A Study of Ramucirumab (LY3009806) Versus Placebo in Participants With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (REACH-2)

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ClinicalTrials.gov Identifier: NCT02435433

Recruitment Status : Completed

First Posted : May 6, 2015

Results First Posted : May 17, 2019

Last Update Posted : January 20, 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	Hepatocellular Carcinoma
Interventions	Drug: Ramucirumab Drug: Placebo
Enrollment	399

Participant Flow

Recruitment Details

Main study: Participants who received sorafenib as first-line therapy were randomized to ramucirumab or placebo.
Open-Label Expansion: Participants who were not previously treated with sorafenib were enrolled into this single-arm addenda and treated with ramucirumab. The purpose of this addenda is to monitor safety, and data was reported under AE section.

(Continued...)

Pre-assignment Details

c. China Maximized Extended Enrollment: This is an extension phase of the main study, with an additional 60 participants enrolled in China. Safety was monitored and data was reported under AE section.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC	Open Label Ramucirumab + BSC	Ramucirumab MEE Cohort	Placebo MEE Cohort
Arm/Group Description	8 milligrams per kilogram (mg/kg) r...	Placebo administered IV on day 1 of...	8 mg/kg ramucirumab administered IV...	8 mg/kg ramucirumab administered IV...	Placebo administered IV on day 1 of...
Arm/Group Description	8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Period Title: Overall Study
Started	197	95	47	39	21
Participants Who Received Study Drug	197	95	47	39	21
Completed ^[1]	193	90	42	38	21
Not Completed	4	5	5	1	0
Reason Not Completed
Withdrawal by Subject	2	3	1	0	0
Lost to Follow-up	2	2	4	1	0
[1] Completers include participants who had died due to any cause or alive and on study at the end of study, but off treatment.

Baseline Characteristics

Arm/Group Title		Ramucirumab + BSC	Placebo + Best Supportive Care (BSC)	Open Label Ramucirumab + BSC	Ramucirumab MEE Cohort	Placebo MEE Cohort	Total
Arm/Group Description		8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...	8 mg/kg ramucirumab administered IV...	8 mg/kg ramucirumab administered IV...	Placebo administered IV on day 1 of...	Total of all reporting groups
Arm/Group Description		8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.	8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.	Total of all reporting groups
Overall Number of Baseline Participants		197	95	47	39	21	399
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All participants who received at least one dose of study drug.
Age, Continuous Median (Full Range) Unit of measure: Years
	Number Analyzed	197 participants	95 participants	47 participants	39 participants	21 participants	399 participants
		64 (30 to 88)	64 (26 to 85)	61 (36 to 82)	54 (24 to 74)	54 (31 to 66)	62 (24 to 88)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	197 participants	95 participants	47 participants	39 participants	21 participants	399 participants
	Female	43	16	6	7	1	73
	Male	154	79	41	32	20	326
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	197 participants	95 participants	47 participants	39 participants	21 participants	399 participants
	Hispanic or Latino	12	9	1	0	0	22
	Not Hispanic or Latino	129	58	40	12	9	248
	Unknown or Not Reported	56	28	6	27	12	129
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	197 participants	95 participants	47 participants	39 participants	21 participants	399 participants
	American Indian or Alaska Native	0	0	0	0	0	0
	Asian	102	45	26	39	21	233
	Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
	Black or African American	1	1	4	0	0	6
	White	60	31	13	0	0	104
	More than one race	0	1	4	0	0	5
	Unknown or Not Reported	34	17	0	0	0	51
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	197 participants	95 participants	47 participants	39 participants	21 participants	399 participants
Hong Kong		6	1	8	0	0	15
United States		10	1	12	0	0	23
Czechia		4	2	0	0	0	6
Japan		41	18	0	0	0	59
United Kingdom		9	2	0	0	0	11
Switzerland		2	2	1	0	0	5
Spain		3	2	0	0	0	5
Canada		1	1	0	0	0	2
Austria		1	1	0	0	0	2
South Korea		24	14	0	0	0	38
Belgium		2	2	0	0	0	4
China		3	1	8	39	21	72
Taiwan		22	11	10	0	0	43
Brazil		5	4	0	0	0	9
Poland		2	3	0	0	0	5
Italy		13	9	0	0	0	22
Israel		1	0	0	0	0	1
Australia		2	1	0	0	0	3
France		34	17	0	0	0	51
Germany		12	3	8	0	0	23

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	OS time was measured from date of randomization to date of death from ...
Description	OS time was measured from date of randomization to date of death from any cause. Participants who were not known to have died on or before the date of data cut-off, OS data was censored on the last date (on or before the cut-off date) the participant was known to be alive.
Time Frame	From Date of Randomization to Death from Any Cause (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Participants were censored in Ramucirumab arm = 50 and Placebo arm = 21. All randomized participants (including the censored participants) were included in the analyses.


