiratory arrest
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
respiratory failure
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
stridor
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
anxiety
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
confusional state
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
depression
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
mental status changes
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	2 / 69 (2.90%)	2 / 71 (2.82%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
aspartate aminotransferase increased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
oxygen saturation decreased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
platelet count decreased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
Injury, poisoning and procedural complications
accidental overdose
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
drug administration error
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
fall
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
gastroenteritis radiation
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
hip fracture
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
incorrect dose administered
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	3 / 69 (4.35%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
lumbar vertebral fracture
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
medication error
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	1 / 69 (1.45%)	1 / 71 (1.41%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
overdose
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
radiation mucositis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
transfusion-related acute lung injury
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
underdose
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	2 / 69 (2.90%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 11	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
acute coronary syndrome
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
acute myocardial infarction
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
angina pectoris
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
atrial fibrillation
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	0 / 69 (0.00%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
bradycardia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
bundle branch block left
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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 arrest
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
cardiac failure congestive
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
cardio-respiratory arrest
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
cardiovascular disorder
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
coronary artery occlusion
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
left ventricular dysfunction
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	1 / 69 (1.45%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
supraventricular tachycardia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
tachycardia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
cerebral haemorrhage
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
cerebrovascular accident
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
encephalopathy
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
facial paresis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
ischaemic cerebral infarction
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
lethargy
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
paraplegia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
syncope
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	1 / 69 (1.45%)	5 / 71 (7.04%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
febrile neutropenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	1 / 69 (1.45%)	2 / 71 (2.82%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
leukopenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
neutropenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	1 / 69 (1.45%)	4 / 71 (5.63%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pancytopenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
thrombocytopenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	2 / 69 (2.90%)	8 / 71 (11.27%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 10	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
vision blurred
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
Gastrointestinal disorders
abdominal pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	2 / 69 (2.90%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
abdominal pain upper
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
colitis ischaemic
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
constipation
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
diarrhoea
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	2 / 69 (2.90%)	0 / 71 (0.00%)	0 / 63 (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 / 0	0 / 0	0 / 0
duodenal ulcer
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
gastritis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
gastrointestinal haemorrhage
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
intestinal ischaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
intestinal perforation
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
lip haemorrhage
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
nausea
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	4 / 69 (5.80%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pancreatitis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
vomiting
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	4 / 69 (5.80%)	0 / 71 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 6	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
cholangitis acute
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
cholecystitis acute
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
Skin and subcutaneous tissue disorders
rash papular
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
Renal and urinary disorders
acute kidney injury
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
nephrolithiasis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
renal failure
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
urinary retention
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
Endocrine disorders
inappropriate antidiuretic hormone secretion
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
back pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
groin pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
muscular weakness
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
musculoskeletal chest pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
bacteraemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
bronchitis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
cellulitis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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
diverticulitis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
gastroenteritis viral
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
infection
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
lung abscess
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
pharyngeal abscess
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
pneumonia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	6 / 69 (8.70%)	7 / 71 (9.86%)	6 / 63 (9.52%)
occurrences causally related to treatment / all	0 / 1	0 / 8	0 / 8	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pneumonia bacterial
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
pneumonia pseudomonal
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
pyelonephritis acute
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
sepsis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
staphylococcal infection
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
upper respiratory tract infection
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
urinary tract infection
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
decreased appetite
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
dehydration
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	2 / 69 (2.90%)	3 / 71 (4.23%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
failure to thrive
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	0 / 63 (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
fluid overload
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	0 / 71 (0.00%)	0 / 63 (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
hyperglycaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	1 / 69 (1.45%)	1 / 71 (1.41%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
hypoglycaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	1 / 71 (1.41%)	0 / 63 (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
hyponatraemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
hypovolaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	0 / 67 (0.00%)	0 / 69 (0.00%)	0 / 71 (0.00%)	1 / 63 (1.59%)
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

