A Study of Ramucirumab (LY3009806) Plus Docetaxel in Participants With Urothelial Cancer (RANGE)

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ClinicalTrials.gov Identifier: NCT02426125

Recruitment Status : Completed

First Posted : April 24, 2015

Results First Posted : March 8, 2019

Last Update Posted : August 21, 2023

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Sponsor:

Information provided by (Responsible Party):

Eli Lilly and Company

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Urothelial Carcinoma
Interventions	Drug: Ramucirumab Drug: Docetaxel Drug: Placebo
Enrollment	530

Participant Flow

Recruitment Details
Pre-assignment Details	Completers include participants who are confirmed to be alive at study completion.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description	Ramucirumab (10 milligram/kilogram ...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description	Ramucirumab (10 milligram/kilogram [mg/kg]) intravenously (IV) plus docetaxel (75 milligram/square meter [mg/m²]) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Period Title: Overall Study
Started	263	267
Received at Least One Dose of Study Drug	258	265
Completed	46	39
Not Completed	217	228
Reason Not Completed
Lost to Follow-up	14	12
Withdrawal by Subject	13	14
Death	185	200
Randomized, But Never Treated	5	2

Baseline Characteristics

Arm/Group Title		Ramucirumab + Docetaxel	Placebo + Docetaxel	Total
Arm/Group Description		Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...	Total of all reporting groups
Arm/Group Description		Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Total of all reporting groups
Overall Number of Baseline Participants		263	267	530
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized participants.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	263 participants	267 participants	530 participants
		64.6 (9.9)	64.8 (9.2)	64.7 (9.6)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	263 participants	267 participants	530 participants
	Female	50	52	102
	Male	213	215	428
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	263 participants	267 participants	530 participants
	Hispanic or Latino	13	10	23
	Not Hispanic or Latino	208	219	427
	Unknown or Not Reported	42	38	80
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	263 participants	267 participants	530 participants
	American Indian or Alaska Native	1	0	1
	Asian	54	61	115
	Native Hawaiian or Other Pacific Islander	0	0	0
	Black or African American	3	2	5
	White	203	204	407
	More than one race	0	0	0
	Unknown or Not Reported	2	0	2
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	263 participants	267 participants	530 participants
Romania		5	5	10
Hungary		5	8	13
United States		17	18	35
Japan		24	30	54
Ukraine		5	3	8
United Kingdom		18	24	42
Russia		18	12	30
Spain		22	15	37
Greece		13	13	26
Canada		4	5	9
South Korea		16	9	25
Netherlands		17	18	35
Turkey		11	17	28
Belgium		6	1	7
Taiwan		13	18	31
Denmark		5	6	11
Poland		4	4	8
Italy		23	14	37
Mexico		3	1	4
Israel		7	11	18
Australia		6	6	12
France		16	18	34
Germany		5	11	16

Outcome Measures

1.Primary Outcome


Title	Progression Free Survival (PFS)
Description	PFS defined as time from first day of therapy to first evidence of dis...
Description	PFS defined as time from first day of therapy to first evidence of disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or death from any cause. Progressive Disease (PD) is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If participant does not have complete baseline disease assessment, then PFS time was censored at date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for participant. If participant is not known to have died or have objective progression as of data inclusion cutoff date for analysis, PFS time was censored at last adequate tumor assessment date.
Time Frame	Randomization to Radiological Disease Progression or Death from Any Cause (Up to 18 Months)

Outcome Measure Data

Analysis Population Description

The first randomized participants. Censored participants: Ramucirumab + Docetaxel = 58, Placebo + Docetaxel =38.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	216	221
Median (95% Confidence Interval) Unit of Measure: Months
	4.07 (2.96 to 4.47)	2.76 (2.60 to 2.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0118
	Comments	Stratified
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.757
	Confidence Interval	(2-Sided) 95% 0.607 to 0.943
	Estimation Comments	Stratified

2.Secondary Outcome


Title	Overall Survival (OS)
Description	OS is the time from the date of randomization to the date of death fro...
Description	OS is the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data inclusion cutoff date for a particular analysis, OS was censored for that analysis at the last known alive date prior to the data inclusion cutoff date.
Time Frame	Randomization to Date of Death from Any Cause (Up to 31.1 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Censored participants: Ramucirumab + Docetaxel = 78, Placebo + Docetaxel = 67.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	263	267
Median (95% Confidence Interval) Unit of Measure: Months
	9.40 (7.89 to 11.43)	7.85 (7.00 to 9.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2461
	Comments	Stratified
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.887
	Confidence Interval	(2-Sided) 95% 0.724 to 1.086
	Estimation Comments	Stratified

3.Secondary Outcome


Title	Percentage of Participants With an Objective Response Rate (ORR)
Description	ORR is defined as the percentage of participants who achieve a best ov...
Description	ORR is defined as the percentage of participants who achieve a best overall response of complete response (CR) + partial response (PR). ORR = CR + PR. CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 millimeter (mm). Tumor-marker results must have normalized. PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Best overall response is classified based on the overall responses assessed by study investigators according to RECIST v1.1.
Time Frame	Randomization to Disease Progression (Up to 29.7 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	263	267
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	25.9 (20.6 to 31.1)	13.9 (9.7 to 18.0)

4.Secondary Outcome


Title	Percentage of Participants With Disease Control Rate (DCR)
Description	DCR is the percentage of participants with a best overall response of ...
Description	DCR is the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1. Target lesions - CR: Disappearance of all lesions; any pathological lymph nodes must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of lesions vs the baseline sum. Progressive Disease (PD): At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study (the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s). SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Non target lesions - CR: Disappearance of all lesions and normalization of tumor marker levels; all lymph nodes must be non-pathological in size. Non-CR/Non-PD: Persistence of lesion(s) and/or maintenance of abnormal tumor marker levels. PD: Unequivocal progression of existing lesions or the appearance of new lesion(s).
Time Frame	Randomization to Disease Progression (Up to 29.7 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	263	267
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	65.4 (59.7 to 71.1)	55.1 (49.1 to 61.0)

