A Study of Chemotherapy and Ramucirumab Versus Chemotherapy Alone in Second Line Non-Small Cell Lung Cancer (NSCLC) Participants Who Received Prior First Line Platinum-based Chemotherapy

• ClinicalTrials.gov Identifier: NCT01168973
• Recruitment Status: Completed
• First Posted: July 23, 2010
• Results First Posted: December 29, 2014
• Last Update Posted: September 25, 2019
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non-Small Cell Lung Cancer
• Interventions: Biological: Ramucirumab; Drug: Placebo (for Ramucirumab); Drug: Docetaxel
• Enrollment: 1253

Participant Flow

Recruitment Details
Pre-assignment Details	Participants who died, due to any cause, or were alive at the end of the study but off study drug were considered to have completed the study.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description	On Day 1 of each 21-day cycle, participants received ramucirumab drug product (DP) followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 milligrams per kilogram (mg/kg) administered intravenously.; Docetaxel: 75 milligrams per square meter (mg/m^2) (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Period Title: Overall Study
Started	628	625
Received Any Quantity of Any Study Drug	624	621 [1]
Completed	15	14
Not Completed	613	611
Reason Not Completed
Progressive Disease	341	429
Adverse Event	94	55
Withdrawal by Subject	90	53
Death	42	45
Physician Decision	37	19
Sponsor Decision	2	1
Protocol Criterion Not Met and Deviation	7	9
[1] Three participants randomized to placebo and docetaxel received 1 dose of ramucirumab in error.

Baseline Characteristics

Arm/Group Title		Ramucirumab and Docetaxel	Placebo and Docetaxel	Total
Arm/Group Description		On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	Total of all reporting groups
Overall Number of Baseline Participants		628	625	1253
Baseline Analysis Population Description		Intent-to-Treat (ITT) population: All randomized participants grouped according to their assigned treatment at randomization.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	628 participants	625 participants	1253 participants
	<=18 years	0	0	0
	Between 18 and 65 years	391	407	798
	>=65 years	237	218	455
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	628 participants	625 participants	1253 participants
	Female	209	210	419
	Male	419	415	834
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	628 participants	625 participants	1253 participants
	Hispanic or Latino	43	53	96
	Not Hispanic or Latino	387	380	767
	Unknown or Not Reported	198	192	390
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	628 participants	625 participants	1253 participants
	American Indian or Alaska Native	9	20	29
	Asian	74	86	160
	Native Hawaiian or Other Pacific Islander	1	0	1
	Black or African American	17	16	33
	White	526	503	1029
	More than one race	0	0	0
	Unknown or Not Reported	1	0	1
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	628 participants	625 participants	1253 participants
United States		156	152	308
Taiwan		9	18	27
Greece		25	19	44
Spain		27	23	50
Israel		14	8	22
Russian Federation		28	33	61
Italy		26	28	54
Switzerland		12	14	26
India		22	33	55
France		21	24	45
Puerto Rico		1	2	3
Netherlands		15	16	31
Korea, Republic of		34	28	62
Turkey		22	23	45
Austria		11	9	20
United Kingdom		19	19	38
Hungary		9	4	13
Mexico		11	20	31
Canada		12	7	19
Argentina		16	17	33
Brazil		4	3	7
Poland		30	33	63
Romania		41	36	77
Norway		10	3	13
Germany		40	42	82
New Zealand		3	4	7
Sweden		10	7	17

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival was the time from randomization until the date of death from any cause. Participants who were alive at the end of the follow-up period (or lost to follow-up) were censored on the last date the participant was known to be alive.
Time Frame	Randomization to date of death from any cause (up to 34 months)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population: All randomized participants grouped according to their assigned treatment at randomization. Participants censored: ramucirumab and docetaxel arm = 200 participants; placebo and docetaxel arm = 169 participants.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	628	625
Median (95% Confidence Interval); Unit of Measure: months
	10.5; (9.5 to 11.2)	9.1; (8.4 to 10.0)

