Phase III Trial BI 695502 Plus Chemotherapy vs. Avastin®... | NCT02272413

ID	Type	Description	Link
2014-002161-30	EudraCT Number

Label	Type	Description	Intervention Names
BI 695502	Experimental		Drug: BI 695502
Avastin	Active Comparator		Drug: Avastin

Name	Type	Description	Arm Group Labels	Other Names
BI 695502	Drug		BI 695502
Avastin

Measure	Description	Time Frame
Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment	ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration, until 18 weeks.	Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier.

Measure	Description	Time Frame
Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin®	The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®: Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), Thromboembolic events (arterial or venous), Febrile neutropenia, Gastrointestinal perforations, Hypertension, Proteinuria, Pulmonary hemorrhage, Other hemorrhages (not including pulmonary hemorrhages), Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Pacific Cancer Medical Center, Inc.		Anaheim	California	92801	United States
Comprehensive Blood and Cancer Center

ID	Title	Description
FG000	BI 695502	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jan 17, 2018	Oct 30, 2019

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment

ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration, until 18 weeks.

The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Best ORR (CR+PR) is reported for observed values.

Posted

Number

Percentage of patients (%)

Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier.

ID	Title	Description
OG000	BI 695502	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
OG001	Avastin® US	Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Units	Counts
Participants	OG000335 OG001328

Title

Denominators

Categories

Title	Measurements
	OG00054.0 OG00163.1

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian).	Log-binomial regression				Ratio of best ORR	0.8550			2-Sided	90	0.7697	0.9506					Equivalence	The null hypothesis was to be rejected in favor of equivalence if the 2-sided 90% confidence interval (CI) for the ratio in best ORR between the treatments was entirely contained within the equivalence margins of 0.736 to 1.359.

Secondary

Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin®

The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®:

Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions),
Thromboembolic events (arterial or venous),
Febrile neutropenia,
Gastrointestinal perforations,
Hypertension,
Proteinuria,
Pulmonary hemorrhage,
Other hemorrhages (not including pulmonary hemorrhages),
Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs.

The Treated Set contained all patients who signed informed consent and who received at least one dose of trial drug.

Posted

Number

95% Confidence Interval

Percentage of patients (%)

From first dose of trial drug until 16 weeks after the last dose of trial medication, up to 218 days.

ID	Title	Description
OG000	BI 695502	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Secondary

Progression-Free Survival (PFS) Time as Determined by Investigator Assessment

PFS was defined as the time from randomization until disease progression as determined by Investigator assessment or death from any cause, whichever occurred first during the pre-switch period. Disease progression was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters. Tumor assessments were performed prior to trial drug administration. PFS was calculated using the Kaplan-Meier technique.

The Full Analysis Set (FAS) contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.

Posted

Median

95% Confidence Interval

Months

Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression. Analysis performed for pre-switch period only; maximum duration of up to 35 cycles (105 weeks).

ID	Title	Description
OG000	BI 695502	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Secondary

Overall Survival (OS) Time

OS was defined as the time randomization until death from any cause during the pre-switch period. OS was calculated using the Kaplan-Meier technique.

The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.

Posted

Median

95% Confidence Interval

Months

From baseline until death due to any cause, ie., up to 35 cycles (105 weeks).

ID	Title	Description
OG000	BI 695502	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
OG001	Avastin® US	Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Secondary

Duration of Response (DOR) as Determined by Investigator Assessment

DOR was the time from first documented CR or PR until time of progression as determined by Investigator assessment during the pre-switch period. Tumor assessments were performed prior to trial drug administration. DOR was calculated using the Kaplan-Meier technique.

The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Only patients with an objective response were included in the analysis.

Posted

Median

95% Confidence Interval

Months

Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression., ie up to 35 cycles (105 weeks).