5.Secondary Outcome


Title	Duration of Response (DoR)
Description	Objective response was achieved if they had a best overall response of...
Description	Objective response was achieved if they had a best overall response of CR or PR. Target lesions- CR: Disappearance of all lesions; any pathological lymph nodes have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of lesions vs the baseline sum. PD: At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study(the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s). Non target lesions - CR: Disappearance of all lesions and normalization of tumour marker levels; all lymph nodes must be non-pathological in size. Non-CR/Non-PD: Persistence of lesion(s) and/or maintenance of abnormal tumor marker levels. PD: Unequivocal progression of existing lesions or the appearance of new lesion(s). If a participant was not known to have died or have radiographically documented PD as of the data inclusion cutoff date, DOR was censored at the date of the last adequate tumor assessment.
Time Frame	Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up to 28.4 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants with CR or PR. Participants censored in Ramucirumab + Docetaxel = 12 and in Placebo + Docetaxel = 5.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	68	37
Median (95% Confidence Interval) Unit of Measure: Months
	5.32 (3.94 to 6.87)	4.17 (3.29 to 5.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.189
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.740
	Confidence Interval	(2-Sided) 95% 0.473 to 1.158
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Time to Deterioration in Quality of Life (QoL) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Global Health Status/ QoL Scale
Description	Time to sustained deterioration was defined as time from randomization...
Description	Time to sustained deterioration was defined as time from randomization to first worsening in QoL with no subsequent non-worsened assessment. Worsening in global health status/QoL was defined as a decrease of ≥10 points on a 100-point scale. If a participant did not report worsening, time to sustained deterioration was censored at date of last non-worsened assessment. Scores for global health status/QoL range from 0 to 100 with; higher scores representing better QoL.
Time Frame	Randomization, 30 Days After Treatment Discontinuation (Up to 18 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Censored participants: Ramucirumab + Docetaxel = 160, Placebo + Docetaxel = 173.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	263	267
Median (95% Confidence Interval) Unit of Measure: Months
	6.87 (4.24 to 8.90)	4.60 (3.52 to 5.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + Docetaxel, Placebo + Docetaxel
	Comments	Global health status/QoL
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.357
	Comments	Stratified
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.879
	Confidence Interval	(2-Sided) 95% 0.663 to 1.167
	Estimation Comments	Stratified

7.Secondary Outcome


Title	Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
Description	The EQ-5D-5L is a standardized instrument for use as a measure of self...
Description	The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Participants completed the 5-level (no problem, slight problem, moderate problem, severe problem, and inability or extreme problem), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. A unique EQ-5D health state is defined by combining 1 level from each of the 5 dimensions. Scores range from 0 (death) to 1 (perfect health), but scores <0 are possible based on the algorithm.
Time Frame	Randomization, 30 Days After Treatment Discontinuation (Up to 18 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants with baseline and 30-day follow-up data.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	83	102
Mean (Standard Deviation) Unit of Measure: units on a scale
	-0.10 (0.26)	-0.19 (0.26)

8.Secondary Outcome


Title	Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS)
Description	The EQ-5D-5L is a standardized instrument for use as a measure of self...
Description	The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. A unique EQ-5D health state is defined by combining 1 level from each of the 5 dimensions. Participants indicated their current health status by marking on a VAS ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).
Time Frame	Randomization, 30 Days After Treatment Discontinuation (Up to 18 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants with baseline and 30-day follow-up data.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV ion day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	86	105
Mean (Standard Deviation) Unit of Measure: millimeter (mm)
	-7.87 (17.95)	-10.91 (16.77)

9.Secondary Outcome


Title	Pharmacokinetics (PK): Maximum Concentration (Cmax) of Ramucirumab
Description	Cmax of Ramucirumab at the end of ramucirumab infusion.
Description	Cmax of Ramucirumab at the end of ramucirumab infusion.
Time Frame	Cycle 1 and Cycle 9, Day 1: Predose, Postdose

Outcome Measure Data

Analysis Population Description

All randomized participants who had evaluable PK data.


Arm/Group Title		Ramucirumab + Docetaxel
Arm/Group Description:		Ramucirumab (10 mg/kg) IV plus doce...
Arm/Group Description:		Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed		209
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: microgram/milliliter (μg/mL)
Cycle 1	Number Analyzed	209 participants
Cycle 1		199 (28%)
Cycle 9	Number Analyzed	22 participants
Cycle 9		265 (29%)

10.Secondary Outcome


Title	PK: Minimum Concentration (Cmin) of Ramucirumab
Description	Cmin of Ramucirumab following administration every 3 weeks.
Description	Cmin of Ramucirumab following administration every 3 weeks.
Time Frame	Day 1 of Cycle 2, 3, 5 and 9 (Predose and Postdose)

Outcome Measure Data

Analysis Population Description

All randomized participants who had evaluable PK data.


Arm/Group Title		Ramucirumab + Docetaxel
Arm/Group Description:		Ramucirumab (10 mg/kg) IV plus doce...
Arm/Group Description:		Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed		188
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: μg/mL
Cycle 2	Number Analyzed	188 participants
Cycle 2		14.9 (64%)
Cycle 3	Number Analyzed	146 participants
Cycle 3		23.5 (63%)
Cycle 5	Number Analyzed	94 participants
Cycle 5		32.5 (70%)
Cycle 9	Number Analyzed	25 participants
Cycle 9		48.9 (56%)

11.Secondary Outcome


Title	Number of Participants With Anti-Ramucirumab Antibodies
Description	Number of participants with positive treatment emergent anti-ramucirum...
Description	Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group.
Time Frame	29.7 Months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug at baseline and post-baseline.


Arm/Group Title	Ramucirumab + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus doce...	Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description:	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	199	213
Measure Type: Count of Participants Unit of Measure: Participants
	3	8

Adverse Events

Time Frame	Up to 64.7 Months
Adverse Event Reporting Description	All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.

