Trial Outcomes & Findings for First-line Treatment of Participants With Stage IV Squamous Non-Small Cell Lung Cancer With Necitumumab and Gemcitabine-Cisplatin (NCT NCT00981058)

NCT ID: NCT00981058

Last Updated: 2025-06-18

Results Overview

Overall survival is defined as the time from randomization to death from any cause. Participants who do not die at the end of the extended follow-up period, or were lost to follow-up during the study, were censored at the last date they were known to be alive. OS was estimated by the Kaplan-Meier method.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1093 participants
• Primary outcome timeframe: Randomization to Death from Any Cause (Up to 31 Months)
• Results posted on: 2025-06-18

Participant Flow

Completers are defined as those participants who died due to any cause in this study.

Participant milestones

Measure	Necitumumab + Gemcitabine + Cisplatin Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Overall Study STARTED	545	548
Overall Study Received at Least 1 Dose of Study Drug	538	541
Overall Study COMPLETED	476	487
Overall Study NOT COMPLETED	69	61

Reasons for withdrawal

Measure	Necitumumab + Gemcitabine + Cisplatin Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Overall Study Progressive Disease	38	31
Overall Study Lost to Follow-up	3	2
Overall Study Physician Decision	4	5
Overall Study Randomization Error	0	1
Overall Study Withdrawal by Subject	24	22

Baseline Characteristics

First-line Treatment of Participants With Stage IV Squamous Non-Small Cell Lung Cancer With Necitumumab and Gemcitabine-Cisplatin

