Trial Outcomes & Findings for Study of Nivolumab in Unresectable Advanced or Recurrent Esophageal Cancer (NCT NCT02569242)

NCT ID: NCT02569242

Last Updated: 2022-07-06

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

419 participants

Primary outcome timeframe

("Date of death from any cause" - "Date of randomization" + 1) / 30.4375. For subjects lost to follow-up and subjects who are alive at the time of data cutoff date, data will be censored at the time the subject was last confirmed to be alive.

Results posted on

2022-07-06

Participant Flow

Participant milestones

Participant milestones
Measure	Nivolumab Arm Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Overall Study STARTED	210	209
Overall Study COMPLETED	209	208
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Nivolumab Arm Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Overall Study Death	1	0
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Summarized for subjects with non-recurrent esophageal cancer.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Nivolumab Arm n=210 Participants Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） n=209 Participants Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Total n=419 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=210 Participants	0 Participants n=209 Participants	0 Participants n=419 Participants
Age, Categorical Between 18 and 65 years	112 Participants n=210 Participants	85 Participants n=209 Participants	197 Participants n=419 Participants
Age, Categorical >=65 years	98 Participants n=210 Participants	124 Participants n=209 Participants	222 Participants n=419 Participants
Age, Continuous	64 years n=210 Participants	67 years n=209 Participants	65 years n=419 Participants
Sex: Female, Male Female	31 Participants n=210 Participants	24 Participants n=209 Participants	55 Participants n=419 Participants
Sex: Female, Male Male	179 Participants n=210 Participants	185 Participants n=209 Participants	364 Participants n=419 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=210 Participants	0 Participants n=209 Participants	0 Participants n=419 Participants
Race (NIH/OMB) Asian	201 Participants n=210 Participants	200 Participants n=209 Participants	401 Participants n=419 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=210 Participants	0 Participants n=209 Participants	0 Participants n=419 Participants
Race (NIH/OMB) Black or African American	0 Participants n=210 Participants	0 Participants n=209 Participants	0 Participants n=419 Participants
Race (NIH/OMB) White	9 Participants n=210 Participants	9 Participants n=209 Participants	18 Participants n=419 Participants
Race (NIH/OMB) More than one race	0 Participants n=210 Participants	0 Participants n=209 Participants	0 Participants n=419 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=210 Participants	0 Participants n=209 Participants	0 Participants n=419 Participants
Race/Ethnicity, Customized Asian	201 Participants n=210 Participants	200 Participants n=209 Participants	401 Participants n=419 Participants
Race/Ethnicity, Customized White	9 Participants n=210 Participants	9 Participants n=209 Participants	18 Participants n=419 Participants
ECOG performance status 0	101 Participants n=210 Participants	107 Participants n=209 Participants	208 Participants n=419 Participants
ECOG performance status 1	109 Participants n=210 Participants	102 Participants n=209 Participants	211 Participants n=419 Participants
Disease stage : TNM classification II - III	8 Participants n=107 Participants • Summarized for subjects with non-recurrent esophageal cancer.	13 Participants n=120 Participants • Summarized for subjects with non-recurrent esophageal cancer.	21 Participants n=227 Participants • Summarized for subjects with non-recurrent esophageal cancer.
Disease stage : TNM classification IV	94 Participants n=107 Participants • Summarized for subjects with non-recurrent esophageal cancer.	100 Participants n=120 Participants • Summarized for subjects with non-recurrent esophageal cancer.	194 Participants n=227 Participants • Summarized for subjects with non-recurrent esophageal cancer.
Disease stage : TNM classification unknown	5 Participants n=107 Participants • Summarized for subjects with non-recurrent esophageal cancer.	7 Participants n=120 Participants • Summarized for subjects with non-recurrent esophageal cancer.	12 Participants n=227 Participants • Summarized for subjects with non-recurrent esophageal cancer.
Previous therapies Surgery	111 Participants n=210 Participants	94 Participants n=209 Participants	205 Participants n=419 Participants
Previous therapies Radiothrapy	153 Participants n=210 Participants	142 Participants n=209 Participants	295 Participants n=419 Participants
Previous therapies Systemic anticancer therapy	210 Participants n=210 Participants	208 Participants n=209 Participants	418 Participants n=419 Participants
Number of organs of metastases <=1	89 Participants n=210 Participants	91 Participants n=209 Participants	180 Participants n=419 Participants
Number of organs of metastases >=2	121 Participants n=210 Participants	118 Participants n=209 Participants	239 Participants n=419 Participants
Site of metastases Lymph node	159 Participants n=210 Participants	163 Participants n=209 Participants	322 Participants n=419 Participants
Site of metastases Liver	57 Participants n=210 Participants	54 Participants n=209 Participants	111 Participants n=419 Participants
Site of metastases Lung	98 Participants n=210 Participants	92 Participants n=209 Participants	190 Participants n=419 Participants
Site of metastases Bone	23 Participants n=210 Participants	25 Participants n=209 Participants	48 Participants n=419 Participants
PD-L1 expression <1%	109 Participants n=210 Participants	107 Participants n=209 Participants	216 Participants n=419 Participants
PD-L1 expression >=1%	101 Participants n=210 Participants	102 Participants n=209 Participants	203 Participants n=419 Participants
PD-L1 expression <5%	136 Participants n=210 Participants	137 Participants n=209 Participants	273 Participants n=419 Participants
PD-L1 expression >=5%	74 Participants n=210 Participants	72 Participants n=209 Participants	146 Participants n=419 Participants
PD-L1 expression <10%	146 Participants n=210 Participants	152 Participants n=209 Participants	298 Participants n=419 Participants
PD-L1 expression >=10%	64 Participants n=210 Participants	57 Participants n=209 Participants	121 Participants n=419 Participants
History of smoking Never	30 Participants n=210 Participants	32 Participants n=209 Participants	62 Participants n=419 Participants
History of smoking Former	159 Participants n=210 Participants	147 Participants n=209 Participants	306 Participants n=419 Participants
History of smoking Current	21 Participants n=210 Participants	30 Participants n=209 Participants	51 Participants n=419 Participants

