Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214)

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ClinicalTrials.gov Identifier: NCT02231749

Recruitment Status : Active, not recruiting

First Posted : September 4, 2014

Results First Posted : October 16, 2018

Last Update Posted : November 15, 2023

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Sponsor:

Collaborator:

Ono Pharmaceutical Co. Ltd

Information provided by (Responsible Party):

Bristol-Myers Squibb

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Advanced Renal Cell Carcinoma Metastatic Renal Cell Carcinoma
Interventions	Biological: Nivolumab Biological: Ipilimumab Drug: Sunitinib
Enrollment	1390

Participant Flow

Recruitment Details
Pre-assignment Details	A total 1390 patients were enrolled in the study. Of these, 1096 were randomized. Of those randomized, 1082 received treatment (547 with Nivo+Ipi and 535 with Sunitinib). 240 patients who were not randomized because they no longer met study criteria, 24 withdrew consent, 4 for Adverse Events, 4 for Death, 4 for Poor Compliance, and 18 other.


Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
Period Title: Overall Study
Started ^[1]	550	546
Received Treatment	547	535
Completed ^[2]	128	97
Not Completed	422	449
Reason Not Completed
Disease progression	229	297
Study Drug Toxicity	134	63
Death	1	1
AE unrelated to Study drug	32	31
Participant's request to discontinue	10	21
Participant withdrew Consent	8	15
Lost to Follow-up	1	2
Maximum Clinical Benefit	5	8
Poor/Non-Compliance	0	3
Pregnancy	1	0
other	0	8
No longer meets Study Criteria	1	0
[1] Started = Randomized [2] Completed = Continuing in the Treatment Period

Baseline Characteristics

Arm/Group Title		Nivolumab + Ipilimumab	Sunitinib	Total
Arm/Group Description		Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...	Total of all reporting groups
Arm/Group Description		Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks	Total of all reporting groups
Overall Number of Baseline Participants		550	546	1096
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All Randomized Participants
Age, Continuous ^[1] Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	550 participants	546 participants	1096 participants
		61.1 (9.76)	60.7 (10.10)	60.9 (9.93)
		[1] Measure Analysis Population Description: All Randomized
Sex: Female, Male ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	550 participants	546 participants	1096 participants
	Female	137 24.9%	151 27.7%	288 26.3%
	Male	413 75.1%	395 72.3%	808 73.7%
		[1] Measure Analysis Population Description: All Randomized Participants
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	550 participants	546 participants	1096 participants
	Hispanic or Latino	12 2.2%	17 3.1%	29 2.6%
	Not Hispanic or Latino	264 48.0%	253 46.3%	517 47.2%
	Unknown or Not Reported	274 49.8%	276 50.5%	550 50.2%
Race/Ethnicity, Customized ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	550 participants	546 participants	1096 participants
	White	486 88.4%	483 88.5%	969 88.4%
	Black or African American	7 1.3%	6 1.1%	13 1.2%
	Asian	46 8.4%	47 8.6%	93 8.5%
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Other	10 1.8%	10 1.8%	20 1.8%
	Not Reported	1 0.2%	0 0.0%	1 0.1%
		[1] Measure Analysis Population Description: All Randomized Participants

Outcome Measures

1.Primary Outcome


Title	Investigator-assessed Objective Response Rate(ORR) in Intermediate/Poor Risk Participants Per IRRC Using RECIST v1.1
Description	ORR was defined as the proportion of randomized subjects who achieved ...
Description	ORR was defined as the proportion of randomized subjects who achieved a best response of complete response (CR) or partial response (PR) using the RECIST v1.1 criteria based on IRRC assessment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	From first dose until date of documented disease progression or subsequent therapy, whichever occurs first (assessed up to June 2017, approximately 31 months)

Outcome Measure Data

Analysis Population Description

All Intermediate/Poor-Risk Participants


Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
Overall Number of Participants Analyzed	425	422
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	41.6 (36.9 to 46.5)	26.5 (22.4 to 31.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Sunitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	DerSimonian and Laird Test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Difference
	Estimated Value	16.0
	Confidence Interval	(2-Sided) 95% 9.8 to 22.2
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Overall Survival (OS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
Description	OS was defined as the time from randomization to the date of death fro...
Description	OS was defined as the time from randomization to the date of death from any cause. Survival time was censored at the date of last contact ("last known alive date") for subjects who were alive.
Time Frame	From the date of randomization to the date of death (assessed up to June 2017, approximately 31 months)

Outcome Measure Data

Analysis Population Description

All Intermediate/Poor-Risk Participants


Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
Overall Number of Participants Analyzed	425	422
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (28.16 to NA)	25.95 ^[1] (22.08 to NA)

[1]

The median for Overall Survival and Upper Limit have not been reached. There were an insufficient number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Sunitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 99.8% 0.44 to 0.89
	Estimation Comments	[Not Specified]

3.Primary Outcome


Title	Progression-Free Survival (PFS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
Description	PFS was defined as the time between the date of randomization and the ...
Description	PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the IRRC (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first. Subsequent therapy included anticancer therapy, tumor directed radiotherapy, or tumor directed surgery. Subjects who died without a reported progression were considered to have progressed on the date of their death.
Time Frame	From date of first dose to date of documented disease progression or death due to any cause, whichever occurs first (assessed up to June 2017, approximately 31 months)

Outcome Measure Data

Analysis Population Description

All Intermediate/Poor-Risk Participants


Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
Overall Number of Participants Analyzed	425	422
Median (95% Confidence Interval) Unit of Measure: months
	11.56 (8.71 to 15.51)	8.38 (7.03 to 10.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Sunitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0331
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 99.1% 0.64 to 1.05
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Investigator-assessed Objective Response Rate(ORR) in Any Risk Participants Per IRRC Using RECIST v1.1
Description	ORR was defined as the proportion of randomized subjects who achieved ...
Description	ORR was defined as the proportion of randomized subjects who achieved a best response of complete response (CR) or partial response (PR) using the RECIST v1.1 criteria based on IRRC assessment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	From first dose until date of documented disease progression or subsequent therapy, whichever occurs first (assessed up to June 2017, approximately 31 months)