Baseline characteristics by cohort

Measure	Necitumumab + Gemcitabine + Cisplatin n=545 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=548 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Total n=1093 Participants Total of all reporting groups
Age, Continuous	62.0 years n=5 Participants	62.0 years n=7 Participants	62.0 years n=5 Participants
Sex: Female, Male Female	95 Participants n=5 Participants	90 Participants n=7 Participants	185 Participants n=5 Participants
Sex: Female, Male Male	450 Participants n=5 Participants	458 Participants n=7 Participants	908 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	55 Participants n=5 Participants	56 Participants n=7 Participants	111 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	489 Participants n=5 Participants	490 Participants n=7 Participants	979 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Asian	43 participants n=5 Participants	42 participants n=7 Participants	85 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Race/Ethnicity, Customized White	457 participants n=5 Participants	456 participants n=7 Participants	913 participants n=5 Participants
Race/Ethnicity, Customized More than one race	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Other	38 participants n=5 Participants	43 participants n=7 Participants	81 participants n=5 Participants
Region of Enrollment Russian Federation	94 participants n=5 Participants	101 participants n=7 Participants	195 participants n=5 Participants
Region of Enrollment Singapore	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment United States	20 participants n=5 Participants	16 participants n=7 Participants	36 participants n=5 Participants
Region of Enrollment Thailand	3 participants n=5 Participants	6 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Portugal	8 participants n=5 Participants	9 participants n=7 Participants	17 participants n=5 Participants
Region of Enrollment Greece	18 participants n=5 Participants	14 participants n=7 Participants	32 participants n=5 Participants
Region of Enrollment Austria	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment Brazil	28 participants n=5 Participants	30 participants n=7 Participants	58 participants n=5 Participants
Region of Enrollment Korea, Republic of	24 participants n=5 Participants	23 participants n=7 Participants	47 participants n=5 Participants
Region of Enrollment Poland	69 participants n=5 Participants	59 participants n=7 Participants	128 participants n=5 Participants
Region of Enrollment Slovakia	9 participants n=5 Participants	10 participants n=7 Participants	19 participants n=5 Participants
Region of Enrollment France	34 participants n=5 Participants	39 participants n=7 Participants	73 participants n=5 Participants
Region of Enrollment Serbia	11 participants n=5 Participants	13 participants n=7 Participants	24 participants n=5 Participants
Region of Enrollment Croatia	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Romania	46 participants n=5 Participants	45 participants n=7 Participants	91 participants n=5 Participants
Region of Enrollment Hungary	43 participants n=5 Participants	41 participants n=7 Participants	84 participants n=5 Participants
Region of Enrollment Philippines	12 participants n=5 Participants	8 participants n=7 Participants	20 participants n=5 Participants
Region of Enrollment United Kingdom	9 participants n=5 Participants	10 participants n=7 Participants	19 participants n=5 Participants
Region of Enrollment Spain	33 participants n=5 Participants	25 participants n=7 Participants	58 participants n=5 Participants
Region of Enrollment Canada	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Belgium	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment Taiwan	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Italy	13 participants n=5 Participants	12 participants n=7 Participants	25 participants n=5 Participants
Region of Enrollment South Africa	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Australia	4 participants n=5 Participants	6 participants n=7 Participants	10 participants n=5 Participants
Region of Enrollment Germany	49 participants n=5 Participants	59 participants n=7 Participants	108 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline 0	164 participants n=5 Participants	180 participants n=7 Participants	344 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline 1	332 participants n=5 Participants	320 participants n=7 Participants	652 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline 2	49 participants n=5 Participants	47 participants n=7 Participants	96 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline 3	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Smoking History Ex-Light Smoker	18 participants n=5 Participants	26 participants n=7 Participants	44 participants n=5 Participants
Smoking History Non-Smoker	26 participants n=5 Participants	27 participants n=7 Participants	53 participants n=5 Participants
Smoking History Smoker	500 participants n=5 Participants	495 participants n=7 Participants	995 participants n=5 Participants
Smoking History Missing	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Disease Stage at Study Entry Stage IIIB	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Disease Stage at Study Entry Stage IV	543 participants n=5 Participants	546 participants n=7 Participants	1089 participants n=5 Participants
Disease Stage at Study Entry Missing	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Disease Histology Squamous	543 participants n=5 Participants	545 participants n=7 Participants	1088 participants n=5 Participants
Disease Histology Other Histology	2 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants
Sites of Metastatic Disease Bone	120 participants n=5 Participants	131 participants n=7 Participants	251 participants n=5 Participants
Sites of Metastatic Disease Brain	28 participants n=5 Participants	30 participants n=7 Participants	58 participants n=5 Participants
Sites of Metastatic Disease Liver	109 participants n=5 Participants	117 participants n=7 Participants	226 participants n=5 Participants
Sites of Metastatic Disease Lung	453 participants n=5 Participants	453 participants n=7 Participants	906 participants n=5 Participants
Sites of Metastatic Disease Lymph Nodes	431 participants n=5 Participants	451 participants n=7 Participants	882 participants n=5 Participants
Sites of Metastatic Disease Peritoneal	20 participants n=5 Participants	17 participants n=7 Participants	37 participants n=5 Participants
Sites of Metastatic Disease Pleural	149 participants n=5 Participants	155 participants n=7 Participants	304 participants n=5 Participants
Sites of Metastatic Disease Skin	9 participants n=5 Participants	8 participants n=7 Participants	17 participants n=5 Participants
Sites of Metastatic Disease Soft Tissue	23 participants n=5 Participants	21 participants n=7 Participants	44 participants n=5 Participants
Sites of Metastatic Disease Other	156 participants n=5 Participants	146 participants n=7 Participants	302 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to Death from Any Cause (Up to 31 Months)

Population: All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 127, Gemcitabine + Cisplatin = 106

Overall survival is defined as the time from randomization to death from any cause. Participants who do not die at the end of the extended follow-up period, or were lost to follow-up during the study, were censored at the last date they were known to be alive. OS was estimated by the Kaplan-Meier method.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=545 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=548 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Overall Survival Time (OS)	11.5 Months Interval 10.4 to 12.6	9.9 Months Interval 8.9 to 11.1

SECONDARY outcome

Timeframe: Randomization to Measured Progressive Disease or Death from Any Cause (Up to 31 Months)

Population: All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 114, Gemcitabine + Cisplatin = 131

PFS is defined as the time from randomization until the first radiographic documentation of objective measured progressive disease as defined by RECIST (Version 1.0), or death from any cause. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions. Participants who die without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment. If no baseline or postbaseline radiologic assessment was available, the participants were censored at the date of randomization. If death or PD occurs after two or more consecutive missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=545 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=548 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Progression-Free Survival (PFS)	5.7 months Interval 5.6 to 6.0	5.5 months Interval 4.8 to 5.6

SECONDARY outcome

Timeframe: Baseline to Measured Progressive Disease (Up to 31 Months)

Population: All randomized participants.