Arm/Group Title	Ramucirumab + Best Supportive Care (BSC)	Placebo + BSC
Arm/Group Description:	8 milligrams per kilogram (mg/kg) r...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	197	95
Median (95% Confidence Interval) Unit of Measure: Months
	8.51 (7.00 to 10.58)	7.29 (5.42 to 9.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + Best Supportive Care (BSC), Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0199
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.710
	Confidence Interval	(2-Sided) 95% 0.531 to 0.949
	Estimation Comments	Stratified analysis

2.Secondary Outcome


Title	Progression Free Survival (PFS)
Description	Progression-free survival is defined as time from the date of randomiz...
Description	Progression-free survival is defined as time from the date of randomization to the date of first observation of objective progression or death from any cause.
Time Frame	From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Participants were censored in the Ramucirumab arm = 25 and in the Placebo arm = 9. All randomized participants (including the censored participants) were included in the analyses.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 mg/kg ramucirumab administered as an intravenous IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	197	95
Median (95% Confidence Interval) Unit of Measure: Months
	2.83 (2.76 to 4.11)	1.61 (1.45 to 2.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + BSC, Placebo + BSC
	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	0.452
	Confidence Interval	(2-Sided) 95% 0.339 to 0.603
	Estimation Comments	Stratified analysis

3.Secondary Outcome


Title	Time to Radiographic Progression
Description	Time to radiographic progression is defined as the time from the date ...
Description	Time to radiographic progression is defined as the time from the date of randomization to the date of first observation of objective progression.
Time Frame	From Randomization to Objective Progression (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	197	95
Median (95% Confidence Interval) Unit of Measure: Months
	3.02 (2.79 to 4.17)	1.61 (1.45 to 2.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ramucirumab + BSC, Placebo + BSC
	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	0.427
	Confidence Interval	(2-Sided) 95% 0.313 to 0.582
	Estimation Comments	Stratified analysis

4.Secondary Outcome


Title	Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
Description	Objective response rate is defined as the percentage of participants w...
Description	Objective response rate 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 the disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.
Time Frame	From Randomization to Objective Progression (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	197	95
Measure Type: Number Unit of Measure: percentage of participants
	4.6	1.1

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.1697
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95% 0.6 to 37.3
	Estimation Comments	Stratified analysis

5.Secondary Outcome


Title	Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) Before 2nd, 4th, 7th, and 10th Infusion
Description	PK Cmin of Ramucirumab Blood samples were collected at specified time ...
Description	PK Cmin of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.
Time Frame	Predose, Weeks 2, 6, 12 and 18, Day 1; Up to 3 Days Before Infusion (14-Day Cycles)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug.


Arm/Group Title	Ramucirumab + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	195
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: nanogram/milliliter (ng/mL)
Week 0	NA ^[1] (NA%)
Week 2	23.5 (57%)
Week 6	44.1 (60%)
Week 12	60.2 (46%)
Week 18	63.2 (40%)

[1]

1 trough concentrations that was reported below the limit of quantitation were treated as missing for the concentration summaries.

6.Secondary Outcome


Title	PK: Serum Concentration Maximum (Cmax) After 1st, 2nd, 4th, 7th and 10th Ram Infusion
Description	PK Cmax of Ramucirumab Blood samples were collected at specified time ...
Description	PK Cmax of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.
Time Frame	Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug.