Outcome Measure Data

Analysis Population Description

All Randomized


Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
Overall Number of Participants Analyzed	550	546
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	38.7 (34.6 to 42.9)	32.2 (28.3 to 36.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Sunitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0191
	Comments	[Not Specified]
	Method	DerSimonian and Laird Test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Difference
	Estimated Value	7.2
	Confidence Interval	(2-Sided) 95% 1.8 to 12.7
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Overall Survival (OS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
Description	Overall survival is defined as the time from randomization to the date...
Description	Overall survival is defined as the time from randomization to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact ("last known alive date"). Overall survival will be censored for subjects at the date of randomization if they were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after subject's off-treatment date.
Time Frame	From the date of randomization to the date of death (assessed up to June 2017, approximately 31 months)

Outcome Measure Data

Analysis Population Description

All Randomized


Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
Overall Number of Participants Analyzed	550	546
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (NA to NA)	32.92 ^[2] (NA to NA)

[1]

The median for Overall Survival, Lower limit, and Upper Limit have not been reached. There were an insufficient number of participants with events.

[2]

The Lower Limit and Upper Limit have not been reached. With only 1 participant at that time point, the variance is not estimable and so the Confidence Intervals were N/A.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Sunitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0003
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 99.8% 0.49 to 0.95
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Progression-Free Survival (PFS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
Description	PFS was defined as the time between the date of randomization and the ...
Description	PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the IRRC (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first. Subsequent therapy included anticancer therapy, tumor directed radiotherapy, or tumor directed surgery. Subjects who died without a reported progression were considered to have progressed on the date of their death.
Time Frame	From date of first dose to date of documented disease progression or death due to any cause, whichever occurs first (assessed up to June 2017, approximately 31 months)