ORR is confirmed best overall tumor response of CR or PR. According to RECIST v1.0, CR was defined as the disappearance of all target and non-target lesions. PR defined as a >=30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD; Percentage of participants was calculated as: (total number of participants with CR or PR from start of the treatment until disease progression or recurrence)/total number of participants treated) * 100.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=545 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=548 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Percentage of Participants Achieving Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR])	31.2 percentage of participants Interval 27.4 to 35.2	28.8 percentage of participants Interval 25.2 to 32.8

SECONDARY outcome

Timeframe: Randomization to Measured Progressive Disease, Death From Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up to 31 Months)

Population: All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 16, Gemcitabine + Cisplatin =20

TTF is defined as the time from the date of randomization until the date of the first radiographic documentation of PD, death from any cause, discontinuation of treatment for any reason, or initiation of new cancer therapy. Participants who withdrew from the study for reasons other than progression or death were censored at the date of study withdrawal. Participants who did not meet any of the criteria for treatment failure were censored at their date of last contact in the study.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=545 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=548 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Time to Treatment Failure (TTF)	4.3 Months Interval 4.2 to 4.8	3.6 Months Interval 3.3 to 4.1

SECONDARY outcome

Timeframe: Baseline, Cycle 6 (Cycle = 3 Weeks)

Population: All randomized participants who had evaluable baseline and postbaseline EQ-5D data.

The EQ-5D is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a three level scale 1-3 (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension).

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=305 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=245 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Mean Change From Baseline in Patient Reported Outcomes (PRO) Using the European Quality of Life-5 Dimension (EQ-5D)	-0.0053 units on a scale Standard Deviation 0.23626	-0.0083 units on a scale Standard Deviation 0.23866

SECONDARY outcome

Timeframe: Baseline, Cycle 6 (Cycle = 3 Weeks)

Population: All randomized participants who had evaluable data for LCSS.

The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 items were global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-mm lines. A higher score for any item represented a higher level of symptoms/problems. Scores for each of the reported categories ranged from 0 (for best outcome) to 100 (for worst outcome). The Average Symptom Burden Index (ASBI) was the mean of the 6 symptom items of the LCSS, and the Total LCSS was the mean of all 9 LCSS items. ASBI and Total LCSS were not computed for a participant if he/she had 1 or more missing values for the 6 and 9 items, respectively.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=545 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=548 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Quality of Life (n=305, 243)	-0.3 millimeter (mm) Standard Deviation 27.35	-1.6 millimeter (mm) Standard Deviation 24.71
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Loss of Appetite (n=304, 242)	1.8 millimeter (mm) Standard Deviation 31.84	1.5 millimeter (mm) Standard Deviation 29.30
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Fatigue (n=302, 242)	6.3 millimeter (mm) Standard Deviation 29.15	3.5 millimeter (mm) Standard Deviation 25.29
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Cough (n=303, 243)	-7.8 millimeter (mm) Standard Deviation 28.05	-9.1 millimeter (mm) Standard Deviation 25.74
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Dyspnea (n=305, 244)	-2.8 millimeter (mm) Standard Deviation 26.52	-1.8 millimeter (mm) Standard Deviation 25.27
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Pain (n=302, 243)	-3.3 millimeter (mm) Standard Deviation 17.98	-2.2 millimeter (mm) Standard Deviation 17.22
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Overall Symptoms (n=303, 242)	-0.3 millimeter (mm) Standard Deviation 26.19	-0.6 millimeter (mm) Standard Deviation 26.92
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Interference (n=306,241)	3.8 millimeter (mm) Standard Deviation 29.74	2.2 millimeter (mm) Standard Deviation 26.79
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) Average Symptom Burden Index (ASBI) (n=294, 234)	-1.9 millimeter (mm) Standard Deviation 16.55	-1.5 millimeter (mm) Standard Deviation 16.52
Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) LCSS Total Score (n=290, 228)	-0.8 millimeter (mm) Standard Deviation 17.03	-0.8 millimeter (mm) Standard Deviation 16.17