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

Non-serious adverse events	Carb/Cis+Pem+Ram (non-SQ)	Carb/Cis+Pem (non-SQ)	Carb/Cis+Gem+Ram (SQ)	Carb/Cis+Gem (SQ)
Total subjects affected by non serious adverse events
subjects affected / exposed	66 / 67 (98.51%)	67 / 69 (97.10%)	71 / 71 (100.00%)	62 / 63 (98.41%)
Vascular disorders
hypertension
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	12 / 67 (17.91%)	4 / 69 (5.80%)	8 / 71 (11.27%)	3 / 63 (4.76%)
occurrences all number	15	5	16	4
hypotension
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	3 / 69 (4.35%)	3 / 71 (4.23%)	2 / 63 (3.17%)
occurrences all number	7	3	3	2
General disorders and administration site conditions
asthenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	2 / 69 (2.90%)	5 / 71 (7.04%)	7 / 63 (11.11%)
occurrences all number	12	2	8	10
chills
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	5 / 69 (7.25%)	5 / 71 (7.04%)	2 / 63 (3.17%)
occurrences all number	1	5	6	2
fatigue
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	44 / 67 (65.67%)	43 / 69 (62.32%)	39 / 71 (54.93%)	34 / 63 (53.97%)
occurrences all number	97	85	79	62
infusion site pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	1 / 71 (1.41%)	4 / 63 (6.35%)
occurrences all number	1	0	1	4
mucosal inflammation
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	6 / 69 (8.70%)	3 / 71 (4.23%)	5 / 63 (7.94%)
occurrences all number	14	11	3	5
non-cardiac chest pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	3 / 69 (4.35%)	4 / 71 (5.63%)	4 / 63 (6.35%)
occurrences all number	11	3	4	4
oedema peripheral
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	17 / 67 (25.37%)	16 / 69 (23.19%)	14 / 71 (19.72%)	10 / 63 (15.87%)
occurrences all number	23	19	23	12
pyrexia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	12 / 69 (17.39%)	6 / 71 (8.45%)	6 / 63 (9.52%)
occurrences all number	9	19	8	7
Respiratory, thoracic and mediastinal disorders
cough
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	13 / 67 (19.40%)	11 / 69 (15.94%)	14 / 71 (19.72%)	9 / 63 (14.29%)
occurrences all number	15	18	21	9
dysphonia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	5 / 69 (7.25%)	0 / 71 (0.00%)	1 / 63 (1.59%)
occurrences all number	4	5	0	1
dyspnoea
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	17 / 67 (25.37%)	16 / 69 (23.19%)	10 / 71 (14.08%)	11 / 63 (17.46%)
occurrences all number	29	24	19	19
dyspnoea exertional
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	3 / 71 (4.23%)	4 / 63 (6.35%)
occurrences all number	3	0	6	5
epistaxis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	17 / 67 (25.37%)	5 / 69 (7.25%)	12 / 71 (16.90%)	6 / 63 (9.52%)
occurrences all number	36	6	17	6
haemoptysis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	1 / 69 (1.45%)	4 / 71 (5.63%)	3 / 63 (4.76%)
occurrences all number	3	1	9	3
oropharyngeal pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	2 / 69 (2.90%)	4 / 71 (5.63%)	3 / 63 (4.76%)
occurrences all number	10	2	6	3
productive cough
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	1 / 69 (1.45%)	6 / 71 (8.45%)	8 / 63 (12.70%)
occurrences all number	4	1	10	9
rhinorrhoea
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	6 / 67 (8.96%)	2 / 69 (2.90%)	3 / 71 (4.23%)	1 / 63 (1.59%)
occurrences all number	7	2	3	1
wheezing
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	4 / 69 (5.80%)	1 / 71 (1.41%)	2 / 63 (3.17%)
occurrences all number	3	4	1	2
Psychiatric disorders
anxiety
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	6 / 67 (8.96%)	4 / 69 (5.80%)	1 / 71 (1.41%)	4 / 63 (6.35%)
occurrences all number	6	4	1	4
depression
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	6 / 69 (8.70%)	5 / 71 (7.04%)	1 / 63 (1.59%)
occurrences all number	5	7	5	1
insomnia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	15 / 67 (22.39%)	10 / 69 (14.49%)	5 / 71 (7.04%)	7 / 63 (11.11%)
occurrences all number	15	10	5	7
Investigations
alanine aminotransferase increased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	7 / 69 (10.14%)	6 / 71 (8.45%)	6 / 63 (9.52%)
occurrences all number	10	10	17	6
aspartate aminotransferase increased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	4 / 69 (5.80%)	11 / 71 (15.49%)	6 / 63 (9.52%)
occurrences all number	8	6	24	6
blood alkaline phosphatase increased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	3 / 69 (4.35%)	7 / 71 (9.86%)	3 / 63 (4.76%)
occurrences all number	1	6	12	5
blood creatinine increased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	6 / 67 (8.96%)	7 / 69 (10.14%)	4 / 71 (5.63%)	3 / 63 (4.76%)
occurrences all number	7	8	6	3
neutrophil count decreased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	7 / 69 (10.14%)	6 / 71 (8.45%)	3 / 63 (4.76%)