ID	Title	Description
OG000	BI 695502	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
OG001

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pneumonia	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0009 affected335 at risk EG0019 affected328 at risk EG0021 affected42 at risk EG0030 affected46 at risk
Lung infection	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Peritonitis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Pyelonephritis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Anal abscess	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Anorectal infection	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Appendicitis perforated	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Klebsiella infection	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Lower respiratory tract infection	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Lung abscess	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Osteomyelitis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Pulmonary mycosis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Respiratory tract infection	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Bronchitis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Campylobacter gastroenteritis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Diverticulitis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Herpes zoster	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Infectious pleural effusion	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Pneumonia bacterial	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Respiratory tract infection bacteria	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Subcutaneous abscess	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Urosepsis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Bladder transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Brain neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Intracranial tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG00013 affected335 at risk EG00111 affected328 at risk EG0020 affected42 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG0006 affected335 at risk EG00111 affected328 at risk EG0020 affected42 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG0004 affected335 at risk EG0019 affected328 at risk EG0020 affected42 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG0004 affected335 at risk EG0015 affected328 at risk EG0020 affected42 at risk EG003
Bone marrow failure	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Pancytopenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Disseminated intravascular coagulati	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Anaphylactic reaction	Immune system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Anaphylactic shock	Immune system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Drug hypersensitivity	Immune system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hypersensitivity	Immune system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0004 affected335 at risk EG0013 affected328 at risk EG0020 affected42 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Electrolyte imbalance	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Hypochloraemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Delirium	Psychiatric disorders	MedDRA 21.1	Systematic Assessment	EG0003 affected335 at risk EG0013 affected328 at risk EG0020 affected42 at risk EG003
Anxiety	Psychiatric disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Suicide attempt	Psychiatric disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Confusional state	Psychiatric disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Cerebral infarction	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Headache	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hemiparesis	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Intracranial pressure increased	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Neuropathy peripheral	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Spinal cord compression	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Transient ischaemic attack	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Brain oedema	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Cerebrovascular accident	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Seizure	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Retinal artery occlusion	Eye disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Vision blurred	Eye disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Deafness bilateral	Ear and labyrinth disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Acute myocardial infarction	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0021 affected42 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0013 affected328 at risk EG0020 affected42 at risk EG003
Cardiac arrest	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Cardiac failure acute	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Cardiopulmonary failure	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Arrhythmia	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Cardiac failure	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Coronary artery occlusion	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Sinus tachycardia	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0004 affected335 at risk EG0016 affected328 at risk EG0020 affected42 at risk EG003
Shock haemorrhagic	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0003 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hypotension	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hypertensive crisis	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Internal haemorrhage	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Microembolism	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Peripheral embolism	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Arterial thrombosis	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Embolism venous	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Vascular stenosis	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Vasoconstriction	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG00011 affected335 at risk EG0015 affected328 at risk EG0020 affected42 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0006 affected335 at risk EG0014 affected328 at risk EG0020 affected42 at risk EG003
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0005 affected335 at risk EG0017 affected328 at risk EG0020 affected42 at risk EG003