Outcome Measure Data

Analysis Population Description

All Randomized


Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description:	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
Overall Number of Participants Analyzed	550	546
Median (95% Confidence Interval) Unit of Measure: months
	12.42 (9.89 to 16.53)	12.32 (9.79 to 15.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Sunitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8498
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 99.1% 0.79 to 1.23
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	From first dose to 30 days after last dose of study therapy (assessed up to June 2017, approximately 31 months)
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Nivolumab + Ipilimumab	Sunitinib
Arm/Group Description	Nivolumab 3 mg/kg combined with Ipi...	Sunitinib 50 mg capsules by mouth o...
Arm/Group Description	Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks
All-Cause Mortality
	Nivolumab + Ipilimumab	Sunitinib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	159/547 (29.07%)	202/535 (37.76%)
Serious Adverse Events Serious Adverse Events
	Nivolumab + Ipilimumab	Sunitinib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	305/547 (55.76%)	213/535 (39.81%)
Blood and lymphatic system disorders
Anaemia ^† 1	6/547 (1.10%)	7/535 (1.31%)
Autoimmune neutropenia ^† 1	1/547 (0.18%)	0/535 (0.00%)
Pancytopenia ^† 1	0/547 (0.00%)	1/535 (0.19%)
Splenic lesion ^† 1	0/547 (0.00%)	1/535 (0.19%)
Thrombocytopenia ^† 1	0/547 (0.00%)	1/535 (0.19%)
Cardiac disorders
Acute coronary syndrome ^† 1	1/547 (0.18%)	1/535 (0.19%)
Acute myocardial infarction ^† 1	2/547 (0.37%)	0/535 (0.00%)
Angina pectoris ^† 1	1/547 (0.18%)	1/535 (0.19%)
Arrhythmia ^† 1	1/547 (0.18%)	1/535 (0.19%)
Atrial fibrillation ^† 1	2/547 (0.37%)	0/535 (0.00%)
Cardiac arrest ^† 1	3/547 (0.55%)	2/535 (0.37%)
Cardiac failure ^† 1	1/547 (0.18%)	1/535 (0.19%)
Cardiac failure congestive ^† 1	0/547 (0.00%)	3/535 (0.56%)
Cardio-respiratory arrest ^† 1	1/547 (0.18%)	0/535 (0.00%)
Cardiopulmonary failure ^† 1	1/547 (0.18%)	0/535 (0.00%)
Cardiovascular disorder ^† 1	1/547 (0.18%)	0/535 (0.00%)
Myocardial infarction ^† 1	6/547 (1.10%)	1/535 (0.19%)
Myocarditis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Right ventricular failure ^† 1	0/547 (0.00%)	1/535 (0.19%)
Sinus node dysfunction ^† 1	1/547 (0.18%)	0/535 (0.00%)
Tachycardia ^† 1	0/547 (0.00%)	1/535 (0.19%)
Ear and labyrinth disorders
Vertigo ^† 1	1/547 (0.18%)	1/535 (0.19%)
Endocrine disorders
Adrenal insufficiency ^† 1	10/547 (1.83%)	0/535 (0.00%)
Adrenocortical insufficiency acute ^† 1	2/547 (0.37%)	0/535 (0.00%)
Adrenocorticotropic hormone deficiency ^† 1	1/547 (0.18%)	0/535 (0.00%)
Autoimmune hypothyroidism ^† 1	1/547 (0.18%)	0/535 (0.00%)
Basedow's disease ^† 1	2/547 (0.37%)	0/535 (0.00%)
Goitre ^† 1	1/547 (0.18%)	0/535 (0.00%)
Hyperthyroidism ^† 1	3/547 (0.55%)	0/535 (0.00%)
Hypophysitis ^† 1	14/547 (2.56%)	0/535 (0.00%)
Hypopituitarism ^† 1	2/547 (0.37%)	0/535 (0.00%)
Hypothalamo-pituitary disorder ^† 1	1/547 (0.18%)	0/535 (0.00%)
Hypothyroidism ^† 1	2/547 (0.37%)	1/535 (0.19%)
Secondary adrenocortical insufficiency ^† 1	2/547 (0.37%)	0/535 (0.00%)
Steroid withdrawal syndrome ^† 1	1/547 (0.18%)	0/535 (0.00%)
Thyroiditis ^† 1	3/547 (0.55%)	0/535 (0.00%)
Eye disorders
Diplopia ^† 1	2/547 (0.37%)	0/535 (0.00%)
Eye pain ^† 1	1/547 (0.18%)	0/535 (0.00%)
Inflammation of lacrimal passage ^† 1	1/547 (0.18%)	0/535 (0.00%)
Gastrointestinal disorders
Abdominal pain ^† 1	5/547 (0.91%)	4/535 (0.75%)
Abdominal pain upper ^† 1	0/547 (0.00%)	1/535 (0.19%)
Anal fistula ^† 1	0/547 (0.00%)	1/535 (0.19%)
Autoimmune colitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Colitis ^† 1	10/547 (1.83%)	0/535 (0.00%)
Diarrhoea ^† 1	24/547 (4.39%)	3/535 (0.56%)
Diarrhoea haemorrhagic ^† 1	1/547 (0.18%)	0/535 (0.00%)
Diverticular perforation ^† 1	0/547 (0.00%)	1/535 (0.19%)
Duodenal obstruction ^† 1	1/547 (0.18%)	0/535 (0.00%)
Duodenal ulcer ^† 1	0/547 (0.00%)	1/535 (0.19%)
Dysphagia ^† 1	1/547 (0.18%)	0/535 (0.00%)
Enterocolitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Gastric haemorrhage ^† 1	0/547 (0.00%)	1/535 (0.19%)
Gastric ulcer ^† 1	1/547 (0.18%)	0/535 (0.00%)
Gastric ulcer haemorrhage ^† 1	0/547 (0.00%)	1/535 (0.19%)
Gastritis ^† 1	1/547 (0.18%)	1/535 (0.19%)
Gastrointestinal haemorrhage ^† 1	1/547 (0.18%)	4/535 (0.75%)
Haemorrhoidal haemorrhage ^† 1	0/547 (0.00%)	1/535 (0.19%)
Ileus ^† 1	1/547 (0.18%)	0/535 (0.00%)
Intestinal obstruction ^† 1	1/547 (0.18%)	0/535 (0.00%)
Intestinal perforation ^† 1	0/547 (0.00%)	1/535 (0.19%)
Intussusception ^† 1	0/547 (0.00%)	1/535 (0.19%)
Large intestine perforation ^† 1	0/547 (0.00%)	2/535 (0.37%)