occurrences all number	3	16	9	10
platelet count decreased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	4 / 69 (5.80%)	7 / 71 (9.86%)	2 / 63 (3.17%)
occurrences all number	10	7	31	3
weight decreased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	12 / 67 (17.91%)	11 / 69 (15.94%)	12 / 71 (16.90%)	4 / 63 (6.35%)
occurrences all number	17	15	16	5
white blood cell count decreased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	5 / 69 (7.25%)	5 / 71 (7.04%)	5 / 63 (7.94%)
occurrences all number	8	6	15	10
Cardiac disorders
atrial fibrillation
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	0 / 69 (0.00%)	0 / 71 (0.00%)	4 / 63 (6.35%)
occurrences all number	1	0	0	4
tachycardia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	4 / 69 (5.80%)	3 / 71 (4.23%)	4 / 63 (6.35%)
occurrences all number	2	4	3	4
Nervous system disorders
dizziness
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	13 / 69 (18.84%)	4 / 71 (5.63%)	6 / 63 (9.52%)
occurrences all number	8	18	4	7
dysgeusia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	12 / 67 (17.91%)	6 / 69 (8.70%)	7 / 71 (9.86%)	8 / 63 (12.70%)
occurrences all number	16	10	7	10
headache
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	19 / 67 (28.36%)	8 / 69 (11.59%)	14 / 71 (19.72%)	5 / 63 (7.94%)
occurrences all number	33	12	20	6
hypoaesthesia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	4 / 69 (5.80%)	3 / 71 (4.23%)	1 / 63 (1.59%)
occurrences all number	6	8	3	1
neuropathy peripheral
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	4 / 69 (5.80%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences all number	4	4	0	2
paraesthesia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	4 / 69 (5.80%)	2 / 71 (2.82%)	1 / 63 (1.59%)
occurrences all number	5	8	2	1
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	32 / 67 (47.76%)	37 / 69 (53.62%)	38 / 71 (53.52%)	40 / 63 (63.49%)
occurrences all number	95	103	111	94
leukopenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	4 / 69 (5.80%)	10 / 71 (14.08%)	10 / 63 (15.87%)
occurrences all number	20	14	36	23
neutropenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	22 / 67 (32.84%)	17 / 69 (24.64%)	52 / 71 (73.24%)	35 / 63 (55.56%)
occurrences all number	70	42	152	94
thrombocytopenia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	22 / 67 (32.84%)	15 / 69 (21.74%)	36 / 71 (50.70%)	27 / 63 (42.86%)
occurrences all number	72	48	128	73
Ear and labyrinth disorders
tinnitus
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	2 / 69 (2.90%)	1 / 71 (1.41%)	3 / 63 (4.76%)
occurrences all number	7	2	1	3
Eye disorders
lacrimation increased
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	10 / 69 (14.49%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences all number	10	10	0	2
Gastrointestinal disorders
abdominal distension
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	6 / 69 (8.70%)	0 / 71 (0.00%)	0 / 63 (0.00%)
occurrences all number	6	8	0	0
abdominal pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	12 / 67 (17.91%)	7 / 69 (10.14%)	2 / 71 (2.82%)	3 / 63 (4.76%)
occurrences all number	17	9	3	4
abdominal pain upper
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	0 / 69 (0.00%)	4 / 71 (5.63%)	5 / 63 (7.94%)
occurrences all number	4	0	5	6
constipation
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	19 / 67 (28.36%)	21 / 69 (30.43%)	18 / 71 (25.35%)	21 / 63 (33.33%)
occurrences all number	27	29	29	28
diarrhoea
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	19 / 67 (28.36%)	19 / 69 (27.54%)	9 / 71 (12.68%)	12 / 63 (19.05%)
occurrences all number	23	28	12	14
dry mouth
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	2 / 69 (2.90%)	0 / 71 (0.00%)	2 / 63 (3.17%)
occurrences all number	4	2	0	2
dyspepsia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	6 / 67 (8.96%)	5 / 69 (7.25%)	0 / 71 (0.00%)	3 / 63 (4.76%)
occurrences all number	8	6	0	3
dysphagia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	2 / 69 (2.90%)	1 / 71 (1.41%)	4 / 63 (6.35%)
occurrences all number	7	3	1	4
gastrooesophageal reflux disease
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	3 / 69 (4.35%)	4 / 71 (5.63%)	1 / 63 (1.59%)
occurrences all number	4	3	4	1
gingival bleeding
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	0 / 69 (0.00%)	2 / 71 (2.82%)	1 / 63 (1.59%)
occurrences all number	6	0	2	1
nausea
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	35 / 67 (52.24%)	39 / 69 (56.52%)	27 / 71 (38.03%)	36 / 63 (57.14%)
occurrences all number	65	71	44	51
stomatitis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	9 / 67 (13.43%)	6 / 69 (8.70%)	3 / 71 (4.23%)	6 / 63 (9.52%)
occurrences all number	13	6	3	9
vomiting