SECONDARY outcome

Timeframe: 31 Months

Population: All randomized participants who received at least one dose of study drug and had evaluable data for EGFR IHC.

EGFR IHC Histoscore H-score = weighted sum of % 1+ cells, twice % 2+ cells, and three times % 3+ cells. IHC H-score criteria was used to assess participants with a low EGFR expression defined by a H-score cutoff value of <200 and participants with a high EGFR expression defined by a H-score of cutoff value of >=200.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=486 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=496 Participants Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC) 0	24 participants	23 participants
Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC) >0	462 participants	473 participants
Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC) <200	295 participants	313 participants
Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC) ≥200	191 participants	183 participants

SECONDARY outcome

Timeframe: Day 1 of Cycle 2, 3, 4, 5 and 6 Prior to Necitumumab Drug Infusion, Up to 24 Months

Population: All randomized participants who received at least one dose of study drug and had evaluable data for PK.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=545 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab Predose Cycle 2 Day 1 (n=419)	52.4 micrograms/milliliter (ug/mL) Geometric Coefficient of Variation 95.9	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab Predose Cycle3 Day 1 (n=386)	76.6 micrograms/milliliter (ug/mL) Geometric Coefficient of Variation 80.6	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab Predose Cycle 4 Day 1 (n=344)	94.5 micrograms/milliliter (ug/mL) Geometric Coefficient of Variation 92.2	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab Predose Cycle 5 Day 1 (n=297)	101 micrograms/milliliter (ug/mL) Geometric Coefficient of Variation 90	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab Predose Cycle 6 Day 1 (n=262)	98.5 micrograms/milliliter (ug/mL) Geometric Coefficient of Variation 80	—

SECONDARY outcome

Timeframe: Baseline through 31 Months

Population: All randomized participants who received who received at least 1 dose of drug and had evaluable data for antibodies.

A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point.

Outcome measures

Measure	Necitumumab + Gemcitabine + Cisplatin n=528 Participants Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Number of Participants With a Serum Anti-Necitumumab Antibody Assessment Participants with at least 1 positive titer	81 participants	—
Number of Participants With a Serum Anti-Necitumumab Antibody Assessment Neutralizing antibody detected	5 participants	—