Arm/Group Title	Ramucirumab + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Overall Number of Participants Analyzed	195
Geometric Mean (Geometric Coefficient of Variation) Unit of Measure: ng/mL
Week 0	156 (22%)
Week 2	181 (24%)
Week 6	205 (24%)
Week 12	221 (24%)
Week 18	228 (22%)

7.Secondary Outcome


Title	Percentage of Participants With Anti-Ramucirumab Antibodies
Description	Percentage of participants with positive treatment emergent anti-drug ...
Description	Percentage of participants with positive treatment emergent anti-drug antibodies was summarized by treatment group. A treatment-emergent ADA (TEADA) was defined as: having a negative ADA at baseline and an ADA titer greater than or equal to 1:20 (that is (i.e.), greater than 2-fold from the minimal required dilution of 1:10) any time post baseline (i.e., treatment-induced); or a 4-fold or greater change in ADA titer from baseline for participants that had a detectable ADA titer at baseline (i.e., treatment boosted).
Time Frame	Predose Cycle 1: 7 Days prior to First Infusion, Cycle 4: 3 Days Prior to Infusion, Cycle 7 through Follow Up (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had evaluable anti-ramucirumab data.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	161	76
Measure Type: Number Unit of Measure: percentage of participants
	5.0	9.2

8.Secondary Outcome


Title	Time to Deterioration of Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)
Description	The FACT Hepatobiliary Symptom Index (FHSI-8) is a instrument with spe...
Description	The FACT Hepatobiliary Symptom Index (FHSI-8) is a instrument with specific focus regarding the most frequent and concerning symptoms experienced by participants with hepatobiliary malignancies, including lack of energy, nausea, pain, weight loss, pain in back, fatigue, jaundice, stomach pain or discomfort. The (FHSI-8) questionnaire was used to assess the time to deterioration of FSHI-8 total score issued from the date of randomization to the first date observing deterioration, with the deterioration threshold defined as a decrease ≥ 3-points from baseline. In case of no deterioration, the participants were censored at the time of the last FSHI-8 item recording. FHSI-8 total score ranges from 0 to 32 where "0" is a severely symptomatic participant and the highest score indicates an asymptomatic participant. Kaplan-Meier method Hazard ratio was used to estimate (Ramucirumab versus Placebo) and 95% Confidence Interval (CI) (Wald) were estimated from un-stratified/stratified Cox model.
Time Frame	From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants who had evaluable FHSI-8 data.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	197	95
Median (95% Confidence Interval) Unit of Measure: Months
	3.71 (2.79 to 4.40)	2.79 (1.64 to 2.89)

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.2382
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.799
	Confidence Interval	(2-Sided) 95% 0.545 to 1.171
	Estimation Comments	Stratified analysis

9.Secondary Outcome


Title	Change From Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
Description	The EQ-5D-5L is a nonspecific and standardized instrument for use as a...
Description	The EQ-5D-5L is a nonspecific and standardized instrument for use as a measure of self-reported health status (EuroQol Group 1990; Herdman et al. 2011). Participants completed the 5-level (no problems, slight problems, moderate problems, severe problems, and extreme problems), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. A unique EQ-5D-5L health state scale ranges from 0 to 100 and is defined by combining 1 level from each of the 5 dimensions. Participants indicated their current health status by marking on a continuum ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).
Time Frame	From Randomization through End of Study (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants and had evaluable EQ-5D-5L data.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	197	95
Mean (Standard Deviation) Unit of Measure: units on a scale
	-0.105 (0.201)	-0.099 (0.170)

10.Secondary Outcome


Title	Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS)
Description	Time to deterioration in ECOG PS is defined as the time from the date ...
Description	Time to deterioration in ECOG PS is defined as the time from the date of randomization to the first date observing ECOG PS 2 (ie, deterioration from baseline status of 0 [fully active] or 1 [restricted in physically strenuous activity but ambulatory and able to carry out light work]). Participants without PS deterioration were censored at their last documented assessments of 0 or 1. Assessments included ECOG Performance Status (PS): 2- Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours, 3 -Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours, 4 -Completely disabled, cannot carry on any self-care. Totally confined to bed or chair, 5- Dead.
Time Frame	From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants and had evaluable ECOG data. Censored participants without any post baseline assessments at randomization date were in the Ramucirumab + BSC arm = 141 and the Placebo + BSC arm =75. All randomized participants (including the censored participants) were included in the analyses.


Arm/Group Title	Ramucirumab + BSC	Placebo + BSC
Arm/Group Description:	8 mg/kg ramucirumab administered as...	Placebo administered IV on day 1 of...
Arm/Group Description:	8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.	Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
Overall Number of Participants Analyzed	197	95
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (9.33 to NA)	NA ^[2] (5.26 to NA)

[1]

The median and upper limit 95% confidence interval upper limit had insufficient events to perform a meaningful statistical evaluation.

[2]

The median and upper limit 95% confidence interval had insufficient events to perform a meaningful statistical evaluation.