Arm/Group Title	Ramucirumab + Docetaxel		Placebo+Docetaxel
Arm/Group Description	Ramucirumab (10 mg/kg) IV plus doce...		Placebo IV plus docetaxel (75 mg/m²...
Arm/Group Description	Ramucirumab (10 mg/kg) IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.		Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
All-Cause Mortality
	Ramucirumab + Docetaxel		Placebo+Docetaxel
	Affected / at Risk (%)		Affected / at Risk (%)
Total	193/258 (74.81%)		209/265 (78.87%)
Serious Adverse Events Serious Adverse Events
	Ramucirumab + Docetaxel		Placebo+Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	111/258 (43.02%)		107/265 (40.38%)
Blood and lymphatic system disorders
Anaemia ^† 1	0/258 (0.00%)	0	4/265 (1.51%)	4
Blood loss anaemia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Febrile neutropenia ^† 1	17/258 (6.59%)	20	13/265 (4.91%)	14
Leukopenia ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	3
Neutropenia ^† 1	4/258 (1.55%)	5	2/265 (0.75%)	2
Pancytopenia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Cardiac disorders
Arteriospasm coronary ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cardiac arrest ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cardiac failure ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Cardiac failure congestive ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Intracardiac thrombus ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Myocardial infarction ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Pericardial effusion ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Supraventricular tachycardia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Ear and labyrinth disorders
Vertigo ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Endocrine disorders
Adrenal insufficiency ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Gastrointestinal disorders
Abdominal pain ^† 1	1/258 (0.39%)	2	1/265 (0.38%)	1
Anal fistula ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Ascites ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Colitis ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Constipation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Diarrhoea ^† 1	6/258 (2.33%)	6	4/265 (1.51%)	5
Enterocolitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Enterovesical fistula ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Fistula of small intestine ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gastric haemorrhage ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gastrointestinal haemorrhage ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Gastrointestinal ulcer ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Haemorrhoids ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Ileal perforation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Intestinal ischaemia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Intestinal obstruction ^† 1	3/258 (1.16%)	3	2/265 (0.75%)	2
Intestinal perforation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Large intestine perforation ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Nausea ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Oesophagitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Rectal haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Small intestinal obstruction ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Small intestinal perforation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Stomatitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Tooth disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Upper gastrointestinal haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Vomiting ^† 1	3/258 (1.16%)	3	2/265 (0.75%)	2
General disorders
Asthenia ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Chest pain ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Death ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Fatigue ^† 1	5/258 (1.94%)	5	2/265 (0.75%)	2
General physical health deterioration ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Generalised oedema ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Malaise ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Mucosal inflammation ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Non-cardiac chest pain ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Pain ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Pyrexia ^† 1	3/258 (1.16%)	3	9/265 (3.40%)	10
Sudden death ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hepatobiliary disorders
Cholelithiasis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Infections and infestations
Abdominal abscess ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Appendicitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Bacteraemia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Bronchitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Cellulitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Clostridium difficile colitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cystitis ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Device related infection ^† 1	3/258 (1.16%)	3	0/265 (0.00%)	0
Diverticulitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Gastroenteritis ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Gingivitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Infection ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Kidney infection ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Lower respiratory tract infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Neutropenic sepsis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pneumonia ^† 1	5/258 (1.94%)	5	8/265 (3.02%)	8
Pneumonia aspiration ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Pyelonephritis ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Respiratory tract infection ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Sepsis ^† 1	7/258 (2.71%)	7	5/265 (1.89%)	5
Stoma site abscess ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Toxic shock syndrome ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Urinary tract infection ^† 1	10/258 (3.88%)	11	11/265 (4.15%)	15
Urosepsis ^† 1	2/258 (0.78%)	2	5/265 (1.89%)	5
Injury, poisoning and procedural complications
Fall ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Infusion related reaction ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Lower limb fracture ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Urostomy complication ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Investigations
Blood creatinine increased ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Neutrophil count decreased ^† 1	2/258 (0.78%)	3	2/265 (0.75%)	3
Platelet count decreased ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Metabolism and nutrition disorders
Decreased appetite ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Dehydration ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Diabetic metabolic decompensation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hyperglycaemia ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Hyperkalaemia ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Hyponatraemia ^† 1	3/258 (1.16%)	3	0/265 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Bone pain ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Fistula ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Muscular weakness ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Myalgia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Nervous system disorders
Basilar artery thrombosis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cerebral ischaemia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cerebrovascular accident ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Dizziness ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Headache ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Presyncope ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Subarachnoid haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Syncope ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Transient ischaemic attack ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Product Issues
Device connection issue ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Psychiatric disorders
Delirium ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Mental status changes ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	3/258 (1.16%)	3	1/265 (0.38%)	1
Haematuria ^† 1	4/258 (1.55%)	4	6/265 (2.26%)	6
Hydronephrosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Renal failure ^† 1	3/258 (1.16%)	3	0/265 (0.00%)	0
Ureteric stenosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Urinary tract obstruction ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Reproductive system and breast disorders
Female genital tract fistula ^† 1	1/49 (2.04%)	1	0/51 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Dyspnoea ^† 1	3/258 (1.16%)	4	3/265 (1.13%)	3
Epistaxis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Hiccups ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Laryngeal inflammation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Obstructive airways disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Pleural effusion ^† 1	0/258 (0.00%)	0	7/265 (2.64%)	8