Lower gastrointestinal haemorrhage ^† 1	1/547 (0.18%)	0/535 (0.00%)
Nausea ^† 1	8/547 (1.46%)	2/535 (0.37%)
Oesophagitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Oesophagitis ulcerative ^† 1	1/547 (0.18%)	0/535 (0.00%)
Pancreatitis ^† 1	3/547 (0.55%)	4/535 (0.75%)
Pancreatitis acute ^† 1	0/547 (0.00%)	1/535 (0.19%)
Rectal haemorrhage ^† 1	1/547 (0.18%)	2/535 (0.37%)
Retroperitoneal haemorrhage ^† 1	0/547 (0.00%)	1/535 (0.19%)
Small intestinal obstruction ^† 1	0/547 (0.00%)	1/535 (0.19%)
Stomatitis ^† 1	0/547 (0.00%)	2/535 (0.37%)
Upper gastrointestinal haemorrhage ^† 1	0/547 (0.00%)	2/535 (0.37%)
Vomiting ^† 1	5/547 (0.91%)	4/535 (0.75%)
General disorders
Asthenia ^† 1	1/547 (0.18%)	4/535 (0.75%)
Chest discomfort ^† 1	1/547 (0.18%)	0/535 (0.00%)
Chest pain ^† 1	1/547 (0.18%)	2/535 (0.37%)
Death ^† 1	1/547 (0.18%)	0/535 (0.00%)
Fatigue ^† 1	4/547 (0.73%)	5/535 (0.93%)
Gait disturbance ^† 1	0/547 (0.00%)	1/535 (0.19%)
General physical health deterioration ^† 1	4/547 (0.73%)	4/535 (0.75%)
Influenza like illness ^† 1	1/547 (0.18%)	0/535 (0.00%)
Malaise ^† 1	2/547 (0.37%)	2/535 (0.37%)
Mucosal inflammation ^† 1	0/547 (0.00%)	1/535 (0.19%)
Oedema peripheral ^† 1	1/547 (0.18%)	1/535 (0.19%)
Pain ^† 1	0/547 (0.00%)	2/535 (0.37%)
Pyrexia ^† 1	18/547 (3.29%)	9/535 (1.68%)
Sudden death ^† 1	0/547 (0.00%)	1/535 (0.19%)
Hepatobiliary disorders
Biliary colic ^† 1	0/547 (0.00%)	2/535 (0.37%)
Cholangitis ^† 1	0/547 (0.00%)	1/535 (0.19%)
Cholangitis acute ^† 1	0/547 (0.00%)	1/535 (0.19%)
Cholecystitis ^† 1	0/547 (0.00%)	3/535 (0.56%)
Cholelithiasis ^† 1	0/547 (0.00%)	1/535 (0.19%)
Gallbladder disorder ^† 1	1/547 (0.18%)	0/535 (0.00%)
Gallbladder obstruction ^† 1	0/547 (0.00%)	1/535 (0.19%)
Hepatic function abnormal ^† 1	1/547 (0.18%)	0/535 (0.00%)
Hepatic pain ^† 1	0/547 (0.00%)	1/535 (0.19%)
Hepatitis ^† 1	3/547 (0.55%)	0/535 (0.00%)
Hepatitis acute ^† 1	1/547 (0.18%)	0/535 (0.00%)
Hepatitis toxic ^† 1	1/547 (0.18%)	0/535 (0.00%)
Hepatotoxicity ^† 1	1/547 (0.18%)	0/535 (0.00%)
Jaundice ^† 1	0/547 (0.00%)	1/535 (0.19%)
Jaundice cholestatic ^† 1	1/547 (0.18%)	2/535 (0.37%)
Portal vein thrombosis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Immune system disorders
Anaphylactic reaction ^† 1	0/547 (0.00%)	1/535 (0.19%)
Autoimmune disorder ^† 1	1/547 (0.18%)	0/535 (0.00%)
Contrast media allergy ^† 1	3/547 (0.55%)	0/535 (0.00%)
Contrast media reaction ^† 1	2/547 (0.37%)	0/535 (0.00%)
Infections and infestations
Abdominal infection ^† 1	0/547 (0.00%)	1/535 (0.19%)
Appendicitis ^† 1	2/547 (0.37%)	1/535 (0.19%)
Bronchitis ^† 1	3/547 (0.55%)	0/535 (0.00%)
Cellulitis ^† 1	3/547 (0.55%)	0/535 (0.00%)
Cholecystitis infective ^† 1	0/547 (0.00%)	1/535 (0.19%)
Diarrhoea infectious ^† 1	1/547 (0.18%)	0/535 (0.00%)
Diverticulitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Encephalitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Epididymitis ^† 1	0/547 (0.00%)	1/535 (0.19%)
Gastroenteritis ^† 1	3/547 (0.55%)	1/535 (0.19%)
Herpes zoster disseminated ^† 1	1/547 (0.18%)	0/535 (0.00%)
Infected skin ulcer ^† 1	0/547 (0.00%)	1/535 (0.19%)
Infection ^† 1	0/547 (0.00%)	2/535 (0.37%)
Influenza ^† 1	1/547 (0.18%)	2/535 (0.37%)
Laryngitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Lower respiratory tract infection ^† 1	2/547 (0.37%)	2/535 (0.37%)
Lung abscess ^† 1	0/547 (0.00%)	1/535 (0.19%)
Lung infection ^† 1	2/547 (0.37%)	1/535 (0.19%)
Meningitis aseptic ^† 1	2/547 (0.37%)	0/535 (0.00%)
Peritonsillar abscess ^† 1	0/547 (0.00%)	1/535 (0.19%)
Pneumonia ^† 1	17/547 (3.11%)	8/535 (1.50%)
Pulmonary sepsis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Rectal abscess ^† 1	0/547 (0.00%)	1/535 (0.19%)
Respiratory syncytial virus infection ^† 1	1/547 (0.18%)	0/535 (0.00%)
Respiratory tract infection ^† 1	1/547 (0.18%)	0/535 (0.00%)
Sepsis ^† 1	5/547 (0.91%)	6/535 (1.12%)
Septic shock ^† 1	2/547 (0.37%)	0/535 (0.00%)
Soft tissue infection ^† 1	1/547 (0.18%)	0/535 (0.00%)
Upper respiratory tract infection ^† 1	1/547 (0.18%)	0/535 (0.00%)
Urinary tract infection ^† 1	6/547 (1.10%)	0/535 (0.00%)
Urosepsis ^† 1	1/547 (0.18%)	1/535 (0.19%)
Viral infection ^† 1	1/547 (0.18%)	0/535 (0.00%)
Injury, poisoning and procedural complications
Contusion ^† 1	1/547 (0.18%)	0/535 (0.00%)
Drug administration error ^† 1	1/547 (0.18%)	0/535 (0.00%)
Fall ^† 1	0/547 (0.00%)	1/535 (0.19%)
Femur fracture ^† 1	1/547 (0.18%)	1/535 (0.19%)
Fracture ^† 1	0/547 (0.00%)	1/535 (0.19%)
Hip fracture ^† 1	0/547 (0.00%)	1/535 (0.19%)
Humerus fracture ^† 1	0/547 (0.00%)	2/535 (0.37%)
Incisional hernia ^† 1	1/547 (0.18%)	0/535 (0.00%)
Injury ^† 1	0/547 (0.00%)	1/535 (0.19%)
Joint dislocation ^† 1	1/547 (0.18%)	0/535 (0.00%)
Lumbar vertebral fracture ^† 1	0/547 (0.00%)	1/535 (0.19%)
Pneumonitis chemical ^† 1	1/547 (0.18%)	0/535 (0.00%)
