Trial Outcomes & Findings for Phase 3 Trial in Squamous Non Small Cell Lung Cancer Subjects Comparing Ipilimumab Versus Placebo in Addition to Paclitaxel and Carboplatin (NCT NCT01285609)

NCT ID: NCT01285609

Last Updated: 2020-06-18

Results Overview

Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Analysis for the Primary Endpoint occurred when the following 2 conditions were both met: (1) 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and (2) 705 deaths were observed in all randomized participants.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1289 participants
• Primary outcome timeframe: Randomization until 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and 705 deaths were observed in all randomized participants, up to June 2015 (approximately 48 months post study start)
• Results posted on: 2020-06-18

Participant Flow

1289 participants were enrolled and 956 were randomized (479 Ipilimumab, 477 Placebo). 948 were treated (475 Ipilimumab, 473 Placebo). Reasons for non-treatment is 4 no longer met study criteria, 2 adverse events unrelated to study drug, 1 participant request to discontinue, and 1 other.

Participant milestones

Measure	Ipilimumab With Paclitaxel/Carboplatin Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Placebo With Paclitaxel/Carboplatin Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
Randomized STARTED	479	477
Randomized Treated With Chemotherapy (1st Dose)	475	473
Randomized COMPLETED	388	361
Randomized NOT COMPLETED	91	116
Treated With Blinded Therapy STARTED	388	361
Treated With Blinded Therapy COMPLETED	1	2
Treated With Blinded Therapy NOT COMPLETED	387	359

Reasons for withdrawal

Measure	Ipilimumab With Paclitaxel/Carboplatin Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Placebo With Paclitaxel/Carboplatin Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
Randomized Progressive Disease	41	61
Randomized Adverse Event Unrelated to Study Drug	18	18
Randomized Study Drug Toxicity	13	14
Randomized Death	5	7
Randomized Withdrawal by Subject	8	11
Randomized Subject No Longer Met Study Criteria	1	1
Randomized Undisclosed Reasons	1	0
Randomized Randomized but not Treated	4	4
Treated With Blinded Therapy Progressive Disease	223	305
Treated With Blinded Therapy Study Drug Toxicity	87	14
Treated With Blinded Therapy Adverse Event Unrelated to Study Drug	36	14
Treated With Blinded Therapy Withdrawal by Subject	20	7
Treated With Blinded Therapy Death	11	3
Treated With Blinded Therapy Maximum Clinical Benefit	2	4
Treated With Blinded Therapy Not Reported	0	2
Treated With Blinded Therapy Poor/Non-Compliance	1	2
Treated With Blinded Therapy Subject No Longer Met Study Criteria	1	0
Treated With Blinded Therapy Administrative Reason by Sponsor	1	3
Treated With Blinded Therapy Physician and Patient decision	1	3
Treated With Blinded Therapy Participant refused participation	1	0
Treated With Blinded Therapy Participant started radiotherapy	1	0
Treated With Blinded Therapy Participant hospitalized	1	0
Treated With Blinded Therapy Investigator's assessment	1	0
Treated With Blinded Therapy PI decision to discontinue	0	1
Treated With Blinded Therapy Worsening of general condition	0	1

Baseline Characteristics

Phase 3 Trial in Squamous Non Small Cell Lung Cancer Subjects Comparing Ipilimumab Versus Placebo in Addition to Paclitaxel and Carboplatin