Adverse Events

Necitumumab + Gemcitabine + Cisplatin

Serious events: 262 serious events

Other events: 518 other events

Deaths: 476 deaths

Gemcitabine + Cisplatin

Serious events: 208 serious events

Other events: 512 other events

Deaths: 487 deaths

Serious adverse events

Measure	Necitumumab + Gemcitabine + Cisplatin n=538 participants at risk Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=541 participants at risk Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Blood and lymphatic system disorders Agranulocytosis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Anaemia	4.1% 22/538 • Number of events 22 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.1% 17/541 • Number of events 17 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Febrile neutropenia	1.1% 6/538 • Number of events 6 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.3% 7/541 • Number of events 7 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Leukopenia	1.1% 6/538 • Number of events 6 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.74% 4/541 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Myelosuppression	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Neutropenia	3.7% 20/538 • Number of events 20 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	6.1% 33/541 • Number of events 33 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Pancytopenia	1.1% 6/538 • Number of events 6 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Thrombocytopenia	3.2% 17/538 • Number of events 17 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.7% 20/541 • Number of events 20 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Thrombocytosis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Acute coronary syndrome	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Acute myocardial infarction	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Atrial fibrillation	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.74% 4/541 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Atrial flutter	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Cardiac arrest	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Cardiac failure	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Cardiac failure acute	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Cardiac failure congestive	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Cardiac tamponade	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Cardio-respiratory arrest	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Coronary artery disease	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Myocardial infarction	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Myocardial ischaemia	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Pericardial effusion	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Pericardial effusion malignant	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Pericarditis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Cardiac disorders Supraventricular tachycardia	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Congenital, familial and genetic disorders Tracheo-oesophageal fistula	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Ear and labyrinth disorders Deafness bilateral	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Ear and labyrinth disorders Ototoxicity	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Abdominal pain	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Abdominal pain upper	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Colitis ischaemic	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Constipation	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Diarrhoea	1.5% 8/538 • Number of events 8 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.92% 5/541 • Number of events 5 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Duodenal ulcer perforation	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Dysphagia	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Enteritis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Gastric haemorrhage	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Gastric ulcer	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Gastroduodenal ulcer	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Gastrointestinal disorder	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Haematemesis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Haematochezia	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Ileus	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Intestinal obstruction	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Mesenteric vein thrombosis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Nausea	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Pancreatitis acute	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Small intestinal obstruction	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Stomatitis	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Vomiting	2.2% 12/538 • Number of events 12 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Asthenia	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Chills	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Death	1.5% 8/538 • Number of events 8 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Fatigue	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.74% 4/541 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders General physical health deterioration	1.5% 8/538 • Number of events 8 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.3% 7/541 • Number of events 7 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Generalised oedema	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Non-cardiac chest pain	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Oedema	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Oedema peripheral	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Pyrexia	1.3% 7/538 • Number of events 7 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.74% 4/541 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Sudden death	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Hepatobiliary disorders Bile duct stenosis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Hepatobiliary disorders Cholelithiasis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Hepatobiliary disorders Hepatorenal syndrome	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Immune system disorders Drug hypersensitivity	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Appendicitis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Bacterial infection	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Bronchitis	1.1% 6/538 • Number of events 6 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Cystitis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Dental gangrene	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Device related infection	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Escherichia urinary tract infection	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Gastroenteritis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Infectious pleural effusion	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Injection site abscess	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Lower respiratory tract infection	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.74% 4/541 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Neutropenic sepsis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Oral fungal infection	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Pneumonia	2.4% 13/538 • Number of events 13 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.7% 20/541 • Number of events 20 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Pneumonia bacterial	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Pneumonia necrotising	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Pulmonary tuberculosis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Pyelonephritis acute	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Respiratory tract infection	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Respiratory tract infection bacterial	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Sepsis	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.92% 5/541 • Number of events 5 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Septic shock	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Upper respiratory tract infection	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Upper respiratory tract infection bacterial	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Urinary tract infection	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Urosepsis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Femoral neck fracture	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Femur fracture	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Head injury	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Incorrect dose administered	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Medication error	