Adverse Events

Time Frame	Baseline up to 3.2 years
Adverse Event Reporting Description	All 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 + BSC		Placebo+BSC		Open Label Ramucirumab + BSC		Ramucirumab MEE Cohort		Placebo MEE Cohort
Arm/Group Description	8 milligrams per kilogram (mg/kg) r...		Placebo administered IV on day 1 of...		8 mg/kg ramucirumab administered IV...		8 mg/kg ramucirumab administered IV...		Placebo administered IV on day 1 of...
Arm/Group Description	8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.		Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.		8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.		8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.		Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
All-Cause Mortality
	Ramucirumab + BSC		Placebo+BSC		Open Label Ramucirumab + BSC		Ramucirumab MEE Cohort		Placebo MEE Cohort
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	162/197 (82.23%)		76/95 (80.00%)		33/47 (70.21%)		35/39 (89.74%)		18/21 (85.71%)
Serious Adverse Events Serious Adverse Events
	Ramucirumab + BSC		Placebo+BSC		Open Label Ramucirumab + BSC		Ramucirumab MEE Cohort		Placebo MEE Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/197 (36.55%)		27/95 (28.42%)		18/47 (38.30%)		10/39 (25.64%)		3/21 (14.29%)
Blood and lymphatic system disorders
Anaemia ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	1/39 (2.56%)	1	0/21 (0.00%)	0
Neutropenia ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Splenic infarction ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Cardiac disorders
Acute coronary syndrome ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Angina pectoris ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Cardiac arrest ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Myocardial infarction ^† 1	1/197 (0.51%)	1	1/95 (1.05%)	1	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastrointestinal disorders
Abdominal hernia ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Abdominal pain ^† 1	3/197 (1.52%)	3	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Abdominal pain upper ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Ascites ^† 1	6/197 (3.05%)	6	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Colitis ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Constipation ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Enterocolitis ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastric haemorrhage ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastric perforation ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastric ulcer ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastric varices haemorrhage ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastroduodenal ulcer ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastrointestinal haemorrhage ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	1/47 (2.13%)	1	1/39 (2.56%)	3	0/21 (0.00%)	0
Lower gastrointestinal haemorrhage ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Melaena ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Mouth ulceration ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	1/39 (2.56%)	1	0/21 (0.00%)	0
Nausea ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Oesophageal haemorrhage ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Oesophageal varices haemorrhage ^† 1	2/197 (1.02%)	2	1/95 (1.05%)	1	0/47 (0.00%)	0	1/39 (2.56%)	2	0/21 (0.00%)	0
Rectal haemorrhage ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Upper gastrointestinal haemorrhage ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	1/47 (2.13%)	2	3/39 (7.69%)	3	0/21 (0.00%)	0
Varices oesophageal ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
General disorders
Asthenia ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
General physical health deterioration ^† 1	2/197 (1.02%)	3	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Generalised oedema ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Multiple organ dysfunction syndrome ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Oedema peripheral ^† 1	3/197 (1.52%)	3	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Pain ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	1/39 (2.56%)	1	0/21 (0.00%)	0
Pyrexia ^† 1	3/197 (1.52%)	3	1/95 (1.05%)	1	2/47 (4.26%)	2	0/39 (0.00%)	0	0/21 (0.00%)	0