Baseline characteristics by cohort

Measure	Ipilimumab With Paclitaxel/Carboplatin n=388 Participants Ipilimumab + Active Chemo Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Placebo With Paclitaxel/Carboplatin n=361 Participants Placebo + Active Chemo Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Total n=749 Participants Total of all reporting groups
Age, Continuous	63.7 years STANDARD_DEVIATION 8.27 • n=5 Participants	63.7 years STANDARD_DEVIATION 8.70 • n=7 Participants	63.7 years STANDARD_DEVIATION 8.47 • n=5 Participants
Sex: Female, Male Female	62 Participants n=5 Participants	52 Participants n=7 Participants	114 Participants n=5 Participants
Sex: Female, Male Male	326 Participants n=5 Participants	309 Participants n=7 Participants	635 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	106 Participants n=5 Participants	108 Participants n=7 Participants	214 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) White	276 Participants n=5 Participants	243 Participants n=7 Participants	519 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0	135 Participants n=5 Participants	124 Participants n=7 Participants	259 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1	251 Participants n=5 Participants	234 Participants n=7 Participants	485 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 2	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 3	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Disease Stage at Study Entry Stage IV	367 Participants n=5 Participants	333 Participants n=7 Participants	700 Participants n=5 Participants
Disease Stage at Study Entry Recurrent	21 Participants n=5 Participants	28 Participants n=7 Participants	49 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization until 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and 705 deaths were observed in all randomized participants, up to June 2015 (approximately 48 months post study start)

Population: All treated participants who received at least one dose of blinded therapy

Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Analysis for the Primary Endpoint occurred when the following 2 conditions were both met: (1) 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and (2) 705 deaths were observed in all randomized participants.

Outcome measures

Measure	Placebo With Paclitaxel/Carboplatin n=361 Participants Placebo + Active Chemo Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Ipilimumab With Paclitaxel/Carboplatin n=388 Participants Ipilimumab + Active Chemo Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
Overall Survival (OS) in Participants Who Received at Least One Dose of Blinded Study Therapy at Primary Endpoint	12.42 months Interval 11.6 to 13.63	13.37 months Interval 11.76 to 14.78

SECONDARY outcome

Timeframe: Randomization until 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and 705 deaths were observed in all randomized participants, up to June 2015 (approximately 48 months post study start)

Population: All randomized participants

Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Analysis for the Primary Endpoint occurred when the following 2 conditions were both met: (1) 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and (2) 705 deaths were observed in all randomized participants.

Outcome measures

Measure	Placebo With Paclitaxel/Carboplatin n=477 Participants Placebo + Active Chemo Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Ipilimumab With Paclitaxel/Carboplatin n=479 Participants Ipilimumab + Active Chemo Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
Overall Survival (OS) in All Randomized Participants at Primary Endpoint	10.74 months Interval 9.66 to 11.73	10.94 months Interval 9.56 to 12.02

SECONDARY outcome

Timeframe: Randomization until 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and 705 deaths were observed in all randomized participants, up to June 2015 (approximately 48 months post study start)

Population: All treated participants who received at least one dose of blinded therapy

Progression-free survival (PFS) is defined as the time between the date of randomization and the date of tumor progression per Modified World Health Organization (mWHO) criteria or death, whichever occurs first. A participant who died without reported progression per mWHO criteria were considered to have progressed on the date of death. For participants who remain alive and have not progressed, PFS was censored on the date of last evaluable tumor assessment. For participants who remain alive and have no recorded post-baseline tumor assessment, PFS was censored on the day of randomization.

Outcome measures

Measure	Placebo With Paclitaxel/Carboplatin n=361 Participants Placebo + Active Chemo Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Ipilimumab With Paclitaxel/Carboplatin n=388 Participants Ipilimumab + Active Chemo Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
Median Number of Months With Progression Free Survival (PFS) Per mWHO in Participants Who Have Received at Least One Dose of Blinded Study Therapy at Primary Endpoint	5.59 months Interval 5.52 to 5.72	5.55 months Interval 5.36 to 5.85