2. Secondary Outcome

Title	Progression-Free Survival (PFS) Time
Description	PFS time was the time from randomization until the date of objectively determined progressive disease (PD) or death due to any cause, whichever occurred first. According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), PD was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the 20% relative increase, the sum must have also demonstrated an absolute increase of at least 5 millimeters (mm). The appearance of 1 or more new lesions and/or unequivocal progression of existing nontarget lesions was also considered progression. Participants without objectively determined PD who were alive at the end of the follow-up period (or lost to follow-up) were censored on the date of the participant's last complete radiographic tumor assessment; if no baseline or post-baseline radiologic assessment was available, the participant was censored at the date of randomization.
Time Frame	Randomization to measured PD or date of death from any cause (up to 29 months)

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants grouped according to their assigned treatment at randomization. Participants censored: ramucirumab and docetaxel arm = 70 participants; placebo and docetaxel arm = 42 participants.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	628	625
Median (95% Confidence Interval); Unit of Measure: months
	4.5; (4.2 to 5.3)	3.0; (2.8 to 3.9)

3. Secondary Outcome

Title	Percentage of Participants Achieving an Objective Response (Objective Response Rate)
Description	Participants achieved an objective response if they had a best overall response of partial response (PR) or complete response (CR). According to RECIST v1.1, PR was defined as at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph node), taking as reference the baseline sum diameter; CR was the disappearance of all non-nodal target lesions, with the short axes of any target lymph node reduced to <10 mm, the disappearance of all nontarget lesions, and the normalization of tumor marker levels [if tumor markers were initially above the upper limit of normal (ULN)]. The percentage of participants who achieved an objective response=(number of participants with CR or PR)/(number of participants assessed)*100.
Time Frame	Baseline to measured PD (up to 29 months)

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants grouped according to their assigned treatment at randomization.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	628	625
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	22.9; (19.7 to 26.4)	13.6; (11.0 to 16.5)

4. Secondary Outcome

Title	Percentage of Participants Achieving Disease Control (Disease Control Rate)
Description	Participants achieved disease control if they had a best overall response of PR, CR or stable disease (SD). According to RECIST v1.1, PR was defined as at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph node), taking as reference the baseline sum diameter; CR was the disappearance of all non-nodal target lesions, with the short axes of any target lymph node reduced to <10 mm, the disappearance of all nontarget lesions, and the normalization of tumor marker levels (if tumor markers were initially above the ULN). SD was neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD, taking as reference the smallest sum diameter since treatment started. The percentage of participants who achieved disease control=(number of participants with CR, PR, or SD)/(number of participants assessed)*100.
Time Frame	Baseline to measured PD (up to 29 months)

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants grouped according to their assigned treatment at randomization.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	628	625
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	64.0; (60.1 to 67.8)	52.6; (48.6 to 56.6)

5. Secondary Outcome

Title	Maximum Improvement on Lung Cancer Symptom Scale (LCSS)
Description	The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 items were global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-mm lines. A higher score for any item represented a higher level of symptoms/problems. The Average Symptom Burden Index (ASBI) was the mean of the 6 symptom items of the LCSS, and the Total LCSS was the mean of all 9 LCSS items. ASBI and Total LCSS were not computed for a participant if he/she had 1 or more missing values for the 6 and 9 items, respectively. Maximum improvement in LCSS scores, ASBI, and Total LCSS score was the largest decrease from baseline for each variable, which was the smallest (most negative or smallest positive) non-missing value among all change from baseline values for each variable.
Time Frame	Baseline, Day 21 of each cycle, and 30 days following last infusion (up to Cycle 38, 21 days/cycle)

Outcome Measure Data

Analysis Population Description

Randomized participants grouped according to their assigned treatment at randomization, who had a baseline and at least 1 post-baseline LCSS score.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	476	477
Mean (Standard Deviation); Unit of Measure: mm
Loss of Appetite (n=473, 471)	-10.9 (26.11)	-11.0 (26.22)
Fatigue (n=473, 472)	-12.1 (23.86)	-12.0 (27.29)
Cough (n=476, 473)	-13.8 (24.28)	-14.3 (26.28)
Dyspnea (n=472, 477)	-11.0 (23.01)	-10.5 (24.31)
Hemoptysis (n=475, 475)	-1.4 (8.89)	-1.1 (8.79)
Pain (n=476, 475)	-11.3 (23.62)	-11.5 (24.85)
Symptom Distress (n=474, 472)	-10.7 (23.37)	-12.2 (26.25)
Interference With Activity Level (n=474, 472)	-8.5 (24.13)	-7.9 (24.95)
Global Quality of Life (n=467, 469)	-10.4 (22.68)	-8.9 (23.23)
ASBI (n=455, 456)	-6.1 (13.75)	-6.9 (14.50)
Total LCSS (n=446, 446)	-5.2 (13.75)	-6.4 (14.66)