Hepatobiliary disorders
Acute hepatic failure ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Cholestasis ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Hepatic cirrhosis ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	1/39 (2.56%)	1	0/21 (0.00%)	0
Hepatic function abnormal ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	1/21 (4.76%)	1
Hepatic pain ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	1/39 (2.56%)	1	0/21 (0.00%)	0
Hepatorenal syndrome ^† 1	2/197 (1.02%)	3	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Jaundice ^† 1	1/197 (0.51%)	1	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Immune system disorders
Anaphylactic reaction ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Infections and infestations
Abdominal infection ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	1/21 (4.76%)	1
Anal abscess ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Appendicitis ^† 1	1/197 (0.51%)	1	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastroenteritis ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Infection ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	2	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Influenza ^† 1	2/197 (1.02%)	2	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Lower respiratory tract infection ^† 1	2/197 (1.02%)	2	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Peritonitis ^† 1	1/197 (0.51%)	1	2/95 (2.11%)	2	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Pleural infection ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Pneumonia ^† 1	5/197 (2.54%)	5	3/95 (3.16%)	4	2/47 (4.26%)	3	2/39 (5.13%)	2	0/21 (0.00%)	0
Post procedural infection ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Post procedural pneumonia ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Respiratory tract infection ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Sepsis ^† 1	3/197 (1.52%)	3	3/95 (3.16%)	3	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Septic shock ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Urinary tract infection ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	1/47 (2.13%)	2	0/39 (0.00%)	0	0/21 (0.00%)	0
Injury, poisoning and procedural complications
Ankle fracture ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Fall ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Hip fracture ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Infusion related reaction ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Investigations
Aspartate aminotransferase increased ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Aspiration pleural cavity ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Blood bilirubin increased ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
General physical condition abnormal ^† 1	1/197 (0.51%)	2	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Dehydration ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Hypercalcaemia ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	2	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Hyponatraemia ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Muscular weakness ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Liver carcinoma ruptured ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Metastases to bone ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Metastases to spine ^† 1	1/197 (0.51%)	1	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Tumour haemorrhage ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	1/39 (2.56%)	1	0/21 (0.00%)	0
Tumour pain ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Tumour rupture ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Nervous system disorders
Cerebral ischaemia ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Cerebrovascular accident ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Coma hepatic ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Epilepsy ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Hepatic encephalopathy ^† 1	3/197 (1.52%)	3	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	1/21 (4.76%)	1
Somnolence ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Syncope ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Confusional state ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Mental status changes ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	3/197 (1.52%)	3	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Haematuria ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	2	0/39 (0.00%)	0	0/21 (0.00%)	0