Adverse Events

10 MG/KG Ipilimumab + Paclitaxel/ Carbop

Serious events: 300 serious events

Other events: 437 other events

Deaths: 359 deaths

Placebo + Paclitaxel/ Carboplatin

Serious events: 235 serious events

Other events: 428 other events

Deaths: 371 deaths

Serious adverse events

Measure	10 MG/KG Ipilimumab + Paclitaxel/ Carbop n=475 participants at risk Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Placebo + Paclitaxel/ Carboplatin n=473 participants at risk Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
Infections and infestations Lung abscess	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Anaemia	4.4% 21/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.1% 10/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Apnoea	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Autoimmune colitis	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Blood pressure decreased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Bronchitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Cholangitis acute	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.84% 4/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.7% 8/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Psychiatric disorders Completed suicide	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Decreased appetite	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Depressed level of consciousness	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Dermatitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Device related infection	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Haemoglobin decreased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Hepatotoxicity	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Idiopathic pulmonary fibrosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm progression	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.85% 4/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Overdose	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.1% 5/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Performance status decreased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Pericardial effusion	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Peripheral sensory neuropathy	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Pneumonia bacterial	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Post procedural complication	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Spinal cord paralysis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Swelling face	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations White blood cell count decreased	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Angina pectoris	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Asbestosis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Aspartate aminotransferase increased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Asthenia	1.1% 5/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.5% 7/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Atrial flutter	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Bile duct stenosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Blood creatinine increased	1.1% 5/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Blood thyroid stimulating hormone decreased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Bone marrow failure	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardiac tamponade	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Cerebral infarction	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Chest pain	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.85% 4/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Cholestasis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Colitis	2.9% 14/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colorectal cancer	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Device dislocation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Diverticular perforation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Diverticulitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Dysuria	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Embolism venous	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Encephalopathy	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Exfoliative rash	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Femur fracture	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders General physical health deterioration	1.5% 7/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.1% 10/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Haematemesis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Hemiparesis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Hepatic function abnormal	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Hepatocellular injury	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Hiccups	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Immune system disorders Hypersensitivity	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Liver disorder	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Lobar pneumonia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	7.4% 35/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	7.8% 37/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Pancytopenia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Paraesthesia	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Pathological fracture	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Peripheral ischaemia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Portal vein thrombosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Eye disorders Pupils unequal	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Staphylococcal infection	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Psychiatric disorders Suicide attempt	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Superior vena cava syndrome	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Swelling	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Tachycardia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Toxicity to various agents	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Upper respiratory tract infection	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Ventricular fibrillation	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Weight decreased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Agranulocytosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Arrhythmia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Atrial fibrillation	1.1% 5/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.7% 8/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Bronchial disorder	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Bronchostenosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardiac failure	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardio-respiratory arrest	1.1% 5/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardiovascular insufficiency	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Psychiatric disorders Confusional state	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Crohn's disease	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Disease progression	0.84% 4/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.1% 5/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Fulminant type 1 diabetes mellitus	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Headache	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Hip fracture	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Hydrocholecystis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Hypertension	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Hypophysitis	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Ileal perforation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Intestinal perforation	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Leukopenia	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.1% 5/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Nasopharyngitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine carcinoma	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Peripheral embolism	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.3% 11/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.1% 10/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.84% 4/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Pulmonary sepsis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Pulmonary tuberculosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Radiation pneumonitis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Shock haemorrhagic	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Tachypnoea	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Thrombocytopenia	1.5% 7/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.3% 11/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Traumatic haemorrhage	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Viraemia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Adrenocortical insufficiency acute	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Brain oedema	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Bronchopneumonia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Cervical radiculopathy	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Contusion	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Death	2.1% 10/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.5% 7/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Immune system disorders Drug hypersensitivity	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Empyema	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Erythema multiforme	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Extravasation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Gastroenteritis rotavirus	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.9% 9/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.1% 10/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Heart injury	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Hyperthyroidism	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hypomagnesaemia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Infection	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.85% 4/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Joint dislocation	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Large intestine perforation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Leukocytosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung squamous cell carcinoma metastatic	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Migraine	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Necrotising fasciitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Neuropathy peripheral	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Partial seizures	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Pericarditis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Platelet count decreased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.84% 4/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Pyrexia	4.4% 21/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	3.0% 14/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Red blood cell count decreased	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Renal failure	0.84% 4/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Septic shock	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Sinusitis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small intestine carcinoma	