6. Secondary Outcome

Title	Change From Baseline to 30-Day Follow-Up Visit on European Quality of Life Questionnaire-5 Dimension (EQ-5D) Health State Scores
Description	The EQ-5D is a quality-of-life instrument that consists of 2 parts. The first part (Health State Index score) allowed participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a scale from 1 to 3 (no problem, some problems, and extreme problems, respectively). These combinations of attributes were converted into a weighted Health State Index score according to a United Kingdom population-based algorithm; the possible values for the Health State Index score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). The second part of the EQ-5D was a VAS that allowed participants to rate their present health condition. Possible EQ-5D VAS scores ranged from 0 (worst imaginable health state) to 100 (best imaginable health state).
Time Frame	Baseline, 30 days following last infusion (up to Cycle 38, 21 days/cycle)

Outcome Measure Data

Analysis Population Description

Randomized participants grouped according to their assigned treatment at randomization, who had an EQ-5D assessment at a baseline and 30 days post treatment.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	272	272
Mean (Standard Deviation); Unit of Measure: units on a scale
Health State Index Score (n=266, 272)	-0.140 (0.308)	-0.126 (0.294)
Health State VAS Score (n=272, 254)	-5.9 (21.02)	-6.1 (20.31)

7. Secondary Outcome

Title	Maximum and Minimum Serum Concentrations (Cmax and Cmin) of Ramucirumab
Description	[Not Specified]
Time Frame	Prior to infusion and 1 hour following infusion for 4 and 8 (cycles 3 and 5 at 21 days/cycle)

Outcome Measure Data

Analysis Population Description

Participants assigned to the ramucirumab and docetaxel arm at randomization, who had evaluable ramucirumab pharmacokinetic (PK) data to calculate Cmax and Cmin.

Arm/Group Title	Ramucirumab and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	594
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: micrograms per milliliter (mcg/mL)
Cmax at Cycle 3	262; (30%)
Cmin at Cycle 3	28.3; (65%)
Cmax at Cycle 5	237; (38%)
Cmin at Cycle 5	38.4; (63%)

8. Secondary Outcome

Title	Number of Participants With Anti-Ramucirumab Antibodies
Description	The number of participants who had treatment-emergent or follow-up emergent anti-drug antibodies (ADA) is reported. Participants with treatment-emergent ADA were defined as participants who had any sample from baseline through Cycle 5 pre-infusion that was a 4-fold increase (2 dilution increase) in immunogenicity titer over the baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20). Participants with follow-up emergent ADA were defined as participants who had any sample during 30 days post last infusion that was a 4-fold increase (2 dilution increase) in immunogenicity titer over the baseline titer.
Time Frame	Baseline, prior to infusion for week 4 and 8 (cycles 3 and 5), and 30 days following last infusion (up to Cycle 38, 21 days/cycle)

Outcome Measure Data

Analysis Population Description

Randomized participants who received any quantity of study treatment, grouped by the treatment they actually received, who had a baseline and at least 1 post-baseline ADA assessment.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	599	598
Measure Type: Number; Unit of Measure: participants
Treatment-Emergent ADA (n=599, 598)	9	16
Follow-Up Emergent ADA (n=506, 481)	9	16

9. Other Pre-specified Outcome

Title	Number of Participants Who Had Treatment-Emergent Adverse Events (TEAEs) or Died
Description	Data presented are the number of participants who experienced at least 1 TEAE, Grade 3, 4, or 5 TEAE, treatment-emergent serious adverse event (SAE), TEAE leading to discontinuation of study treatment (ramucirumab/placebo or docetaxel), and TEAE leading to death. Clinically significant events were defined as treatment-emergent SAEs and other non-serious adverse events (AEs) regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time Frame	First infusion up to 30 days following last infusion (up to Cycle 38, 21 days/cycle)

Outcome Measure Data

Analysis Population Description

Safety population: Randomized participants who received any quantity of study drug, grouped by the treatment they actually received.