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0005 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0003 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Pulmonary haemorrhage	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0003 affected335 at risk EG0011 affected328 at risk EG0021 affected42 at risk EG003
Acquired tracheo-oesophageal fistula	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Bronchial fistula	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Chronic obstructive pulmonary diseas	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Atelectasis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Bronchospasm	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Idiopathic pulmonary fibrosis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Pulmonary necrosis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0004 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0003 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0016 affected328 at risk EG0020 affected42 at risk EG003
Anal incontinence	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Diverticular perforation	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Diverticulum intestinal	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Duodenal perforation	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Duodenal ulcer	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Gastric ulcer	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Gastrointestinal perforation	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Lower gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Colitis	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Dysphagia	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Ileus paralytic	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Bile duct obstruction	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Cholecystitis acute	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hepatitis toxic	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hepatocellular injury	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Jaundice cholestatic	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Drug-induced liver injury	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hepatic failure	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Liver injury	Hepatobiliary disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Exposed bone in jaw	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Osteonecrosis of jaw	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Bladder obstruction	Renal and urinary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Hydronephrosis	Renal and urinary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Renal impairment	Renal and urinary disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Renal failure	Renal and urinary disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Urinary retention	Renal and urinary disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Benign prostatic hyperplasia	Reproductive system and breast disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Pyloric stenosis	Congenital, familial and genetic disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Chest pain	General disorders	MedDRA 21.1	Systematic Assessment	EG0003 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Pyrexia	General disorders	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0015 affected328 at risk EG0020 affected42 at risk EG003
Death	General disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Non-cardiac chest pain	General disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Pain	General disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Sudden cardiac death	General disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Sudden death	General disorders	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Asthenia	General disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Fatigue	General disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0013 affected328 at risk EG0020 affected42 at risk EG003
General physical health deterioratio	General disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Neutrophil count decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG0005 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Platelet count decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG0002 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Blood creatinine increased	Investigations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Blood magnesium decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
White blood cell count decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Clavicle fracture	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Femoral neck fracture	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Infusion related reaction	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Procedural pneumothorax	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected328 at risk EG0020 affected42 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Hip fracture	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0012 affected328 at risk EG0020 affected42 at risk EG003
Meniscus injury	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Spinal compression fracture	Injury, poisoning and procedural complications	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected328 at risk EG0020 affected42 at risk EG003
Sepsis	Infections and infestations	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0010 affected328 at risk EG0021 affected42 at risk EG003
Cardiac tamponade	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0010 affected328 at risk EG0021 affected42 at risk EG003
Myocardial ischaemia	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0010 affected328 at risk EG0021 affected42 at risk EG003
Myocardial rupture	Cardiac disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0010 affected328 at risk EG0021 affected42 at risk EG003
Oesophageal perforation	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0010 affected328 at risk EG0021 affected42 at risk EG003
Oesophagobronchial fistula	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG0000 affected335 at risk EG0010 affected328 at risk EG0021 affected42 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG000112 affected335 at risk EG00184 affected328 at risk EG0022 affected42 at risk EG0034 affected46 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG00061 affected335 at risk EG00152 affected328 at risk EG0020 affected42 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG00044 affected335 at risk EG00147 affected328 at risk EG0021 affected42 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA 21.1	Systematic Assessment	EG00018 affected335 at risk EG00123 affected328 at risk EG0020 affected42 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG00054 affected335 at risk EG00154 affected328 at risk EG0022 affected42 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 21.1	Systematic Assessment	EG00021 affected335 at risk EG00128 affected328 at risk EG0020 affected42 at risk EG003