PRIMARY outcome

Timeframe: ("Date of death from any cause" - "Date of randomization" + 1) / 30.4375. For subjects lost to follow-up and subjects who are alive at the time of data cutoff date, data will be censored at the time the subject was last confirmed to be alive.

Outcome measures

Outcome measures
Measure	Nivolumab Arm n=210 Participants Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） n=209 Participants Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Overall Survival	10.9 months Interval 9.2 to 13.3	8.4 months Interval 7.2 to 9.9

SECONDARY outcome

Timeframe: ("Earlier date on which either the overall response was assessed as PD or the subject died of any cause" - "Date of randomization" + 1) / 30.4375.

Please refer to the protocol, overall response and best overall response will be determined solely by imaging assessment according to the RECIST Guideline Version 1.1, and will not take into account any clinical/symptomatic progression. Evaluable imaging data will be overall response without an overall response of "Not Evaluable (NE)."

Outcome measures

Outcome measures
Measure	Nivolumab Arm n=210 Participants Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） n=209 Participants Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Progression-free Survival	1.7 months Interval 1.5 to 2.7	3.4 months Interval 3.0 to 4.2

SECONDARY outcome

Timeframe: ("Earlier date on which either the overall response was assessed as PD for the first time after confirmed response or the subject died of any cause" - "Date of first assessment of confirmed CR or PR" + 1) / 30.4375.

Outcome measures

Outcome measures
Measure	Nivolumab Arm n=210 Participants Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） n=209 Participants Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Duration of Response	6.9 months Interval 5.4 to 11.1	3.9 months Interval 2.8 to 4.2

Adverse Events

Nivolumab Arm

Serious events: 68 serious events

Other events: 185 other events

Deaths: 7 deaths

Active Comparator Arm （Docetaxel/Paclitaxel）

Serious events: 77 serious events

Other events: 204 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Information Center