Postoperative hernia ^† 1	1/547 (0.18%)	0/535 (0.00%)
Seroma ^† 1	0/547 (0.00%)	1/535 (0.19%)
Subarachnoid haemorrhage ^† 1	0/547 (0.00%)	1/535 (0.19%)
Upper limb fracture ^† 1	0/547 (0.00%)	1/535 (0.19%)
Wound ^† 1	1/547 (0.18%)	0/535 (0.00%)
Wrist fracture ^† 1	0/547 (0.00%)	1/535 (0.19%)
Investigations
Activated partial thromboplastin time prolonged ^† 1	0/547 (0.00%)	1/535 (0.19%)
Alanine aminotransferase increased ^† 1	9/547 (1.65%)	0/535 (0.00%)
Aspartate aminotransferase increased ^† 1	4/547 (0.73%)	0/535 (0.00%)
Blood bilirubin increased ^† 1	0/547 (0.00%)	1/535 (0.19%)
Blood creatinine increased ^† 1	5/547 (0.91%)	1/535 (0.19%)
Blood potassium increased ^† 1	0/547 (0.00%)	1/535 (0.19%)
Lipase increased ^† 1	1/547 (0.18%)	0/535 (0.00%)
Pancreatic enzymes increased ^† 1	1/547 (0.18%)	0/535 (0.00%)
Platelet count decreased ^† 1	0/547 (0.00%)	4/535 (0.75%)
Transaminases increased ^† 1	3/547 (0.55%)	0/535 (0.00%)
Troponin increased ^† 1	0/547 (0.00%)	1/535 (0.19%)
Metabolism and nutrition disorders
Acidosis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Decreased appetite ^† 1	2/547 (0.37%)	0/535 (0.00%)
Dehydration ^† 1	7/547 (1.28%)	8/535 (1.50%)
Diabetes mellitus ^† 1	2/547 (0.37%)	0/535 (0.00%)
Diabetes mellitus inadequate control ^† 1	1/547 (0.18%)	0/535 (0.00%)
Diabetic ketoacidosis ^† 1	2/547 (0.37%)	0/535 (0.00%)
Fluid overload ^† 1	1/547 (0.18%)	0/535 (0.00%)
Fulminant type 1 diabetes mellitus ^† 1	2/547 (0.37%)	0/535 (0.00%)
Hypercalcaemia ^† 1	4/547 (0.73%)	3/535 (0.56%)
Hyperglycaemia ^† 1	6/547 (1.10%)	1/535 (0.19%)
Hyperkalaemia ^† 1	1/547 (0.18%)	2/535 (0.37%)
Hypoglycaemia ^† 1	3/547 (0.55%)	3/535 (0.56%)
Hypokalaemia ^† 1	2/547 (0.37%)	0/535 (0.00%)
Hypomagnesaemia ^† 1	0/547 (0.00%)	2/535 (0.37%)
Hyponatraemia ^† 1	9/547 (1.65%)	5/535 (0.93%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	4/547 (0.73%)	0/535 (0.00%)
Arthritis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Back pain ^† 1	4/547 (0.73%)	4/535 (0.75%)
Fistula ^† 1	1/547 (0.18%)	0/535 (0.00%)
Flank pain ^† 1	1/547 (0.18%)	0/535 (0.00%)
Groin pain ^† 1	1/547 (0.18%)	0/535 (0.00%)
Muscular weakness ^† 1	1/547 (0.18%)	1/535 (0.19%)
Musculoskeletal pain ^† 1	0/547 (0.00%)	1/535 (0.19%)
Myalgia ^† 1	1/547 (0.18%)	0/535 (0.00%)
Neck pain ^† 1	0/547 (0.00%)	2/535 (0.37%)
Osteolysis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Osteonecrosis ^† 1	0/547 (0.00%)	1/535 (0.19%)
Osteonecrosis of jaw ^† 1	0/547 (0.00%)	1/535 (0.19%)
Pain in extremity ^† 1	1/547 (0.18%)	0/535 (0.00%)
Pathological fracture ^† 1	3/547 (0.55%)	0/535 (0.00%)
Rhabdomyolysis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Synovitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	1/547 (0.18%)	3/535 (0.56%)
Brain neoplasm ^† 1	1/547 (0.18%)	0/535 (0.00%)
Cancer pain ^† 1	1/547 (0.18%)	1/535 (0.19%)
Gastric adenoma ^† 1	1/547 (0.18%)	0/535 (0.00%)
Malignant neoplasm progression ^† 1	22/547 (4.02%)	31/535 (5.79%)
Malignant pleural effusion ^† 1	1/547 (0.18%)	0/535 (0.00%)
Metastases to bone ^† 1	2/547 (0.37%)	1/535 (0.19%)
Metastases to central nervous system ^† 1	2/547 (0.37%)	3/535 (0.56%)
Metastatic neoplasm ^† 1	0/547 (0.00%)	1/535 (0.19%)
Metastatic renal cell carcinoma ^† 1	0/547 (0.00%)	1/535 (0.19%)
Prostate cancer ^† 1	0/547 (0.00%)	1/535 (0.19%)
Small intestine adenocarcinoma ^† 1	1/547 (0.18%)	0/535 (0.00%)
Squamous cell carcinoma ^† 1	0/547 (0.00%)	1/535 (0.19%)
Tumour haemorrhage ^† 1	1/547 (0.18%)	1/535 (0.19%)
Tumour pain ^† 1	1/547 (0.18%)	0/535 (0.00%)
Nervous system disorders
Aphasia ^† 1	1/547 (0.18%)	0/535 (0.00%)
Brain oedema ^† 1	1/547 (0.18%)	0/535 (0.00%)
Central nervous system lesion ^† 1	1/547 (0.18%)	0/535 (0.00%)
Cerebral haemorrhage ^† 1	2/547 (0.37%)	0/535 (0.00%)
Cerebral infarction ^† 1	3/547 (0.55%)	0/535 (0.00%)
Cerebrovascular accident ^† 1	0/547 (0.00%)	2/535 (0.37%)
Cervical cord compression ^† 1	0/547 (0.00%)	1/535 (0.19%)
Dysarthria ^† 1	0/547 (0.00%)	1/535 (0.19%)
Embolic cerebral infarction ^† 1	1/547 (0.18%)	0/535 (0.00%)
Encephalopathy ^† 1	1/547 (0.18%)	0/535 (0.00%)
Facial nerve disorder ^† 1	1/547 (0.18%)	0/535 (0.00%)
Facial paralysis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Facial paresis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Haemorrhage intracranial ^† 1	1/547 (0.18%)	1/535 (0.19%)
Headache ^† 1	3/547 (0.55%)	1/535 (0.19%)
Iiird nerve paralysis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Intracranial aneurysm ^† 1	0/547 (0.00%)	1/535 (0.19%)
Intracranial pressure increased ^† 1	1/547 (0.18%)	0/535 (0.00%)
Ischaemic stroke ^† 1	1/547 (0.18%)	0/535 (0.00%)
Myasthenia gravis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Neuropathy peripheral ^† 1	1/547 (0.18%)	0/535 (0.00%)