Nephrotic syndrome ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Renal failure ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^† 1	3/197 (1.52%)	3	2/95 (2.11%)	2	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Epistaxis ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Haemothorax ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Hypoxia ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Lung disorder ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Pleural effusion ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Pulmonary oedema ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Respiratory failure ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Surgical and medical procedures
Tumour excision ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	1/39 (2.56%)	1	0/21 (0.00%)	0
Vascular disorders
Deep vein thrombosis ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Haemorrhage ^† 1	0/197 (0.00%)	0	1/95 (1.05%)	1	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Hypertensive crisis ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Thrombophlebitis migrans ^† 1	1/197 (0.51%)	1	0/95 (0.00%)	0	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
1 Term from vocabulary, MedDRA 25.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ramucirumab + BSC		Placebo+BSC		Open Label Ramucirumab + BSC		Ramucirumab MEE Cohort		Placebo MEE Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	189/197 (95.94%)		77/95 (81.05%)		40/47 (85.11%)		39/39 (100.00%)		17/21 (80.95%)
Blood and lymphatic system disorders
Anaemia ^† 1	19/197 (9.64%)	28	6/95 (6.32%)	7	4/47 (8.51%)	5	7/39 (17.95%)	13	1/21 (4.76%)	1
Thrombocytopenia ^† 1	7/197 (3.55%)	16	1/95 (1.05%)	1	3/47 (6.38%)	3	0/39 (0.00%)	0	0/21 (0.00%)	0
Gastrointestinal disorders
Abdominal distension ^† 1	16/197 (8.12%)	18	5/95 (5.26%)	6	4/47 (8.51%)	4	4/39 (10.26%)	4	1/21 (4.76%)	1
Abdominal pain ^† 1	36/197 (18.27%)	46	12/95 (12.63%)	16	4/47 (8.51%)	4	7/39 (17.95%)	10	2/21 (9.52%)	2
Abdominal pain upper ^† 1	10/197 (5.08%)	10	3/95 (3.16%)	3	3/47 (6.38%)	3	2/39 (5.13%)	2	1/21 (4.76%)	1
Ascites ^† 1	34/197 (17.26%)	47	7/95 (7.37%)	7	6/47 (12.77%)	6	7/39 (17.95%)	8	2/21 (9.52%)	2
Constipation ^† 1	27/197 (13.71%)	33	18/95 (18.95%)	19	1/47 (2.13%)	1	0/39 (0.00%)	0	1/21 (4.76%)	1
Diarrhoea ^† 1	33/197 (16.75%)	46	14/95 (14.74%)	18	9/47 (19.15%)	13	2/39 (5.13%)	3	0/21 (0.00%)	0
Mouth haemorrhage ^† 1	4/197 (2.03%)	4	0/95 (0.00%)	0	0/47 (0.00%)	0	2/39 (5.13%)	5	0/21 (0.00%)	0
Mouth ulceration ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	4/39 (10.26%)	4	0/21 (0.00%)	0
Nausea ^† 1	37/197 (18.78%)	47	10/95 (10.53%)	12	6/47 (12.77%)	6	4/39 (10.26%)	4	1/21 (4.76%)	2
Upper gastrointestinal haemorrhage ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	3/39 (7.69%)	3	0/21 (0.00%)	0
Vomiting ^† 1	20/197 (10.15%)	24	7/95 (7.37%)	7	4/47 (8.51%)	5	3/39 (7.69%)	4	3/21 (14.29%)	3
General disorders
Asthenia ^† 1	17/197 (8.63%)	41	3/95 (3.16%)	6	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Chills ^† 1	0/197 (0.00%)	0	5/95 (5.26%)	6	1/47 (2.13%)	2	1/39 (2.56%)	1	0/21 (0.00%)	0
Face oedema ^† 1	4/197 (2.03%)	4	0/95 (0.00%)	0	0/47 (0.00%)	0	2/39 (5.13%)	4	0/21 (0.00%)	0
Fatigue ^† 1	54/197 (27.41%)	79	16/95 (16.84%)	23	7/47 (14.89%)	8	1/39 (2.56%)	1	2/21 (9.52%)	2
Influenza like illness ^† 1	10/197 (5.08%)	10	1/95 (1.05%)	1	0/47 (0.00%)	0	1/39 (2.56%)	1	0/21 (0.00%)	0
Malaise ^† 1	16/197 (8.12%)	19	5/95 (5.26%)	6	0/47 (0.00%)	0	5/39 (12.82%)	12	0/21 (0.00%)	0
Oedema ^† 1	6/197 (3.05%)	6	1/95 (1.05%)	1	3/47 (6.38%)	3	0/39 (0.00%)	0	0/21 (0.00%)	0
Oedema peripheral ^† 1	52/197 (26.40%)	69	13/95 (13.68%)	13	7/47 (14.89%)	10	6/39 (15.38%)	13	2/21 (9.52%)	2
Pyrexia ^† 1	19/197 (9.64%)	23	3/95 (3.16%)	3	3/47 (6.38%)	3	6/39 (15.38%)	8	3/21 (14.29%)	4
Hepatobiliary disorders
Hepatic function abnormal ^† 1	4/197 (2.03%)	5	0/95 (0.00%)	0	0/47 (0.00%)	0	3/39 (7.69%)	5	0/21 (0.00%)	0
Hepatic pain ^† 1	2/197 (1.02%)	3	0/95 (0.00%)	0	1/47 (2.13%)	1	1/39 (2.56%)	1	3/21 (14.29%)	4
Portal hypertension ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	2/39 (5.13%)	2	0/21 (0.00%)	0