Pneumonitis ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Pneumothorax ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pulmonary embolism ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Pulmonary hypertension ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Skin and subcutaneous tissue disorders
Dermatitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Rash ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Vascular disorders
Aortic aneurysm ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Arterial haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Deep vein thrombosis ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Embolism ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Haematoma ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hypertension ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Hypotension ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Venous occlusion ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
1 Term from vocabulary, MedDRA 26.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Ramucirumab + Docetaxel		Placebo+Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	241/258 (93.41%)		251/265 (94.72%)
Blood and lymphatic system disorders
Anaemia ^† 1	50/258 (19.38%)	87	76/265 (28.68%)	140
Blood loss anaemia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Febrile neutropenia ^† 1	9/258 (3.49%)	9	5/265 (1.89%)	5
Leukocytosis ^† 1	1/258 (0.39%)	1	3/265 (1.13%)	3
Leukopenia ^† 1	8/258 (3.10%)	25	5/265 (1.89%)	9
Lymph node pain ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Lymphopenia ^† 1	2/258 (0.78%)	7	2/265 (0.75%)	2
Neutropenia ^† 1	18/258 (6.98%)	36	14/265 (5.28%)	14
Thrombocytopenia ^† 1	6/258 (2.33%)	13	3/265 (1.13%)	3
Thrombocytosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Cardiac disorders
Angina pectoris ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Arrhythmia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Atrial fibrillation ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Atrioventricular block first degree ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Bradycardia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cardiac failure ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Cardiovascular disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Left ventricular dysfunction ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Palpitations ^† 1	2/258 (0.78%)	3	2/265 (0.75%)	2
Pericardial effusion ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Right atrial enlargement ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Sinus bradycardia ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Sinus tachycardia ^† 1	0/258 (0.00%)	0	4/265 (1.51%)	4
Tachyarrhythmia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Tachycardia ^† 1	3/258 (1.16%)	3	2/265 (0.75%)	2
Congenital, familial and genetic disorders
Haemophilia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Ear and labyrinth disorders
Ear canal stenosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Ear discomfort ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Hypoacusis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Middle ear inflammation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Otorrhoea ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Tinnitus ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Vertigo ^† 1	0/258 (0.00%)	0	3/265 (1.13%)	4
Vestibular disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Endocrine disorders
Adrenal insufficiency ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hypothyroidism ^† 1	2/258 (0.78%)	3	1/265 (0.38%)	1
Eye disorders
Dry eye ^† 1	3/258 (1.16%)	3	2/265 (0.75%)	2
Eczema eyelids ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Eye discharge ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Eye disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Eye pain ^† 1	2/258 (0.78%)	4	0/265 (0.00%)	0
Eye pruritus ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Eyelid function disorder ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Eyelid oedema ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Eyelid ptosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Glaucoma ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Lacrimation increased ^† 1	24/258 (9.30%)	28	12/265 (4.53%)	12
Ocular discomfort ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Photopsia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Retinal vascular disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Vision blurred ^† 1	3/258 (1.16%)	3	1/265 (0.38%)	1
Visual impairment ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Vitreous detachment ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Vitreous haemorrhage ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gastrointestinal disorders
Abdominal discomfort ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Abdominal distension ^† 1	7/258 (2.71%)	7	5/265 (1.89%)	5
Abdominal pain ^† 1	20/258 (7.75%)	26	17/265 (6.42%)	22
Abdominal pain lower ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Abdominal pain upper ^† 1	12/258 (4.65%)	15	10/265 (3.77%)	10
Abdominal wall disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Anal fistula ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Anal haemorrhage ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Anal incontinence ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Anal inflammation ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Angular cheilitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Ascites ^† 1	7/258 (2.71%)	8	1/265 (0.38%)	1
Cheilitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Colitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Constipation ^† 1	35/258 (13.57%)	46	45/265 (16.98%)	58
Diarrhoea ^† 1	81/258 (31.40%)	131	56/265 (21.13%)	81
Dry mouth ^† 1	11/258 (4.26%)	13	5/265 (1.89%)	5
Dyschezia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Dyspepsia ^† 1	9/258 (3.49%)	10	7/265 (2.64%)	7
Dysphagia ^† 1	6/258 (2.33%)	6	2/265 (0.75%)	2
Ectopic gastric mucosa ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Enterocolitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Epigastric discomfort ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Eructation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Faeces discoloured ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Flatulence ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Food poisoning ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gastric polyps ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Gastritis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gastrointestinal motility disorder ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gastrointestinal obstruction ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gastrooesophageal reflux disease ^† 1	3/258 (1.16%)	8	4/265 (1.51%)	4
Gingival atrophy ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gingival bleeding ^† 1	3/258 (1.16%)	3	0/265 (0.00%)	0
Gingival pain ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Glossitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Haematochezia ^† 1	3/258 (1.16%)	3	2/265 (0.75%)	2
Haemorrhoidal haemorrhage ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Haemorrhoids ^† 1	8/258 (3.10%)	9	2/265 (0.75%)	2
Hiatus hernia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hyperchlorhydria ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Ileus ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Intestinal haemorrhage ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Intra-abdominal haematoma ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Large intestinal haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Lip blister ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Lip dry ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Melaena ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	2
Mouth ulceration ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Mucous stools ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Nausea ^† 1	71/258 (27.52%)	102	55/265 (20.75%)	82
Obstruction gastric ^† 1	1/258 (0.39%)	5	0/265 (0.00%)	0
Odynophagia ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Oral disorder ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Oral hyperaesthesia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Oral pain ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Periodontal disease ^† 1	1/258 (0.39%)	2	2/265 (0.75%)	2
Proctalgia ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Proctitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Rectal haemorrhage ^† 1	1/258 (0.39%)	1	3/265 (1.13%)	3
Rectal prolapse ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Rectal tenesmus ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Stomatitis ^† 1	66/258 (25.58%)	117	30/265 (11.32%)	36
Toothache ^† 1	1/258 (0.39%)	1	4/265 (1.51%)	4
Upper gastrointestinal haemorrhage ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Vomiting ^† 1	41/258 (15.89%)	62	40/265 (15.09%)	56
General disorders