Paraesthesia ^† 1	1/547 (0.18%)	0/535 (0.00%)
Paraparesis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Peripheral motor neuropathy ^† 1	2/547 (0.37%)	0/535 (0.00%)
Polyneuropathy ^† 1	1/547 (0.18%)	0/535 (0.00%)
Seizure ^† 1	3/547 (0.55%)	0/535 (0.00%)
Somnolence ^† 1	0/547 (0.00%)	1/535 (0.19%)
Speech disorder ^† 1	1/547 (0.18%)	0/535 (0.00%)
Spinal cord compression ^† 1	2/547 (0.37%)	1/535 (0.19%)
Syncope ^† 1	2/547 (0.37%)	1/535 (0.19%)
Thecal sac compression ^† 1	0/547 (0.00%)	1/535 (0.19%)
Transient ischaemic attack ^† 1	1/547 (0.18%)	1/535 (0.19%)
Visual field defect ^† 1	0/547 (0.00%)	1/535 (0.19%)
Pregnancy, puerperium and perinatal conditions
Pregnancy ^† 1	0/547 (0.00%)	1/535 (0.19%)
Product Issues
Device breakage ^† 1	1/547 (0.18%)	0/535 (0.00%)
Psychiatric disorders
Confusional state ^† 1	6/547 (1.10%)	0/535 (0.00%)
Delirium ^† 1	1/547 (0.18%)	1/535 (0.19%)
Depression ^† 1	0/547 (0.00%)	1/535 (0.19%)
Suicide attempt ^† 1	1/547 (0.18%)	0/535 (0.00%)
Renal and urinary disorders
Acute kidney injury ^† 1	8/547 (1.46%)	8/535 (1.50%)
Autoimmune nephritis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Haematuria ^† 1	2/547 (0.37%)	8/535 (1.50%)
Micturition urgency ^† 1	1/547 (0.18%)	0/535 (0.00%)
Nephritis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Polyuria ^† 1	1/547 (0.18%)	0/535 (0.00%)
Renal failure ^† 1	1/547 (0.18%)	3/535 (0.56%)
Renal impairment ^† 1	1/547 (0.18%)	2/535 (0.37%)
Renal injury ^† 1	2/547 (0.37%)	0/535 (0.00%)
Renal mass ^† 1	0/547 (0.00%)	1/535 (0.19%)
Tubulointerstitial nephritis ^† 1	0/547 (0.00%)	1/535 (0.19%)
Urinary retention ^† 1	1/547 (0.18%)	0/535 (0.00%)
Urinary tract obstruction ^† 1	2/547 (0.37%)	0/535 (0.00%)
Reproductive system and breast disorders
Ovarian cyst ^† 1	0/547 (0.00%)	1/535 (0.19%)
Prostatitis ^† 1	1/547 (0.18%)	0/535 (0.00%)
Uterine haemorrhage ^† 1	0/547 (0.00%)	1/535 (0.19%)
Respiratory, thoracic and mediastinal disorders
Acquired diaphragmatic eventration ^† 1	0/547 (0.00%)	1/535 (0.19%)
Acute respiratory failure ^† 1	1/547 (0.18%)	0/535 (0.00%)
Asthma ^† 1	0/547 (0.00%)	1/535 (0.19%)
Bronchial obstruction ^† 1	1/547 (0.18%)	1/535 (0.19%)
Chronic obstructive pulmonary disease ^† 1	2/547 (0.37%)	0/535 (0.00%)
Chylothorax ^† 1	1/547 (0.18%)	0/535 (0.00%)
Cough ^† 1	2/547 (0.37%)	0/535 (0.00%)
Dyspnoea ^† 1	9/547 (1.65%)	9/535 (1.68%)
Epistaxis ^† 1	0/547 (0.00%)	3/535 (0.56%)
Haemoptysis ^† 1	0/547 (0.00%)	3/535 (0.56%)
Hydrothorax ^† 1	0/547 (0.00%)	1/535 (0.19%)
Hypoxia ^† 1	0/547 (0.00%)	1/535 (0.19%)
Interstitial lung disease ^† 1	1/547 (0.18%)	0/535 (0.00%)
Laryngeal oedema ^† 1	0/547 (0.00%)	1/535 (0.19%)
Lung disorder ^† 1	1/547 (0.18%)	0/535 (0.00%)
Orthopnoea ^† 1	0/547 (0.00%)	1/535 (0.19%)
Pleural effusion ^† 1	7/547 (1.28%)	9/535 (1.68%)
Pneumonitis ^† 1	15/547 (2.74%)	1/535 (0.19%)
Pneumothorax ^† 1	1/547 (0.18%)	0/535 (0.00%)
Pulmonary embolism ^† 1	4/547 (0.73%)	3/535 (0.56%)
Pulmonary haemorrhage ^† 1	2/547 (0.37%)	1/535 (0.19%)
Reflux laryngitis ^† 1	0/547 (0.00%)	1/535 (0.19%)
Respiratory failure ^† 1	2/547 (0.37%)	0/535 (0.00%)
Skin and subcutaneous tissue disorders
Diabetic foot ^† 1	0/547 (0.00%)	1/535 (0.19%)
Drug eruption ^† 1	1/547 (0.18%)	0/535 (0.00%)
Erythema multiforme ^† 1	0/547 (0.00%)	1/535 (0.19%)
Haemorrhage subcutaneous ^† 1	1/547 (0.18%)	0/535 (0.00%)
Pruritus ^† 1	1/547 (0.18%)	0/535 (0.00%)
Rash ^† 1	2/547 (0.37%)	0/535 (0.00%)
Rash maculo-papular ^† 1	2/547 (0.37%)	0/535 (0.00%)
Stevens-johnson syndrome ^† 1	1/547 (0.18%)	0/535 (0.00%)
Social circumstances
Immobile ^† 1	1/547 (0.18%)	0/535 (0.00%)
Vascular disorders
Angiopathy ^† 1	1/547 (0.18%)	0/535 (0.00%)
Deep vein thrombosis ^† 1	1/547 (0.18%)	3/535 (0.56%)
Embolism ^† 1	2/547 (0.37%)	1/535 (0.19%)
Haematoma ^† 1	0/547 (0.00%)	1/535 (0.19%)
Hypertension ^† 1	0/547 (0.00%)	3/535 (0.56%)
Hypotension ^† 1	4/547 (0.73%)	2/535 (0.37%)
Orthostatic hypotension ^† 1	1/547 (0.18%)	0/535 (0.00%)
Shock ^† 1	1/547 (0.18%)	0/535 (0.00%)
Subclavian vein occlusion ^† 1	1/547 (0.18%)	0/535 (0.00%)
Vein rupture ^† 1	1/547 (0.18%)	0/535 (0.00%)
Venous thrombosis ^† 1	1/547 (0.18%)	0/535 (0.00%)
1 Term from vocabulary, MedDRA 20.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Nivolumab + Ipilimumab	Sunitinib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	530/547 (96.89%)	522/535 (97.57%)
Blood and lymphatic system disorders
Anaemia ^† 1	71/547 (12.98%)	108/535 (20.19%)
Leukopenia ^† 1	1/547 (0.18%)	31/535 (5.79%)
Neutropenia ^† 1	3/547 (0.55%)	73/535 (13.64%)
Thrombocytopenia ^† 1	6/547 (1.10%)	98/535 (18.32%)
Endocrine disorders
Hyperthyroidism ^† 1	63/547 (11.52%)	16/535 (2.99%)
Hypothyroidism ^† 1	94/547 (17.18%)	144/535 (26.92%)
Eye disorders
Vision blurred ^† 1	28/547 (5.12%)	10/535 (1.87%)