Arm/Group Title	Ramucirumab and Docetaxel	Placebo and Docetaxel
Arm/Group Description:	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.	On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
Overall Number of Participants Analyzed	627	618
Measure Type: Number; Unit of Measure: participants
At least 1 TEAE	613	594
At least 1 Grade 3, 4, or 5 TEAE	495	444
At least 1 treatment-emergent SAE	269	262
TEAE leading to study drug discontinuation	58	32
TEAE leading to death	34	35
Deaths While On Treatment	428	451
Deaths During 30 Days Post Last Dose	53	58

Adverse Events

Time Frame	Randomization through 30 days following last infusion (up to Cycle 38, 21 days/cycle).
Adverse Event Reporting Description	Safety Population: All randomized participants who received any quantity of study treatment, grouped by the treatment they actually received. Three participants randomized to placebo and docetaxel received 1 dose of ramucirumab in error.
Arm/Group Title	Ramucirumab and Docetaxel		Placebo and Docetaxel
Arm/Group Description	On Day 1 of each 21-day cycle, participants received ramucirumab DP followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Ramucirumab DP: 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.		On Day 1 of each 21-day cycle, participants received placebo followed by docetaxel. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria were met.; Placebo (matching Ramucirumab DP): 10 mg/kg administered intravenously.; Docetaxel: 75 mg/m^2 (60 mg/m^2 for the countries of Korea and Taiwan only, with protocol amendment dated 22 May 2012) administered intravenously.
All-Cause Mortality
	Ramucirumab and Docetaxel		Placebo and Docetaxel
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Ramucirumab and Docetaxel		Placebo and Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	284/627 (45.30%)		281/618 (45.47%)
Blood and lymphatic system disorders
Anaemia † 1	10/627 (1.59%)	16	14/618 (2.27%)	17
Febrile neutropenia † 1	86/627 (13.72%)	104	51/618 (8.25%)	56
Leukopenia † 1	5/627 (0.80%)	6	10/618 (1.62%)	14
Neutropenia † 1	30/627 (4.78%)	38	27/618 (4.37%)	33
Thrombocytopenia † 1	3/627 (0.48%)	3	1/618 (0.16%)	1
Cardiac disorders
Arrhythmia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Atrial fibrillation † 1	6/627 (0.96%)	6	2/618 (0.32%)	2
Atrial flutter † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Atrial tachycardia † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Cardiac arrest † 1	2/627 (0.32%)	2	1/618 (0.16%)	1
Cardiac failure † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Cardiac failure congestive † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Cardiac tamponade † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Cardio-respiratory arrest † 1	2/627 (0.32%)	2	2/618 (0.32%)	2
Coronary artery occlusion † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Myocardial infarction † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pericardial effusion † 1	1/627 (0.16%)	2	6/618 (0.97%)	6
Sinus tachycardia † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Supraventricular tachycardia † 1	2/627 (0.32%)	2	3/618 (0.49%)	4
Tachycardia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Ventricular arrhythmia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Eye disorders
Diplopia † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Retinal vein thrombosis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Gastrointestinal disorders
Abdominal pain † 1	3/627 (0.48%)	3	7/618 (1.13%)	8
Abdominal pain upper † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Anal fistula † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Anal inflammation † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Ascites † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Colitis † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Constipation † 1	0/627 (0.00%)	0	2/618 (0.32%)	2
Diarrhoea † 1	13/627 (2.07%)	13	9/618 (1.46%)	9
Diverticular perforation † 1	2/627 (0.32%)	2	2/618 (0.32%)	2
Duodenal ulcer † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Dysphagia † 1	2/627 (0.32%)	2	3/618 (0.49%)	4
Enteritis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Enterocolitis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Gastric haemorrhage † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Gastritis † 1	0/627 (0.00%)	0	2/618 (0.32%)	3
Gastrointestinal haemorrhage † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Gastrointestinal inflammation † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Gingival bleeding † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Haematemesis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Haemorrhoidal haemorrhage † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Ileal fistula † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Ileus † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Ileus paralytic † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Intestinal ischaemia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Large intestinal obstruction † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Large intestine perforation † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Melaena † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Nausea † 1	7/627 (1.12%)	8	1/618 (0.16%)	2
Neutropenic colitis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Oesophageal fistula † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Oesophageal haemorrhage † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Oesophageal pain † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Oesophageal perforation † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Oesophagitis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Pancreatitis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pancreatitis acute † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Peptic ulcer haemorrhage † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Rectal haemorrhage † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Small intestinal obstruction † 1	0/627 (0.00%)	0	2/618 (0.32%)	2