Administration site extravasation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Administration site rash ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Asthenia ^† 1	29/258 (11.24%)	55	24/265 (9.06%)	38
Catheter site erythema ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Chest discomfort ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Chest pain ^† 1	1/258 (0.39%)	1	4/265 (1.51%)	4
Chills ^† 1	6/258 (2.33%)	7	9/265 (3.40%)	12
Extravasation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Face oedema ^† 1	3/258 (1.16%)	3	1/265 (0.38%)	1
Fatigue ^† 1	98/258 (37.98%)	186	106/265 (40.00%)	188
Gait disturbance ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
General physical health deterioration ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Generalised oedema ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Hypothermia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Influenza like illness ^† 1	14/258 (5.43%)	15	7/265 (2.64%)	7
Infusion site extravasation ^† 1	4/258 (1.55%)	4	0/265 (0.00%)	0
Infusion site reaction ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Injection site extravasation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Injection site reaction ^† 1	5/258 (1.94%)	12	1/265 (0.38%)	1
Localised oedema ^† 1	1/258 (0.39%)	2	6/265 (2.26%)	6
Malaise ^† 1	18/258 (6.98%)	31	10/265 (3.77%)	16
Moaning ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Mucosal disorder ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Mucosal inflammation ^† 1	13/258 (5.04%)	26	4/265 (1.51%)	7
Nodule ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Non-cardiac chest pain ^† 1	4/258 (1.55%)	4	4/265 (1.51%)	6
Oedema ^† 1	3/258 (1.16%)	3	1/265 (0.38%)	1
Oedema peripheral ^† 1	38/258 (14.73%)	52	34/265 (12.83%)	44
Pain ^† 1	10/258 (3.88%)	14	8/265 (3.02%)	8
Peripheral swelling ^† 1	2/258 (0.78%)	3	0/265 (0.00%)	0
Pyrexia ^† 1	44/258 (17.05%)	66	42/265 (15.85%)	63
Swelling ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Swelling face ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Tenderness ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Thirst decreased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hepatobiliary disorders
Cholelithiasis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Hepatic failure ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Hepatic function abnormal ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hepatic pain ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Jaundice ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Immune system disorders
Allergy to arthropod sting ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Drug hypersensitivity ^† 1	1/258 (0.39%)	2	1/265 (0.38%)	1
Hypersensitivity ^† 1	2/258 (0.78%)	2	4/265 (1.51%)	5
Seasonal allergy ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Infections and infestations
Abscess intestinal ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Anal abscess ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Bacteraemia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Bacteriuria ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Breast cellulitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Bronchitis ^† 1	4/258 (1.55%)	4	3/265 (1.13%)	3
Cellulitis ^† 1	2/258 (0.78%)	3	2/265 (0.75%)	2
Conjunctivitis ^† 1	5/258 (1.94%)	6	1/265 (0.38%)	1
Covid-19 ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cystitis ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Dacryocystitis ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Device related infection ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Enterovirus infection ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Eye infection ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Fungal infection ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Furuncle ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Gastroenteritis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Gingivitis ^† 1	4/258 (1.55%)	4	2/265 (0.75%)	2
Helicobacter infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Herpes dermatitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Herpes virus infection ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Herpes zoster ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Infective glossitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Influenza ^† 1	3/258 (1.16%)	3	1/265 (0.38%)	1
Kidney infection ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Lower respiratory tract infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Mucosal infection ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Nail bed infection ^† 1	1/258 (0.39%)	3	0/265 (0.00%)	0
Nail infection ^† 1	5/258 (1.94%)	7	1/265 (0.38%)	1
Nasopharyngitis ^† 1	5/258 (1.94%)	5	3/265 (1.13%)	3
Onychomycosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Oral candidiasis ^† 1	5/258 (1.94%)	5	3/265 (1.13%)	3
Oral fungal infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Oral herpes ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Paronychia ^† 1	2/258 (0.78%)	3	0/265 (0.00%)	0
Parotitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Perineal abscess ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Perineal infection ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Peritonitis bacterial ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pharyngitis ^† 1	1/258 (0.39%)	2	1/265 (0.38%)	1
Pneumonia ^† 1	1/258 (0.39%)	1	3/265 (1.13%)	5
Post procedural infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Postoperative wound infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pyelonephritis ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Pyelonephritis acute ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Respiratory tract infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Respiratory tract infection viral ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Rhinitis ^† 1	3/258 (1.16%)	5	1/265 (0.38%)	1
Sepsis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Sinusitis ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Skin infection ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Spinal cord infection ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Tinea pedis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Tonsillitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Tooth abscess ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Tooth infection ^† 1	3/258 (1.16%)	3	0/265 (0.00%)	0
Tracheitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Upper respiratory tract infection ^† 1	5/258 (1.94%)	5	9/265 (3.40%)	9
Urethritis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Urinary tract infection ^† 1	31/258 (12.02%)	38	34/265 (12.83%)	39
Viral infection ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Viral upper respiratory tract infection ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Injury, poisoning and procedural complications
Contusion ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Eschar ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Fall ^† 1	3/258 (1.16%)	3	1/265 (0.38%)	1
Fracture ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Head injury ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Infusion related reaction ^† 1	7/258 (2.71%)	9	6/265 (2.26%)	6
Jaw fracture ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Joint injury ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Limb injury ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Nail injury ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pelvic fracture ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Penis injury ^† 1	0/209 (0.00%)	0	1/214 (0.47%)	1
Periorbital haematoma ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Post procedural haemorrhage ^† 1	3/258 (1.16%)	3	0/265 (0.00%)	0
Procedural nausea ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Procedural pain ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Rib fracture ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Skin abrasion ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Spinal fracture ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Stoma site pain ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Thermal burn ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Urinary tract stoma complication ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Vascular access complication ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Wound ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Wound complication ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Investigations
Activated partial thromboplastin time prolonged ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Alanine aminotransferase increased ^† 1	9/258 (3.49%)	9	8/265 (3.02%)	8
Aspartate aminotransferase increased ^† 1	11/258 (4.26%)	12	9/265 (3.40%)	9
Blood alkaline phosphatase ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Blood alkaline phosphatase increased ^† 1	4/258 (1.55%)	4	11/265 (4.15%)	14
Blood bilirubin increased ^† 1	2/258 (0.78%)	6	1/265 (0.38%)	1
Blood calcium decreased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Blood creatine increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Blood creatinine increased ^† 1	8/258 (3.10%)	8	21/265 (7.92%)	31