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	22 / 67 (32.84%)	24 / 69 (34.78%)	18 / 71 (25.35%)	12 / 63 (19.05%)
occurrences all number	35	34	23	15
Skin and subcutaneous tissue disorders
alopecia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	9 / 67 (13.43%)	5 / 69 (7.25%)	5 / 71 (7.04%)	8 / 63 (12.70%)
occurrences all number	9	5	5	8
night sweats
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	3 / 69 (4.35%)	2 / 71 (2.82%)	4 / 63 (6.35%)
occurrences all number	4	3	2	4
pruritus
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	1 / 69 (1.45%)	3 / 71 (4.23%)	4 / 63 (6.35%)
occurrences all number	2	1	4	5
Renal and urinary disorders
proteinuria
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	3 / 69 (4.35%)	9 / 71 (12.68%)	1 / 63 (1.59%)
occurrences all number	6	3	11	1
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	11 / 67 (16.42%)	7 / 69 (10.14%)	7 / 71 (9.86%)	5 / 63 (7.94%)
occurrences all number	16	10	16	8
back pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	14 / 67 (20.90%)	12 / 69 (17.39%)	10 / 71 (14.08%)	9 / 63 (14.29%)
occurrences all number	21	18	14	10
bone pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	4 / 67 (5.97%)	1 / 69 (1.45%)	5 / 71 (7.04%)	3 / 63 (4.76%)
occurrences all number	5	1	7	4
muscle spasms
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	1 / 69 (1.45%)	4 / 71 (5.63%)	2 / 63 (3.17%)
occurrences all number	5	1	4	2
musculoskeletal chest pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	4 / 69 (5.80%)	5 / 71 (7.04%)	4 / 63 (6.35%)
occurrences all number	10	6	5	5
musculoskeletal pain
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	7 / 67 (10.45%)	2 / 69 (2.90%)	4 / 71 (5.63%)	3 / 63 (4.76%)
occurrences all number	11	2	5	3
myalgia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	6 / 67 (8.96%)	3 / 69 (4.35%)	3 / 71 (4.23%)	1 / 63 (1.59%)
occurrences all number	6	4	5	1
pain in extremity
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	4 / 69 (5.80%)	2 / 71 (2.82%)	1 / 63 (1.59%)
occurrences all number	9	4	2	1
Infections and infestations
nasopharyngitis
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	4 / 69 (5.80%)	0 / 71 (0.00%)	3 / 63 (4.76%)
occurrences all number	3	8	0	4
pneumonia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	4 / 69 (5.80%)	3 / 71 (4.23%)	6 / 63 (9.52%)
occurrences all number	2	4	4	6
upper respiratory tract infection
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	5 / 69 (7.25%)	4 / 71 (5.63%)	3 / 63 (4.76%)
occurrences all number	13	6	4	3
urinary tract infection
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	7 / 67 (10.45%)	6 / 69 (8.70%)	3 / 71 (4.23%)	4 / 63 (6.35%)
occurrences all number	8	15	4	6
vulvovaginal mycotic infection
alternative dictionary used: MedDRA 18.1
subjects affected / exposed ^[1]	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)
occurrences all number	1	0	1	0
Metabolism and nutrition disorders
decreased appetite
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	20 / 67 (29.85%)	18 / 69 (26.09%)	24 / 71 (33.80%)	15 / 63 (23.81%)
occurrences all number	30	27	35	17
dehydration
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	6 / 67 (8.96%)	12 / 69 (17.39%)	9 / 71 (12.68%)	5 / 63 (7.94%)
occurrences all number	6	12	9	5
hyperglycaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	3 / 67 (4.48%)	7 / 69 (10.14%)	6 / 71 (8.45%)	7 / 63 (11.11%)
occurrences all number	7	12	12	9
hypoalbuminaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	1 / 67 (1.49%)	7 / 69 (10.14%)	10 / 71 (14.08%)	2 / 63 (3.17%)
occurrences all number	1	12	23	3
hypocalcaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	2 / 67 (2.99%)	3 / 69 (4.35%)	6 / 71 (8.45%)	3 / 63 (4.76%)
occurrences all number	2	4	18	3
hypokalaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	8 / 67 (11.94%)	8 / 69 (11.59%)	9 / 71 (12.68%)	8 / 63 (12.70%)
occurrences all number	9	9	14	13
hypomagnesaemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	10 / 67 (14.93%)	11 / 69 (15.94%)	14 / 71 (19.72%)	17 / 63 (26.98%)
occurrences all number	12	15	30	23
hyponatraemia
alternative dictionary used: MedDRA 18.1
subjects affected / exposed	5 / 67 (7.46%)	8 / 69 (11.59%)	8 / 71 (11.27%)	5 / 63 (7.94%)
occurrences all number	11	10	12	5

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

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Were there any global substantial amendments to the protocol? Yes

03 Aug 2012

Version 7: Upon annual review of safety data, the risk profile was revised to reflect the increases in the number of participants with cancer treated with ramucirumab and the number of adverse events reported in the clinical trials.

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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