2.2% 12/538 • Number of events 12 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.9% 21/541 • Number of events 21 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Overdose	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Spinal compression fracture	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Toxicity to various agents	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Underdose	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Injury, poisoning and procedural complications Vascular graft occlusion	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Alanine aminotransferase increased	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Aspartate aminotransferase increased	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Blood creatinine increased	1.1% 6/538 • Number of events 6 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Blood phosphorus decreased	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations C-reactive protein increased	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Ecg signs of myocardial ischaemia	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations False positive investigation result	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Gamma-glutamyltransferase increased	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Haemoglobin decreased	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Platelet count decreased	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Decreased appetite	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Dehydration	0.93% 5/538 • Number of events 5 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.5% 8/541 • Number of events 8 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Electrolyte imbalance	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypercalcaemia	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypercreatininaemia	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hyperglycaemia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hyperkalaemia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hyperuricaemia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypocalcaemia	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypokalaemia	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypomagnesaemia	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hyponatraemia	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.1% 6/541 • Number of events 6 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypophosphataemia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Arthralgia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Back pain	0.93% 5/538 • Number of events 5 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Osteolysis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Pain in extremity	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Pathological fracture	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	4.8% 26/538 • Number of events 26 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	4.3% 23/541 • Number of events 23 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Ataxia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Brain oedema	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Cerebral haemorrhage	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Cerebral infarction	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Cerebral ischaemia	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Dizziness	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Encephalopathy	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Epilepsy	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Headache	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Hemiplegia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Hydrocephalus	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Ischaemic stroke	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Loss of consciousness	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Paraesthesia	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Peripheral motor neuropathy	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Presyncope	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Radial nerve palsy	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Radiculopathy	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Sciatica	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Seizure	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Spinal cord compression	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Syncope	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Transient ischaemic attack	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Vocal cord paralysis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Psychiatric disorders Abnormal behaviour	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Psychiatric disorders Alcohol abuse	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Psychiatric disorders Completed suicide	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Psychiatric disorders Confusional state	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Psychiatric disorders Delirium	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Psychiatric disorders Depression	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Renal and urinary disorders Acute kidney injury	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.92% 5/541 • Number of events 5 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Renal and urinary disorders Nephropathy toxic	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Renal and urinary disorders Nephrotic syndrome	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Renal and urinary disorders Renal failure	1.5% 8/538 • Number of events 8 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.1% 6/541 • Number of events 6 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Renal and urinary disorders Renal infarct	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Renal and urinary disorders Renal tubular necrosis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Renal and urinary disorders Urinary retention	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Reproductive system and breast disorders Pelvic pain	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Bronchitis chronic	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.56% 3/538 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.74% 4/541 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Haemoptysis	2.0% 11/538 • Number of events 11 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.7% 9/541 • Number of events 9 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pharyngeal inflammation	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pulmonary artery thrombosis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.5% 19/538 • Number of events 19 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.7% 9/541 • Number of events 9 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.92% 5/541 • Number of events 5 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pulmonary toxicity	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Pulmonary venous thrombosis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Respiratory tract haemorrhage	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Dermatitis allergic	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Skin fissures	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Skin toxicity	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Skin ulcer	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Social circumstances Social stay hospitalisation	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Deep vein thrombosis	0.74% 4/538 • Number of events 4 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Hypertensive crisis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Hypotension	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Hypovolaemic shock	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Orthostatic hypotension	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.37% 2/541 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Peripheral artery occlusion	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Peripheral artery thrombosis	0.37% 2/538 • Number of events 2 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Peripheral embolism	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Peripheral venous disease	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Superficial vein thrombosis	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Superior vena cava occlusion	0.00% 0/538 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Superior vena cava syndrome	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Thrombosis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Vena cava thrombosis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Venous thrombosis	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Vascular disorders Venous thrombosis limb	0.19% 1/538 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.