Gastrointestinal disorders
Abdominal distension ^† 1	14/547 (2.56%)	27/535 (5.05%)
Abdominal pain ^† 1	69/547 (12.61%)	76/535 (14.21%)
Abdominal pain upper ^† 1	26/547 (4.75%)	44/535 (8.22%)
Constipation ^† 1	93/547 (17.00%)	94/535 (17.57%)
Diarrhoea ^† 1	198/547 (36.20%)	310/535 (57.94%)
Dry mouth ^† 1	35/547 (6.40%)	37/535 (6.92%)
Dyspepsia ^† 1	29/547 (5.30%)	112/535 (20.93%)
Flatulence ^† 1	7/547 (1.28%)	31/535 (5.79%)
Gastrooesophageal reflux disease ^† 1	11/547 (2.01%)	67/535 (12.52%)
Haemorrhoids ^† 1	12/547 (2.19%)	27/535 (5.05%)
Nausea ^† 1	161/547 (29.43%)	230/535 (42.99%)
Oral pain ^† 1	2/547 (0.37%)	30/535 (5.61%)
Stomatitis ^† 1	29/547 (5.30%)	152/535 (28.41%)
Toothache ^† 1	9/547 (1.65%)	27/535 (5.05%)
Vomiting ^† 1	108/547 (19.74%)	148/535 (27.66%)
General disorders
Asthenia ^† 1	88/547 (16.09%)	99/535 (18.50%)
Chest pain ^† 1	23/547 (4.20%)	27/535 (5.05%)
Chills ^† 1	31/547 (5.67%)	42/535 (7.85%)
Fatigue ^† 1	246/547 (44.97%)	291/535 (54.39%)
Influenza like illness ^† 1	46/547 (8.41%)	27/535 (5.05%)
Malaise ^† 1	12/547 (2.19%)	28/535 (5.23%)
Mucosal inflammation ^† 1	18/547 (3.29%)	156/535 (29.16%)
Oedema peripheral ^† 1	75/547 (13.71%)	66/535 (12.34%)
Pain ^† 1	33/547 (6.03%)	45/535 (8.41%)
Pyrexia ^† 1	126/547 (23.03%)	85/535 (15.89%)
Infections and infestations
Upper respiratory tract infection ^† 1	34/547 (6.22%)	35/535 (6.54%)
Urinary tract infection ^† 1	29/547 (5.30%)	24/535 (4.49%)
Viral upper respiratory tract infection ^† 1	46/547 (8.41%)	21/535 (3.93%)
Investigations
Alanine aminotransferase increased ^† 1	63/547 (11.52%)	60/535 (11.21%)
Amylase increased ^† 1	76/547 (13.89%)	42/535 (7.85%)
Aspartate aminotransferase increased ^† 1	69/547 (12.61%)	57/535 (10.65%)
Blood alkaline phosphatase increased ^† 1	32/547 (5.85%)	24/535 (4.49%)
Blood creatinine increased ^† 1	65/547 (11.88%)	49/535 (9.16%)
Blood thyroid stimulating hormone increased ^† 1	12/547 (2.19%)	32/535 (5.98%)
Lipase increased ^† 1	96/547 (17.55%)	65/535 (12.15%)
Neutrophil count decreased ^† 1	5/547 (0.91%)	40/535 (7.48%)
Platelet count decreased ^† 1	9/547 (1.65%)	76/535 (14.21%)
Weight decreased ^† 1	47/547 (8.59%)	41/535 (7.66%)
White blood cell count decreased ^† 1	6/547 (1.10%)	41/535 (7.66%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	114/547 (20.84%)	156/535 (29.16%)
Dehydration ^† 1	28/547 (5.12%)	22/535 (4.11%)
Hyperglycaemia ^† 1	54/547 (9.87%)	23/535 (4.30%)
Hyperkalaemia ^† 1	36/547 (6.58%)	21/535 (3.93%)
Hypomagnesaemia ^† 1	17/547 (3.11%)	32/535 (5.98%)
Hyponatraemia ^† 1	33/547 (6.03%)	28/535 (5.23%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	122/547 (22.30%)	83/535 (15.51%)
Back pain ^† 1	87/547 (15.90%)	89/535 (16.64%)
Muscle spasms ^† 1	34/547 (6.22%)	28/535 (5.23%)
Musculoskeletal pain ^† 1	36/547 (6.58%)	33/535 (6.17%)
Myalgia ^† 1	64/547 (11.70%)	34/535 (6.36%)
Pain in extremity ^† 1	62/547 (11.33%)	76/535 (14.21%)
Nervous system disorders
Dizziness ^† 1	61/547 (11.15%)	61/535 (11.40%)
Dysgeusia ^† 1	40/547 (7.31%)	185/535 (34.58%)
Headache ^† 1	102/547 (18.65%)	120/535 (22.43%)
Paraesthesia ^† 1	33/547 (6.03%)	29/535 (5.42%)
Psychiatric disorders
Anxiety ^† 1	29/547 (5.30%)	21/535 (3.93%)
Insomnia ^† 1	58/547 (10.60%)	35/535 (6.54%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	144/547 (26.33%)	125/535 (23.36%)
Dysphonia ^† 1	18/547 (3.29%)	28/535 (5.23%)
Dyspnoea ^† 1	95/547 (17.37%)	92/535 (17.20%)
Epistaxis ^† 1	7/547 (1.28%)	75/535 (14.02%)
Oropharyngeal pain ^† 1	26/547 (4.75%)	40/535 (7.48%)
Skin and subcutaneous tissue disorders
Alopecia ^† 1	5/547 (0.91%)	27/535 (5.05%)
Dry skin ^† 1	55/547 (10.05%)	53/535 (9.91%)
Hair colour changes ^† 1	0/547 (0.00%)	32/535 (5.98%)
Palmar-plantar erythrodysaesthesia syndrome ^† 1	9/547 (1.65%)	237/535 (44.30%)
Pruritus ^† 1	180/547 (32.91%)	58/535 (10.84%)
Rash ^† 1	139/547 (25.41%)	84/535 (15.70%)
Rash maculo-papular ^† 1	55/547 (10.05%)	28/535 (5.23%)
Skin discolouration ^† 1	3/547 (0.55%)	27/535 (5.05%)
Yellow skin ^† 1	0/547 (0.00%)	45/535 (8.41%)
Vascular disorders
Hypertension ^† 1	52/547 (9.51%)	230/535 (42.99%)
1 Term from vocabulary, MedDRA 20.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Bristol-Myers Squibb Study Director
Organization:	Bristol-Myers Squibb
Phone:	Please Email:
EMail:	Clinical.Trials@bms.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Motzer RJ, McDermott DF, Escudier B, Burotto M, Choueiri TK, Hammers HJ, Barthelemy P, Plimack ER, Porta C, George S, Powles T, Donskov F, Gurney H, Kollmannsberger CK, Grimm MO, Barrios C, Tomita Y, Castellano D, Grunwald V, Rini BI, McHenry MB, Lee CW, McCarthy J, Ejzykowicz F, Tannir NM. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022 Jun 1;128(11):2085-2097. doi: 10.1002/cncr.34180. Epub 2022 Apr 5.