Blood lactate dehydrogenase increased ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Blood pressure decreased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Blood pressure increased ^† 1	3/258 (1.16%)	9	3/265 (1.13%)	7
Blood thyroid stimulating hormone increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Blood urea increased ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Blood uric acid increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Body temperature increased ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Carbon dioxide decreased ^† 1	2/258 (0.78%)	3	0/265 (0.00%)	0
Clostridium test positive ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Creatinine renal clearance decreased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Electrocardiogram st segment depression ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Gamma-glutamyltransferase increased ^† 1	1/258 (0.39%)	1	10/265 (3.77%)	13
Heart rate increased ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
International normalised ratio increased ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Lymphocyte count decreased ^† 1	5/258 (1.94%)	15	8/265 (3.02%)	26
Lymphocyte count increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Neutrophil count decreased ^† 1	29/258 (11.24%)	93	29/265 (10.94%)	71
Neutrophil count increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Platelet count decreased ^† 1	21/258 (8.14%)	56	6/265 (2.26%)	9
Platelet count increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Protein total increased ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Protein urine ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Protein urine present ^† 1	1/258 (0.39%)	4	0/265 (0.00%)	0
Prothrombin time prolonged ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Total lung capacity decreased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Troponin t increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Weight decreased ^† 1	23/258 (8.91%)	26	21/265 (7.92%)	28
Weight increased ^† 1	1/258 (0.39%)	1	3/265 (1.13%)	3
White blood cell count decreased ^† 1	19/258 (7.36%)	77	21/265 (7.92%)	54
White blood cell count increased ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
White blood cells urine ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
White blood cells urine positive ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Metabolism and nutrition disorders
Acidosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Cachexia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Decreased appetite ^† 1	82/258 (31.78%)	128	64/265 (24.15%)	82
Dehydration ^† 1	8/258 (3.10%)	8	5/265 (1.89%)	5
Fluid retention ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gout ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Hypercalcaemia ^† 1	6/258 (2.33%)	11	12/265 (4.53%)	15
Hyperglycaemia ^† 1	8/258 (3.10%)	12	13/265 (4.91%)	15
Hyperkalaemia ^† 1	12/258 (4.65%)	26	7/265 (2.64%)	12
Hypermagnesaemia ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	2
Hypernatraemia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hyperuricaemia ^† 1	10/258 (3.88%)	11	15/265 (5.66%)	17
Hypoalbuminaemia ^† 1	17/258 (6.59%)	25	26/265 (9.81%)	32
Hypocalcaemia ^† 1	2/258 (0.78%)	2	4/265 (1.51%)	6
Hypokalaemia ^† 1	3/258 (1.16%)	3	5/265 (1.89%)	7
Hypomagnesaemia ^† 1	4/258 (1.55%)	4	5/265 (1.89%)	7
Hyponatraemia ^† 1	7/258 (2.71%)	10	10/265 (3.77%)	11
Hypophagia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Hypophosphataemia ^† 1	6/258 (2.33%)	10	7/265 (2.64%)	8
Vitamin d deficiency ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	30/258 (11.63%)	39	26/265 (9.81%)	34
Arthritis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Back pain ^† 1	29/258 (11.24%)	36	21/265 (7.92%)	26
Bone pain ^† 1	15/258 (5.81%)	15	17/265 (6.42%)	19
Flank pain ^† 1	3/258 (1.16%)	3	5/265 (1.89%)	6
Groin pain ^† 1	4/258 (1.55%)	6	7/265 (2.64%)	7
Inguinal mass ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Intervertebral disc disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Intervertebral disc protrusion ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Joint effusion ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Joint swelling ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Limb discomfort ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Muscle fatigue ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Muscle spasms ^† 1	2/258 (0.78%)	4	4/265 (1.51%)	4
Muscle twitching ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Muscular weakness ^† 1	5/258 (1.94%)	6	6/265 (2.26%)	7
Musculoskeletal chest pain ^† 1	4/258 (1.55%)	4	3/265 (1.13%)	3
Musculoskeletal pain ^† 1	1/258 (0.39%)	1	4/265 (1.51%)	4
Myalgia ^† 1	24/258 (9.30%)	39	23/265 (8.68%)	30
Myofascitis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Neck mass ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Neck pain ^† 1	3/258 (1.16%)	3	5/265 (1.89%)	7
Osteoarthritis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Osteonecrosis of jaw ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pain in extremity ^† 1	12/258 (4.65%)	15	16/265 (6.04%)	22
Pain in jaw ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Polymyalgia rheumatica ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pubic pain ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Sacral pain ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Spinal pain ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroma ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pyogenic granuloma ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Tumour necrosis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Tumour pain ^† 1	1/258 (0.39%)	1	9/265 (3.40%)	13
Nervous system disorders
Ageusia ^† 1	0/258 (0.00%)	0	3/265 (1.13%)	3
Amnesia ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Ataxia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Clonus ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Depressed level of consciousness ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	3
Disturbance in attention ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Dizziness ^† 1	7/258 (2.71%)	8	9/265 (3.40%)	9
Dizziness postural ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Drooling ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Dysaesthesia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Dysarthria ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Dysgeusia ^† 1	28/258 (10.85%)	41	18/265 (6.79%)	19
Head titubation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Headache ^† 1	19/258 (7.36%)	27	14/265 (5.28%)	15
Hypoaesthesia ^† 1	2/258 (0.78%)	2	3/265 (1.13%)	3
Hypotonia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Lethargy ^† 1	3/258 (1.16%)	3	1/265 (0.38%)	1
Memory impairment ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Nervous system disorder ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Neuralgia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Neuropathy peripheral ^† 1	7/258 (2.71%)	9	13/265 (4.91%)	16
Neurotoxicity ^† 1	3/258 (1.16%)	3	2/265 (0.75%)	2
Paraesthesia ^† 1	5/258 (1.94%)	7	14/265 (5.28%)	15
Peripheral motor neuropathy ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Peripheral sensory neuropathy ^† 1	18/258 (6.98%)	23	22/265 (8.30%)	31
Peroneal nerve palsy ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Polyneuropathy ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Presyncope ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Radiculopathy ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Sciatica ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Somnolence ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Syncope ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Taste disorder ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Tremor ^† 1	2/258 (0.78%)	3	3/265 (1.13%)	4
Product Issues
Device occlusion ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	6/258 (2.33%)	6	8/265 (3.02%)	10
Confusional state ^† 1	1/258 (0.39%)	1	3/265 (1.13%)	4
Delirium ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Depression ^† 1	3/258 (1.16%)	3	4/265 (1.51%)	4
Depressive symptom ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Disorientation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Emotional distress ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Euphoric mood ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Insomnia ^† 1	23/258 (8.91%)	25	10/265 (3.77%)	11
Irritability ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Restlessness ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Sleep disorder ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Sleep talking ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	5/258 (1.94%)	5	0/265 (0.00%)	0
Anuria ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Bladder pain ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Chromaturia ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Chronic kidney disease ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Cystitis interstitial ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cystitis noninfective ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Dysuria ^† 1	3/258 (1.16%)	3	4/265 (1.51%)	4