Small intestinal perforation † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Stomatitis † 1	14/627 (2.23%)	16	2/618 (0.32%)	2
Subileus † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Upper gastrointestinal haemorrhage † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Vomiting † 1	6/627 (0.96%)	6	8/618 (1.29%)	10
General disorders
Adverse drug reaction † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Asthenia † 1	3/627 (0.48%)	11	4/618 (0.65%)	4
Chest pain † 1	1/627 (0.16%)	1	2/618 (0.32%)	2
Death † 1	5/627 (0.80%)	5	3/618 (0.49%)	3
Disease progression † 1	1/627 (0.16%)	1	2/618 (0.32%)	2
Fatigue † 1	12/627 (1.91%)	18	6/618 (0.97%)	6
General physical health deterioration † 1	5/627 (0.80%)	6	1/618 (0.16%)	1
Malaise † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Mucosal inflammation † 1	2/627 (0.32%)	2	1/618 (0.16%)	1
Multi-organ failure † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Non-cardiac chest pain † 1	2/627 (0.32%)	2	3/618 (0.49%)	3
Oedema peripheral † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Pain † 1	2/627 (0.32%)	2	2/618 (0.32%)	2
Peripheral swelling † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Pyrexia † 1	10/627 (1.59%)	10	10/618 (1.62%)	10
Sudden death † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Hepatobiliary disorders
Cholecystitis † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Hepatic failure † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Hepatitis acute † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Jaundice † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Immune system disorders
Anaphylactic shock † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Drug hypersensitivity † 1	1/627 (0.16%)	2	2/618 (0.32%)	2
Infections and infestations
Anal abscess † 1	2/627 (0.32%)	4	0/618 (0.00%)	0
Appendicitis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Appendicitis perforated † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Biliary tract infection † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Bronchitis † 1	2/627 (0.32%)	2	6/618 (0.97%)	7
Bronchitis moraxella † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Bronchopneumonia † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Candida infection † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Catheter site infection † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Cellulitis † 1	3/627 (0.48%)	4	0/618 (0.00%)	0
Cellulitis staphylococcal † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Clostridium difficile colitis † 1	2/627 (0.32%)	2	1/618 (0.16%)	1
Device related infection † 1	1/627 (0.16%)	1	2/618 (0.32%)	2
Device related sepsis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Diverticulitis † 1	3/627 (0.48%)	4	0/618 (0.00%)	0
Empyema † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Gastroenteritis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Infection † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Lobar pneumonia † 1	7/627 (1.12%)	7	8/618 (1.29%)	8
Localised infection † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Lower respiratory tract infection † 1	2/627 (0.32%)	2	1/618 (0.16%)	3
Lung infection † 1	3/627 (0.48%)	6	5/618 (0.81%)	5
Neutropenic infection † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Neutropenic sepsis † 1	2/627 (0.32%)	2	2/618 (0.32%)	2
Oral candidiasis † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Oral herpes † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Osteomyelitis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Paronychia † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pelvic abscess † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Peritonitis † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Pharyngitis † 1	3/627 (0.48%)	3	0/618 (0.00%)	0
Pneumocystis jirovecii pneumonia † 1	0/627 (0.00%)	0	3/618 (0.49%)	3
Pneumonia † 1	37/627 (5.90%)	43	41/618 (6.63%)	48
Pneumonia bacterial † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Pneumonia escherichia † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pneumonia pneumococcal † 1	0/627 (0.00%)	0	2/618 (0.32%)	2
Pneumonia staphylococcal † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pneumonia streptococcal † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Postoperative wound infection † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Respiratory tract infection † 1	3/627 (0.48%)	3	3/618 (0.49%)	3
Sepsis † 1	3/627 (0.48%)	3	2/618 (0.32%)	2
Septic shock † 1	2/627 (0.32%)	3	3/618 (0.49%)	3
Staphylococcal sepsis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Stenotrophomonas sepsis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Upper respiratory tract infection † 1	2/627 (0.32%)	2	4/618 (0.65%)	4
Urinary tract infection † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Injury, poisoning and procedural complications
Ankle fracture † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Fall † 1	2/627 (0.32%)	2	2/618 (0.32%)	2
Femoral neck fracture † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Femur fracture † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Infusion related reaction † 1	3/627 (0.48%)	3	0/618 (0.00%)	0
Pneumothorax traumatic † 1	3/627 (0.48%)	3	1/618 (0.16%)	1
Pubis fracture † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Rib fracture † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Suture related complication † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Traumatic arthropathy † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Investigations