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Tumour lysis syndrome	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Vomiting	1.3% 6/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.1% 5/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Abdominal abscess	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Abdominal pain upper	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Alanine aminotransferase increased	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Atelectasis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Body temperature increased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Bronchitis chronic	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Cerebral haemorrhage	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Cerebral ischaemia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Cholangitis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Circulatory collapse	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Dehydration	1.7% 8/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.5% 7/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Psychiatric disorders Depression	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Dizziness	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Drug-induced liver injury	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.6% 17/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	3.4% 16/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Embolism	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Endocarditis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Febrile infection	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Hepatitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Hydrocephalus	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hyponatraemia	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Hypopituitarism	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Hypotension	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Impaired gastric emptying	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Infusion related reaction	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Ischaemic stroke	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Localised infection	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Lower respiratory tract infection	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Lung infection	1.9% 9/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.1% 5/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.7% 8/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Orchitis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Pancreatitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Perivascular dermatitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Pneumocystis jirovecii pneumonia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Pruritus	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Rectal haemorrhage	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Spinal pain	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Thyroiditis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Tubulointerstitial nephritis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Ear and labyrinth disorders Vertigo	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Acute myocardial infarction	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Adrenal insufficiency	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Anaemia of malignant disease	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Brain injury	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Cachexia	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardiopulmonary failure	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Cellulitis	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Chills	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Psychiatric disorders Delirium	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Psychiatric disorders Depressed mood	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Fall	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Gastroenteritis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Hypersomnia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hypokalaemia	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Hypoxia	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Laryngitis	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Liver function test abnormal	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung cancer metastatic	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Lung disorder	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Malaise	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic neoplasm	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Nephropathy	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Obstructive uropathy	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Pain	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Peripheral motor neuropathy	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Pneumococcal infection	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Pneumonia	7.8% 37/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	7.2% 34/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.84% 4/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.85% 4/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Rash	1.3% 6/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.3% 6/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.85% 4/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Supraventricular tachycardia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Syncope	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour compression	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Vena cava thrombosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Azotaemia	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Back pain	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Brain contusion	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Brain herniation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations C-reactive protein increased	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardiac arrest	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardiac failure congestive	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Cardiogenic shock	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Cholecystitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Constipation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Device occlusion	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Diarrhoea	7.8% 37/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.1% 10/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Eczema	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Fatigue	1.7% 8/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.5% 7/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Haemorrhagic anaemia	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Herpes zoster	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hyperglycaemia	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Hypothalamo-pituitary disorder	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Intestinal obstruction	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Myositis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Orthostatic hypotension	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.3% 6/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Renal function test abnormal	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Respiratory tract infection	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Sepsis	1.5% 7/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.5% 7/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Injury, poisoning and procedural complications Spinal column injury	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Subileus	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Sudden death	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Superior vena cava occlusion	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Tracheobronchitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour perforation	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Urinary tract infection	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Abdominal pain	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Acute hepatic failure	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Acute kidney injury	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Blood glucose increased	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Cerebrovascular accident	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.85% 4/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Colitis ischaemic	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Dysphagia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Endocrine disorders Endocrine disorder	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Erythema	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Facial paresis	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Febrile neutropenia	4.2% 20/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.3% 11/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations General physical condition abnormal	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hypercalcaemia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Ileus	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.63% 3/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Infectious colitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Hepatobiliary disorders Jaundice cholestatic	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Multi-organ failure	0.63% 3/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Nausea	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Neutropenia	3.4% 16/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.9% 9/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Neutropenic sepsis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Neutrophil count decreased	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Pain in extremity	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Palpitations	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Pharyngitis	0.42% 2/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Phlebitis superficial	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Polyneuropathy	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Pulmonary artery stenosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Renal colic	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Renal and urinary disorders Renal impairment	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.42% 2/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Seizure	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Cardiac disorders Sinus tachycardia	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Stomatitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Systemic inflammatory response syndrome	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Vascular disorders Thrombosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Infections and infestations Tuberculosis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Type 2 diabetes mellitus	0.00% 0/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.21% 1/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Eye disorders Ulcerative keratitis	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Guillain-barre syndrome	0.21% 1/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	0.00% 0/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)