Labriola MK, George DJ. Setting a new standard for long-term survival in metastatic kidney cancer. Cancer. 2022 Jun 1;128(11):2058-2060. doi: 10.1002/cncr.34177. Epub 2022 Apr 5. No abstract available.

Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthelemy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Leung D, Saggi SS, Lee CW, McHenry MB, Motzer RJ. First-line Nivolumab plus Ipilimumab Versus Sunitinib in Patients Without Nephrectomy and With an Evaluable Primary Renal Tumor in the CheckMate 214 Trial. Eur Urol. 2022 Mar;81(3):266-271. doi: 10.1016/j.eururo.2021.10.001. Epub 2021 Nov 5.

Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthelemy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. doi: 10.1136/esmoopen-2020-001079.

Motzer RJ, Escudier B, McDermott DF, Aren Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthelemy P, Hammers HJ, George S, Grunwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. doi: 10.1136/jitc-2020-000891. Erratum In: J Immunother Cancer. 2021 May;9(5):

Ambavane A, Yang S, Atkins MB, Rao S, Shah A, Regan MM, McDermott DF, Michaelson MD. Clinical and economic outcomes of treatment sequences for intermediate- to poor-risk advanced renal cell carcinoma. Immunotherapy. 2020 Jan;12(1):37-51. doi: 10.2217/imt-2019-0199. Epub 2020 Jan 29.

Tomita Y, Kondo T, Kimura G, Inoue T, Wakumoto Y, Yao M, Sugiyama T, Oya M, Fujii Y, Obara W, Motzer RJ, Uemura H. Nivolumab plus ipilimumab versus sunitinib in previously untreated advanced renal-cell carcinoma: analysis of Japanese patients in CheckMate 214 with extended follow-up. Jpn J Clin Oncol. 2020 Jan 24;50(1):12-19. doi: 10.1093/jjco/hyz132.

Motzer RJ, Rini BI, McDermott DF, Aren Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthelemy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grunwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. doi: 10.1016/S1470-2045(19)30413-9. Epub 2019 Aug 16. Erratum In: Lancet Oncol. 2019 Aug 21;: Lancet Oncol. 2020 Jun;21(6):e304. Lancet Oncol. 2020 Nov;21(11):e518.

Cella D, Grunwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. doi: 10.1016/S1470-2045(18)30778-2. Epub 2019 Jan 15. Erratum In: Lancet Oncol. 2019 Jun;20(6):e293.

Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.

Layout table for additonal information

Responsible Party:	Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT02231749
Other Study ID Numbers:	CA209-214 2014-001750-42 ( EudraCT Number )
First Submitted:	September 1, 2014
First Posted:	September 4, 2014
Results First Submitted:	June 21, 2018
Results First Posted:	October 16, 2018
Last Update Posted:	November 15, 2023

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