Other adverse events

Measure	Necitumumab + Gemcitabine + Cisplatin n=538 participants at risk Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin n=541 participants at risk Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Blood and lymphatic system disorders Anaemia	41.1% 221/538 • Number of events 221 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	45.5% 246/541 • Number of events 246 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Leukopenia	13.2% 71/538 • Number of events 71 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	15.7% 85/541 • Number of events 85 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Neutropenia	40.9% 220/538 • Number of events 220 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	42.3% 229/541 • Number of events 229 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Blood and lymphatic system disorders Thrombocytopenia	19.1% 103/538 • Number of events 103 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	22.9% 124/541 • Number of events 124 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Abdominal pain upper	5.8% 31/538 • Number of events 31 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.4% 29/541 • Number of events 29 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Constipation	20.6% 111/538 • Number of events 111 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	18.7% 101/541 • Number of events 101 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Diarrhoea	15.6% 84/538 • Number of events 84 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	11.1% 60/541 • Number of events 60 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Dyspepsia	5.0% 27/538 • Number of events 27 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	4.1% 22/541 • Number of events 22 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Nausea	49.3% 265/538 • Number of events 265 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	52.5% 284/541 • Number of events 284 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Stomatitis	10.8% 58/538 • Number of events 58 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.9% 32/541 • Number of events 32 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Gastrointestinal disorders Vomiting	28.4% 153/538 • Number of events 153 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	24.8% 134/541 • Number of events 134 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Asthenia	23.2% 125/538 • Number of events 125 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	20.7% 112/541 • Number of events 112 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Fatigue	21.7% 117/538 • Number of events 117 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	22.4% 121/541 • Number of events 121 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Oedema peripheral	8.2% 44/538 • Number of events 44 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	7.8% 42/541 • Number of events 42 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
General disorders Pyrexia	13.0% 70/538 • Number of events 70 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	11.3% 61/541 • Number of events 61 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Paronychia	6.7% 36/538 • Number of events 36 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.18% 1/541 • Number of events 1 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Infections and infestations Urinary tract infection	5.8% 31/538 • Number of events 31 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	2.4% 13/541 • Number of events 13 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Blood creatinine increased	9.1% 49/538 • Number of events 49 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	7.6% 41/541 • Number of events 41 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Investigations Weight decreased	13.6% 73/538 • Number of events 73 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	6.7% 36/541 • Number of events 36 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Decreased appetite	30.1% 162/538 • Number of events 162 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	28.3% 153/541 • Number of events 153 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hyperglycaemia	5.2% 28/538 • Number of events 28 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.0% 16/541 • Number of events 16 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hyperkalaemia	5.0% 27/538 • Number of events 27 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.5% 19/541 • Number of events 19 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypokalaemia	6.9% 37/538 • Number of events 37 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.0% 27/541 • Number of events 27 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hypomagnesaemia	29.6% 159/538 • Number of events 159 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	15.2% 82/541 • Number of events 82 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Metabolism and nutrition disorders Hyponatraemia	4.3% 23/538 • Number of events 23 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.4% 29/541 • Number of events 29 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Arthralgia	5.8% 31/538 • Number of events 31 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.7% 31/541 • Number of events 31 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Back pain	7.1% 38/538 • Number of events 38 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.5% 30/541 • Number of events 30 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Musculoskeletal and connective tissue disorders Pain in extremity	5.0% 27/538 • Number of events 27 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.9% 21/541 • Number of events 21 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Dizziness	10.2% 55/538 • Number of events 55 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	7.8% 42/541 • Number of events 42 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Nervous system disorders Headache	10.6% 57/538 • Number of events 57 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.9% 32/541 • Number of events 32 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Psychiatric disorders Insomnia	5.4% 29/538 • Number of events 29 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.5% 30/541 • Number of events 30 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Cough	17.3% 93/538 • Number of events 93 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	13.3% 72/541 • Number of events 72 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Dyspnoea	17.3% 93/538 • Number of events 93 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	14.6% 79/541 • Number of events 79 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Epistaxis	7.4% 40/538 • Number of events 40 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	3.0% 16/541 • Number of events 16 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Haemoptysis	9.1% 49/538 • Number of events 49 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	4.1% 22/541 • Number of events 22 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Respiratory, thoracic and mediastinal disorders Productive cough	5.4% 29/538 • Number of events 29 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	2.2% 12/541 • Number of events 12 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Acne	8.7% 47/538 • Number of events 47 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Alopecia	14.1% 76/538 • Number of events 76 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	12.9% 70/541 • Number of events 70 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Dermatitis acneiform	14.9% 80/538 • Number of events 80 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.55% 3/541 • Number of events 3 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Dry skin	6.5% 35/538 • Number of events 35 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	1.5% 8/541 • Number of events 8 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Pruritus	7.2% 39/538 • Number of events 39 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.92% 5/541 • Number of events 5 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Rash	46.8% 252/538 • Number of events 252 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	5.9% 32/541 • Number of events 32 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
Skin and subcutaneous tissue disorders Skin fissures	5.0% 27/538 • Number of events 27 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.	0.00% 0/541 • Baseline Up To 156 Months All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: GT60