Infections and infestations
Pneumonia ^† 1	4/197 (2.03%)	4	0/95 (0.00%)	0	0/47 (0.00%)	0	3/39 (7.69%)	3	1/21 (4.76%)	1
Urinary tract infection ^† 1	11/197 (5.58%)	18	1/95 (1.05%)	2	0/47 (0.00%)	0	0/39 (0.00%)	0	1/21 (4.76%)	1
Investigations
Alanine aminotransferase increased ^† 1	7/197 (3.55%)	12	5/95 (5.26%)	6	2/47 (4.26%)	3	8/39 (20.51%)	12	5/21 (23.81%)	7
Aspartate aminotransferase increased ^† 1	16/197 (8.12%)	27	10/95 (10.53%)	15	3/47 (6.38%)	3	15/39 (38.46%)	22	7/21 (33.33%)	9
Bilirubin conjugated increased ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	1/47 (2.13%)	1	2/39 (5.13%)	2	3/21 (14.29%)	3
Blood albumin decreased ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	4/39 (10.26%)	6	0/21 (0.00%)	0
Blood alkaline phosphatase increased ^† 1	4/197 (2.03%)	4	2/95 (2.11%)	2	3/47 (6.38%)	4	1/39 (2.56%)	1	2/21 (9.52%)	3
Blood bilirubin increased ^† 1	21/197 (10.66%)	39	8/95 (8.42%)	16	5/47 (10.64%)	5	11/39 (28.21%)	27	6/21 (28.57%)	12
Blood creatinine increased ^† 1	9/197 (4.57%)	15	1/95 (1.05%)	1	1/47 (2.13%)	2	2/39 (5.13%)	2	0/21 (0.00%)	0
Blood urea increased ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	2/39 (5.13%)	2	0/21 (0.00%)	0
Gamma-glutamyltransferase increased ^† 1	2/197 (1.02%)	2	5/95 (5.26%)	6	2/47 (4.26%)	3	3/39 (7.69%)	3	5/21 (23.81%)	6
Neutrophil count decreased ^† 1	12/197 (6.09%)	30	0/95 (0.00%)	0	1/47 (2.13%)	2	6/39 (15.38%)	8	3/21 (14.29%)	6
Platelet count decreased ^† 1	23/197 (11.68%)	72	2/95 (2.11%)	3	6/47 (12.77%)	22	14/39 (35.90%)	27	0/21 (0.00%)	0
Urinary occult blood positive ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	2/39 (5.13%)	9	1/21 (4.76%)	1
Weight decreased ^† 1	22/197 (11.17%)	25	6/95 (6.32%)	7	2/47 (4.26%)	6	3/39 (7.69%)	3	2/21 (9.52%)	2
White blood cell count decreased ^† 1	7/197 (3.55%)	26	0/95 (0.00%)	0	2/47 (4.26%)	3	6/39 (15.38%)	10	2/21 (9.52%)	3
White blood cells urine positive ^† 1	0/197 (0.00%)	0	0/95 (0.00%)	0	0/47 (0.00%)	0	2/39 (5.13%)	4	0/21 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	49/197 (24.87%)	60	19/95 (20.00%)	19	6/47 (12.77%)	6	3/39 (7.69%)	3	5/21 (23.81%)	5
Hyperkalaemia ^† 1	13/197 (6.60%)	21	3/95 (3.16%)	3	1/47 (2.13%)	1	0/39 (0.00%)	0	1/21 (4.76%)	1
Hyperuricaemia ^† 1	1/197 (0.51%)	1	1/95 (1.05%)	1	0/47 (0.00%)	0	2/39 (5.13%)	2	0/21 (0.00%)	0
Hypoalbuminaemia ^† 1	21/197 (10.66%)	29	4/95 (4.21%)	4	4/47 (8.51%)	7	14/39 (35.90%)	24	4/21 (19.05%)	5
Hypocalcaemia ^† 1	5/197 (2.54%)	5	0/95 (0.00%)	0	0/47 (0.00%)	0	2/39 (5.13%)	2	0/21 (0.00%)	0
Hyponatraemia ^† 1	11/197 (5.58%)	16	1/95 (1.05%)	1	4/47 (8.51%)	7	3/39 (7.69%)	9	2/21 (9.52%)	2
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	14/197 (7.11%)	21	5/95 (5.26%)	7	3/47 (6.38%)	3	2/39 (5.13%)	3	1/21 (4.76%)	3
Back pain ^† 1	20/197 (10.15%)	23	7/95 (7.37%)	8	2/47 (4.26%)	2	2/39 (5.13%)	2	0/21 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain ^† 1	4/197 (2.03%)	4	8/95 (8.42%)	9	0/47 (0.00%)	0	0/39 (0.00%)	0	0/21 (0.00%)	0
Nervous system disorders
Dizziness ^† 1	9/197 (4.57%)	10	8/95 (8.42%)	8	1/47 (2.13%)	1	2/39 (5.13%)	2	1/21 (4.76%)	1
Headache ^† 1	28/197 (14.21%)	36	5/95 (5.26%)	5	1/47 (2.13%)	1	2/39 (5.13%)	4	0/21 (0.00%)	0
Psychiatric disorders
Insomnia ^† 1	21/197 (10.66%)	24	6/95 (6.32%)	8	3/47 (6.38%)	3	2/39 (5.13%)	2	0/21 (0.00%)	0
Renal and urinary disorders
Haematuria ^† 1	0/197 (0.00%)	0	2/95 (2.11%)	2	1/47 (2.13%)	2	2/39 (5.13%)	2	0/21 (0.00%)	0
Proteinuria ^† 1	43/197 (21.83%)	74	4/95 (4.21%)	4	12/47 (25.53%)	21	10/39 (25.64%)	16	0/21 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	21/197 (10.66%)	26	6/95 (6.32%)	7	5/47 (10.64%)	6	4/39 (10.26%)	4	4/21 (19.05%)	5
Dysphonia ^† 1	12/197 (6.09%)	12	1/95 (1.05%)	1	1/47 (2.13%)	1	0/39 (0.00%)	0	0/21 (0.00%)	0
Dyspnoea ^† 1	16/197 (8.12%)	19	8/95 (8.42%)	9	3/47 (6.38%)	3	0/39 (0.00%)	0	1/21 (4.76%)	1
Epistaxis ^† 1	27/197 (13.71%)	31	3/95 (3.16%)	3	4/47 (8.51%)	4	0/39 (0.00%)	0	0/21 (0.00%)	0
Skin and subcutaneous tissue disorders
Pruritus ^† 1	15/197 (7.61%)	16	5/95 (5.26%)	5	3/47 (6.38%)	3	0/39 (0.00%)	0	0/21 (0.00%)	0
Rash ^† 1	14/197 (7.11%)	19	5/95 (5.26%)	5	4/47 (8.51%)	4	0/39 (0.00%)	0	1/21 (4.76%)	1
Vascular disorders
Hypertension ^† 1	50/197 (25.38%)	79	12/95 (12.63%)	13	11/47 (23.40%)	16	7/39 (17.95%)	12	2/21 (9.52%)	2
1 Term from vocabulary, MedDRA 25.0 † 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