Insomnia	Psychiatric disorders	MedDRA 21.1	Systematic Assessment	EG00015 affected335 at risk EG00118 affected328 at risk EG0021 affected42 at risk EG003
Neuropathy peripheral	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG00062 affected335 at risk EG00159 affected328 at risk EG0021 affected42 at risk EG003
Peripheral sensory neuropathy	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG00056 affected335 at risk EG00153 affected328 at risk EG0020 affected42 at risk EG003
Headache	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG00026 affected335 at risk EG00125 affected328 at risk EG0021 affected42 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG00020 affected335 at risk EG00119 affected328 at risk EG0020 affected42 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA 21.1	Systematic Assessment	EG00013 affected335 at risk EG00117 affected328 at risk EG0020 affected42 at risk EG003
Hypertension	Vascular disorders	MedDRA 21.1	Systematic Assessment	EG00049 affected335 at risk EG00151 affected328 at risk EG0023 affected42 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG00038 affected335 at risk EG00132 affected328 at risk EG0020 affected42 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG00038 affected335 at risk EG00132 affected328 at risk EG0020 affected42 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG00022 affected335 at risk EG00131 affected328 at risk EG0020 affected42 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.1	Systematic Assessment	EG00017 affected335 at risk EG00110 affected328 at risk EG0020 affected42 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG00073 affected335 at risk EG00175 affected328 at risk EG0022 affected42 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG00060 affected335 at risk EG00145 affected328 at risk EG0021 affected42 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG00056 affected335 at risk EG00137 affected328 at risk EG0021 affected42 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 21.1	Systematic Assessment	EG00051 affected335 at risk EG00144 affected328 at risk EG0021 affected42 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	MedDRA 21.1	Systematic Assessment	EG000155 affected335 at risk EG001149 affected328 at risk EG0020 affected42 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA 21.1	Systematic Assessment	EG00017 affected335 at risk EG00116 affected328 at risk EG0021 affected42 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG00040 affected335 at risk EG00135 affected328 at risk EG0021 affected42 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG00038 affected335 at risk EG00129 affected328 at risk EG0020 affected42 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG00022 affected335 at risk EG00114 affected328 at risk EG0021 affected42 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG00018 affected335 at risk EG00110 affected328 at risk EG0020 affected42 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 21.1	Systematic Assessment	EG00012 affected335 at risk EG00118 affected328 at risk EG0021 affected42 at risk EG003
Proteinuria	Renal and urinary disorders	MedDRA 21.1	Systematic Assessment	EG00051 affected335 at risk EG00146 affected328 at risk EG0028 affected42 at risk EG003
Fatigue	General disorders	MedDRA 21.1	Systematic Assessment	EG00054 affected335 at risk EG00153 affected328 at risk EG0022 affected42 at risk EG003
Asthenia	General disorders	MedDRA 21.1	Systematic Assessment	EG00022 affected335 at risk EG00129 affected328 at risk EG0021 affected42 at risk EG003
Malaise	General disorders	MedDRA 21.1	Systematic Assessment	EG00019 affected335 at risk EG00113 affected328 at risk EG0020 affected42 at risk EG003
Pyrexia	General disorders	MedDRA 21.1	Systematic Assessment	EG00017 affected335 at risk EG00121 affected328 at risk EG0020 affected42 at risk EG003
Platelet count decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG00041 affected335 at risk EG00133 affected328 at risk EG0020 affected42 at risk EG003
Neutrophil count decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG00039 affected335 at risk EG00142 affected328 at risk EG0020 affected42 at risk EG003
White blood cell count decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG00030 affected335 at risk EG00119 affected328 at risk EG0020 affected42 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA 21.1	Systematic Assessment	EG00024 affected335 at risk EG00132 affected328 at risk EG0020 affected42 at risk EG003
Gamma-glutamyltransferase increased	Investigations	MedDRA 21.1	Systematic Assessment	EG00022 affected335 at risk EG00131 affected328 at risk EG0021 affected42 at risk EG003
Weight decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG00021 affected335 at risk EG00122 affected328 at risk EG0022 affected42 at risk EG003
Blood cholesterol increased	Investigations	MedDRA 21.1	Systematic Assessment	EG00020 affected335 at risk EG00116 affected328 at risk EG0021 affected42 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA 21.1	Systematic Assessment	EG00019 affected335 at risk EG00130 affected328 at risk EG0021 affected42 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA 21.1	Systematic Assessment	EG00017 affected335 at risk EG00125 affected328 at risk EG0020 affected42 at risk EG003
Haemoglobin decreased	Investigations	MedDRA 21.1	Systematic Assessment	EG0005 affected335 at risk EG00117 affected328 at risk EG0020 affected42 at risk EG003

ID	Term
D002283	Carcinoma, Bronchogenic
D001984	Bronchial Neoplasms
D008175	Lung Neoplasms
D012142	Respiratory Tract Neoplasms
D013899	Thoracic Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D008171	Lung Diseases
D012140	Respiratory Tract Diseases

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins

ID	Title	Description
BG000	BI 695502	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
BG001	Avastin® US	Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	BI 695502 (Pre-switch)	Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.	193	335	108	335	293	335
EG001	US-licensed Avastin® (Pre-switch)	Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.	184	328	89	328	288	328
EG002	BI 695502 (Post-switch)	Patients switched from BI 695502 to receive commercially available Avastin®.	3	42	5	42	20	42
EG003	US-licensed Avastin® (Post-switch)	Patients switched from US-licensed Avastin® to receive commercially available Avastin®.	2	46	2	46	22	46