Ono Pharmaceutical Co. Ltd

Phone: ー

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Nivolumab Arm n=209 participants at risk Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） n=208 participants at risk Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Blood and lymphatic system disorders Anemia	0.96% 2/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	7.7% 16/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Blood and lymphatic system disorders Bone marrow failure	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Cardiac disorders Angina pectoris	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Cardiac disorders Cardiac failure	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Cardiac disorders Pericarditis	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Congenital, familial and genetic disorders Tracheo-oesophageal fistula	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Endocrine disorders Hyperthyroidism	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Endocrine disorders Hypopituitarism	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Endocrine disorders Adrenocorticotropic hormone deficiency	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Abdominal pain	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.96% 2/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Colitis	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Diarrhoea	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.96% 2/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Duodenitis	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Dysphagia	0.96% 2/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.96% 2/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Ileus	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Intestinal obstruction	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Nausea	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.96% 2/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Vomiting	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.96% 2/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Gastric fistula	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Aorto-oesophageal fistula	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Asthenia	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Fatigue	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Malaise	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Pyrexia	2.9% 6/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Sudden death	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Disease progression	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Stenosis	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.48% 1/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Hepatobiliary disorders Cholecystitis	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Hepatobiliary disorders Hepatic function abnormal	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Hepatobiliary disorders Bile duct obstruction	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Immune system disorders Anaphylactic shock	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Immune system disorders Drug hypersensitivity	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Infections and infestations Appendicitis	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Infections and infestations Bacteraemia	0.96% 2/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Infections and infestations Bronchitis	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	0.00% 0/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.

Other adverse events
Measure	Nivolumab Arm n=209 participants at risk Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Active Comparator Arm （Docetaxel/Paclitaxel） n=208 participants at risk Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends OR Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Blood and lymphatic system disorders Anaemia	11.5% 24/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	29.3% 61/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Blood and lymphatic system disorders Leukopenia	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	8.7% 18/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Blood and lymphatic system disorders Neutropenia	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	19.2% 40/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Endocrine disorders Hypothyroidism	10.0% 21/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	1.4% 3/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Abdominal pain	5.7% 12/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	3.8% 8/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Constipation	16.7% 35/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	19.2% 40/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Diarrhoea	17.2% 36/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	16.3% 34/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Dysphagia	6.2% 13/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	1.4% 3/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Nausea	11.0% 23/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	19.2% 40/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Stomatitis	3.3% 7/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	12.5% 26/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Gastrointestinal disorders Vomiting	5.7% 12/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	8.2% 17/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Chest pain	6.2% 13/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	1.9% 4/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Fatigue	9.1% 19/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	25.0% 52/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Malaise	5.7% 12/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	23.6% 49/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
General disorders Pyrexia	13.9% 29/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	18.3% 38/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Infections and infestations Nasopharyngitis	6.2% 13/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	4.3% 9/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Infections and infestations Upper respiratory tract infection	7.2% 15/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	6.2% 13/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Investigations Alanine aminotransferase increased	5.3% 11/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	3.4% 7/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Investigations Aspartate aminotransferase increased	6.2% 13/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	3.4% 7/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Investigations Lymphocyte count decreased	2.4% 5/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	10.1% 21/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Investigations Neutrophil count decreased	1.4% 3/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	36.5% 76/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Investigations Weight decreased	5.3% 11/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	5.3% 11/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Investigations White blood cell count decreased	0.96% 2/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	34.6% 72/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Metabolism and nutrition disorders Decreased appetite	19.1% 40/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	32.7% 68/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Musculoskeletal and connective tissue disorders Arthralgia	4.8% 10/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	12.0% 25/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Musculoskeletal and connective tissue disorders Myalgia	2.9% 6/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	10.6% 22/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Nervous system disorders Dysgeusia	2.4% 5/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	6.7% 14/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Nervous system disorders Neuropathy peripheral	0.00% 0/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	11.1% 23/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Nervous system disorders Peripheral sensory neuropathy	0.48% 1/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	23.1% 48/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Psychiatric disorders Insomnia	5.3% 11/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	6.2% 13/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Respiratory, thoracic and mediastinal disorders Cough	15.3% 32/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	12.0% 25/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.7% 12/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	3.8% 8/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Skin and subcutaneous tissue disorders Alopecia	1.4% 3/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	48.1% 100/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Skin and subcutaneous tissue disorders Pruritus	12.4% 26/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	7.2% 15/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.
Skin and subcutaneous tissue disorders Rash	12.4% 26/209 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.	19.2% 40/208 • Monitoring for any AEs will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE will be continued until the event is judged not to require further follow-up. SAEs are to be collected during the treatment period and for 100 days following the last dose. For all-cause mortality, the number of adverse events reported as Grade 5 was extracted.