Haematuria ^† 1	30/258 (11.63%)	48	19/265 (7.17%)	20
Hydronephrosis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Hydroureter ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Micturition urgency ^† 1	2/258 (0.78%)	2	0/265 (0.00%)	0
Nocturia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pollakiuria ^† 1	3/258 (1.16%)	3	4/265 (1.51%)	4
Polyuria ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Proteinuria ^† 1	33/258 (12.79%)	60	16/265 (6.04%)	28
Renal failure ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Renal impairment ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Renal pain ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Urethral haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Urinary fistula ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Urinary hesitation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Urinary incontinence ^† 1	1/258 (0.39%)	1	6/265 (2.26%)	6
Urinary retention ^† 1	1/258 (0.39%)	1	5/265 (1.89%)	6
Urinary tract obstruction ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Urinary tract pain ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Urine odour abnormal ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Reproductive system and breast disorders
Breast pain ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Female genital tract fistula ^† 1	1/49 (2.04%)	1	0/51 (0.00%)	0
Genital haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	3
Genital ulceration ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Gynaecomastia ^† 1	1/209 (0.48%)	1	1/214 (0.47%)	1
Intermenstrual bleeding ^† 1	1/49 (2.04%)	2	0/51 (0.00%)	0
Oedema genital ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Pelvic discomfort ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Pelvic organ prolapse ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pelvic pain ^† 1	5/258 (1.94%)	5	4/265 (1.51%)	4
Penile pain ^† 1	0/209 (0.00%)	0	1/214 (0.47%)	1
Perineal pain ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Perineal ulceration ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Scrotal oedema ^† 1	3/209 (1.44%)	3	1/214 (0.47%)	1
Scrotal pain ^† 1	3/209 (1.44%)	3	0/214 (0.00%)	0
Scrotal swelling ^† 1	0/209 (0.00%)	0	1/214 (0.47%)	1
Testicular oedema ^† 1	0/209 (0.00%)	0	1/214 (0.47%)	1
Testicular pain ^† 1	1/209 (0.48%)	1	1/214 (0.47%)	1
Vaginal haemorrhage ^† 1	1/49 (2.04%)	1	1/51 (1.96%)	1
Vulval haemorrhage ^† 1	1/49 (2.04%)	1	0/51 (0.00%)	0
Vulvovaginal pruritus ^† 1	1/49 (2.04%)	1	0/51 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Aphonia ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Bronchospasm ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Chronic obstructive pulmonary disease ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Chylothorax ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Cough ^† 1	21/258 (8.14%)	30	26/265 (9.81%)	29
Dry throat ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Dysphonia ^† 1	8/258 (3.10%)	10	3/265 (1.13%)	3
Dyspnoea ^† 1	32/258 (12.40%)	50	34/265 (12.83%)	40
Dyspnoea exertional ^† 1	1/258 (0.39%)	1	3/265 (1.13%)	3
Epistaxis ^† 1	39/258 (15.12%)	56	14/265 (5.28%)	16
Haemoptysis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Hiccups ^† 1	14/258 (5.43%)	21	8/265 (3.02%)	8
Hypoxia ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Laryngeal inflammation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Laryngeal pain ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Lung opacity ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Nasal dryness ^† 1	2/258 (0.78%)	2	1/265 (0.38%)	1
Oropharyngeal pain ^† 1	10/258 (3.88%)	11	5/265 (1.89%)	5
Pleural effusion ^† 1	4/258 (1.55%)	4	2/265 (0.75%)	2
Pneumonitis ^† 1	4/258 (1.55%)	4	2/265 (0.75%)	2
Productive cough ^† 1	4/258 (1.55%)	5	2/265 (0.75%)	2
Pulmonary embolism ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Pulmonary fibrosis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pulmonary haemorrhage ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Respiratory tract congestion ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Rhinitis allergic ^† 1	3/258 (1.16%)	3	3/265 (1.13%)	3
Rhinorrhoea ^† 1	7/258 (2.71%)	8	6/265 (2.26%)	6
Sinus congestion ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Tracheal inflammation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Upper respiratory tract congestion ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Upper respiratory tract inflammation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Upper-airway cough syndrome ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	3
Wheezing ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Skin and subcutaneous tissue disorders
Acne ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Alopecia ^† 1	66/258 (25.58%)	79	94/265 (35.47%)	115
Decubitus ulcer ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Dermatitis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Dermatitis acneiform ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Drug eruption ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Dry skin ^† 1	11/258 (4.26%)	12	6/265 (2.26%)	6
Eczema ^† 1	2/258 (0.78%)	4	0/265 (0.00%)	0
Epidermolysis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Erythema ^† 1	6/258 (2.33%)	7	3/265 (1.13%)	3
Erythema multiforme ^† 1	0/258 (0.00%)	0	3/265 (1.13%)	3
Hyperhidrosis ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Nail bed disorder ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Nail bed inflammation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Nail discolouration ^† 1	7/258 (2.71%)	7	15/265 (5.66%)	15
Nail disorder ^† 1	3/258 (1.16%)	3	3/265 (1.13%)	3
Nail dystrophy ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Nail ridging ^† 1	6/258 (2.33%)	7	3/265 (1.13%)	3
Nail toxicity ^† 1	2/258 (0.78%)	4	1/265 (0.38%)	1
Night sweats ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Onychalgia ^† 1	1/258 (0.39%)	5	0/265 (0.00%)	0
Onychoclasis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Onycholysis ^† 1	5/258 (1.94%)	7	2/265 (0.75%)	3
Onychomadesis ^† 1	8/258 (3.10%)	10	5/265 (1.89%)	5
Pain of skin ^† 1	3/258 (1.16%)	3	0/265 (0.00%)	0
Palmar-plantar erythrodysaesthesia syndrome ^† 1	19/258 (7.36%)	28	6/265 (2.26%)	15
Photosensitivity reaction ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Pruritus ^† 1	10/258 (3.88%)	11	12/265 (4.53%)	17
Rash ^† 1	11/258 (4.26%)	14	15/265 (5.66%)	18
Rash erythematous ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Rash maculo-papular ^† 1	0/258 (0.00%)	0	5/265 (1.89%)	5
Skin burning sensation ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Skin discolouration ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Skin disorder ^† 1	1/258 (0.39%)	2	0/265 (0.00%)	0
Skin exfoliation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Skin fissures ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Skin hyperpigmentation ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Skin lesion ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Skin ulcer ^† 1	2/258 (0.78%)	3	0/265 (0.00%)	0
Urticaria ^† 1	5/258 (1.94%)	5	4/265 (1.51%)	4
Xeroderma ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Surgical and medical procedures
Catheter placement ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Central venous catheterisation ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Endodontic procedure ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Nail operation ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Paracentesis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Skin lesion removal ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Tooth extraction ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Vascular disorders
Cyanosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Deep vein thrombosis ^† 1	2/258 (0.78%)	2	4/265 (1.51%)	4
Embolism ^† 1	0/258 (0.00%)	0	2/265 (0.75%)	2
Flushing ^† 1	4/258 (1.55%)	5	2/265 (0.75%)	2
Haematoma ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Hot flush ^† 1	2/258 (0.78%)	2	2/265 (0.75%)	2
Hyperaemia ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Hypertension ^† 1	34/258 (13.18%)	66	15/265 (5.66%)	22
Hypotension ^† 1	7/258 (2.71%)	10	8/265 (3.02%)	8
Lymphocele ^† 1	1/258 (0.39%)	1	1/265 (0.38%)	1
Lymphoedema ^† 1	1/258 (0.39%)	1	2/265 (0.75%)	2
Pallor ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Pelvic venous thrombosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	2
Phlebitis ^† 1	2/258 (0.78%)	3	0/265 (0.00%)	0
Thrombosis ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Varicose vein ^† 1	1/258 (0.39%)	1	0/265 (0.00%)	0
Vasculitis ^† 1	1/258 (0.39%)	6	1/265 (0.38%)	1
Vena cava thrombosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Venous occlusion ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
Venous thrombosis ^† 1	0/258 (0.00%)	0	1/265 (0.38%)	1
1 Term from vocabulary, MedDRA 26.0 † 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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Chief Medical Officer
Organization:	Eli Lilly and Company
Phone:	800-545-5979
EMail:	ClinicalTrials.gov@lilly.com