Other adverse events

Measure	10 MG/KG Ipilimumab + Paclitaxel/ Carbop n=475 participants at risk Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses	Placebo + Paclitaxel/ Carboplatin n=473 participants at risk Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
Blood and lymphatic system disorders Anaemia	36.0% 171/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	33.2% 157/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Decreased appetite	30.5% 145/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	24.5% 116/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Haemoglobin decreased	8.0% 38/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	6.3% 30/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Myalgia	13.9% 66/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	12.9% 61/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Oedema peripheral	5.3% 25/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	6.6% 31/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Peripheral sensory neuropathy	14.9% 71/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	20.7% 98/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations White blood cell count decreased	5.3% 25/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	6.6% 31/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Aspartate aminotransferase increased	7.2% 34/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	4.2% 20/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Asthenia	16.8% 80/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	11.6% 55/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Bone pain	6.7% 32/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.5% 26/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Chest pain	5.5% 26/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	9.5% 45/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Paraesthesia	4.2% 20/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.9% 28/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Weight decreased	9.3% 44/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.7% 27/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Headache	6.3% 30/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	4.7% 22/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Leukopenia	9.3% 44/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	11.4% 54/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Thrombocytopenia	16.2% 77/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	14.8% 70/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Alopecia	38.1% 181/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	37.0% 175/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Haemoptysis	7.2% 34/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	8.7% 41/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hypomagnesaemia	5.7% 27/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	3.2% 15/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Psychiatric disorders Insomnia	12.8% 61/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	10.4% 49/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Mucosal inflammation	2.1% 10/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.7% 27/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.2% 20/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.1% 24/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Neuropathy peripheral	12.8% 61/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	12.1% 57/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Platelet count decreased	9.9% 47/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	6.8% 32/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Pyrexia	19.2% 91/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	14.8% 70/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Vomiting	18.7% 89/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	14.4% 68/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Abdominal pain upper	5.1% 24/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	4.9% 23/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Alanine aminotransferase increased	7.8% 37/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.5% 26/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Dehydration	5.1% 24/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	1.5% 7/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Nervous system disorders Dizziness	7.4% 35/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	12.3% 58/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Dyspnoea	19.8% 94/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	20.5% 97/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hyponatraemia	7.8% 37/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	2.3% 11/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Pruritus	16.4% 78/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.7% 27/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Arthralgia	16.2% 77/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	12.3% 58/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Respiratory, thoracic and mediastinal disorders Cough	17.3% 82/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	18.0% 85/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Metabolism and nutrition disorders Hypokalaemia	10.7% 51/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	6.6% 31/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Skin and subcutaneous tissue disorders Rash	18.3% 87/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	9.5% 45/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Back pain	7.2% 34/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	8.0% 38/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Constipation	24.6% 117/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	21.8% 103/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Diarrhoea	30.5% 145/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	18.8% 89/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
General disorders Fatigue	29.9% 142/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	29.6% 140/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Abdominal pain	5.3% 25/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.5% 26/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Nausea	32.0% 152/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	31.9% 151/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Blood and lymphatic system disorders Neutropenia	22.5% 107/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	21.6% 102/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Investigations Neutrophil count decreased	6.5% 31/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	6.6% 31/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Musculoskeletal and connective tissue disorders Pain in extremity	9.1% 43/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	9.1% 43/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)
Gastrointestinal disorders Stomatitis	5.7% 27/475 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)	5.1% 24/473 • Day of first dose to 90 days post final dose, up to August 2017 (approximately 72 months post study start)

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: Clinical.Trials@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
• Publication restrictions are in place

Restriction type: OTHER