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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):

Shao G, Bai Y, Yuan X, Chen X, Gu S, Gu K, Hu C, Liang H, Guo Y, Wang J, Yen CJ, Lee VH, Wang C, Widau RC, Zhang W, Liu J, Zhang Q, Qin S. Ramucirumab as second-line treatment in Chinese patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib (REACH-2 China): A randomised, multicentre, double-blind study. EClinicalMedicine. 2022 Oct 6;54:101679. doi: 10.1016/j.eclinm.2022.101679. eCollection 2022 Dec.

Llovet JM, Singal AG, Villanueva A, Finn RS, Kudo M, Galle PR, Ikeda M, Callies S, McGrath LM, Wang C, Abada P, Widau RC, Gonzalez-Gugel E, Zhu AX. Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials. Clin Cancer Res. 2022 Jun 1;28(11):2297-2305. doi: 10.1158/1078-0432.CCR-21-4000.

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.

Trojan J, Mollon P, Daniele B, Marteau F, Martin L, Li Y, Xu Q, Piscaglia F, Zaucha R, Sarker D, Lim HY, Venerito M. Comparative Efficacy of Cabozantinib and Ramucirumab After Sorafenib for Patients with Hepatocellular Carcinoma and Alpha-fetoprotein >/= 400 ng/mL: A Matching-Adjusted Indirect Comparison. Adv Ther. 2021 May;38(5):2472-2490. doi: 10.1007/s12325-021-01700-2. Epub 2021 Apr 6.

Zhu AX, Finn RS, Kang YK, Yen CJ, Galle PR, Llovet JM, Assenat E, Brandi G, Motomura K, Ohno I, Daniele B, Vogel A, Yamashita T, Hsu CH, Gerken G, Bilbruck J, Hsu Y, Liang K, Widau RC, Wang C, Abada P, Kudo M. Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab. Br J Cancer. 2021 Apr;124(8):1388-1397. doi: 10.1038/s41416-021-01260-w. Epub 2021 Feb 3.

Reig M, Galle PR, Kudo M, Finn R, Llovet JM, Metti AL, Schelman WR, Liang K, Wang C, Widau RC, Abada P, Zhu AX. Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab. Liver Int. 2021 Mar;41(3):598-607. doi: 10.1111/liv.14731. Epub 2020 Dec 5.

Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. doi: 10.1136/esmoopen-2020-000797.

Kudo M, Okusaka T, Motomura K, Ohno I, Morimoto M, Seo S, Wada Y, Sato S, Yamashita T, Furukawa M, Aramaki T, Nadano S, Ohkawa K, Fujii H, Kudo T, Furuse J, Takai H, Homma G, Yoshikawa R, Zhu AX. Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial. J Gastroenterol. 2020 Jun;55(6):627-639. doi: 10.1007/s00535-020-01668-w. Epub 2020 Feb 27.

Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9. Epub 2019 Jan 18.

Layout table for additonal information

Responsible Party:	Eli Lilly and Company
ClinicalTrials.gov Identifier:	NCT02435433
Other Study ID Numbers:	15755 I4T-MC-JVDE ( Other Identifier: Eli Lilly and Company ) 2014-005068-13 ( EudraCT Number )
First Submitted:	May 1, 2015
First Posted:	May 6, 2015
Results First Submitted:	April 8, 2019
Results First Posted:	May 17, 2019
Last Update Posted:	January 20, 2023

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