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

van der Heijden MS, Powles T, Petrylak D, de Wit R, Necchi A, Sternberg CN, Matsubara N, Nishiyama H, Castellano D, Hussain SA, Bamias A, Gakis G, Lee JL, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Eigl BJ, Hozak RR, Rasmussen ER, Xia MS, Rhodes R, Wijayawardana S, Bell-McGuinn KM, Aggarwal A, Drakaki A. Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial. Nat Commun. 2022 Apr 6;13(1):1878. doi: 10.1038/s41467-022-29441-y.

Mitani S, Chen Y, Inoue K, Mori J, Gao L, Long A, Wakabayashi S. Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach. Gan To Kagaku Ryoho. 2021 Nov;48(11):1381-1387.

Necchi A, Nishiyama H, Matsubara N, Lee JL, Petrylak DP, de Wit R, Drakaki A, Liepa AM, Mao H, Bell-McGuinn K, Powles T. Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE). BMC Urol. 2020 Nov 7;20(1):181. doi: 10.1186/s12894-020-00752-w.

Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Flechon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Geczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. doi: 10.1016/S1470-2045(19)30668-0. Epub 2019 Nov 18.

Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Flechon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Geczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. doi: 10.1016/S0140-6736(17)32365-6. Epub 2017 Sep 12.

Layout table for additonal information

Responsible Party:	Eli Lilly and Company
ClinicalTrials.gov Identifier:	NCT02426125
Other Study ID Numbers:	15679 I4T-MC-JVDC ( Other Identifier: Eli Lilly and Company ) 2014-003655-66 ( EudraCT Number )
First Submitted:	April 21, 2015
First Posted:	April 24, 2015
Results First Submitted:	January 25, 2019
Results First Posted:	March 8, 2019
Last Update Posted:	August 21, 2023

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