Blood alkaline phosphatase increased † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Diagnostic aspiration † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Gamma-glutamyltransferase increased † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
International normalised ratio increased † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Liver function test abnormal † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Neutrophil count decreased † 1	9/627 (1.44%)	10	3/618 (0.49%)	3
Platelet count decreased † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Transaminases increased † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
White blood cell count decreased † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Metabolism and nutrition disorders
Cachexia † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Decreased appetite † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Dehydration † 1	15/627 (2.39%)	17	15/618 (2.43%)	18
Failure to thrive † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Hypercalcaemia † 1	0/627 (0.00%)	0	2/618 (0.32%)	3
Hyperglycaemia † 1	1/627 (0.16%)	1	2/618 (0.32%)	3
Hyperkalaemia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Hypoglycaemia † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Hyponatraemia † 1	4/627 (0.64%)	4	3/618 (0.49%)	3
Hypovolaemia † 1	3/627 (0.48%)	3	0/618 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/627 (0.32%)	2	1/618 (0.16%)	1
Arthritis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Flank pain † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Muscular weakness † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Musculoskeletal chest pain † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Musculoskeletal pain † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Myalgia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Osteonecrosis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Pain in extremity † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Pathological fracture † 1	1/627 (0.16%)	1	2/618 (0.32%)	2
Spinal disorder † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial tumour haemorrhage † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Lymphangiosis carcinomatosa † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Malignant ascites † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Malignant pleural effusion † 1	1/627 (0.16%)	1	5/618 (0.81%)	6
Metastases to bone † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Metastases to central nervous system † 1	2/627 (0.32%)	2	3/618 (0.49%)	3
Metastases to liver † 1	0/627 (0.00%)	0	2/618 (0.32%)	2
Metastases to meninges † 1	2/627 (0.32%)	2	1/618 (0.16%)	1
Metastases to spine † 1	2/627 (0.32%)	4	3/618 (0.49%)	3
Metastatic neoplasm † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Metastatic pain † 1	5/627 (0.80%)	6	7/618 (1.13%)	10
Pericardial effusion malignant † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Small intestine carcinoma † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Tumour associated fever † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Tumour compression † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Tumour haemorrhage † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Tumour necrosis † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Nervous system disorders
Aphasia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Brain oedema † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Cerebral haemorrhage † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Cerebral infarction † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Cerebral ischaemia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Cerebrovascular accident † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Cognitive disorder † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Convulsion † 1	3/627 (0.48%)	3	0/618 (0.00%)	0
Dizziness † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Headache † 1	1/627 (0.16%)	2	2/618 (0.32%)	2
Hemiparesis † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Hemiplegia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Ischaemic stroke † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Ivth nerve paralysis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Lethargy † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Migraine with aura † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Neuralgia † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Paraparesis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Peroneal nerve palsy † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Presyncope † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Radicular syndrome † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Senile dementia † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Stupor † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Syncope † 1	4/627 (0.64%)	4	4/618 (0.65%)	4
Toxic encephalopathy † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Tremor † 1	1/627 (0.16%)	2	0/618 (0.00%)	0
Vocal cord paresis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Psychiatric disorders
Anxiety † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Confusional state † 1	7/627 (1.12%)	7	1/618 (0.16%)	1
Conversion disorder † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Delirium † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Depression † 1	1/627 (0.16%)	1	1/618 (0.16%)	2
Echolalia † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Mania † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Mental status changes † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Renal and urinary disorders
Acute prerenal failure † 1	0/627 (0.00%)	0	1/618 (0.16%)	2
Haematuria † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Renal failure † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Renal failure acute † 1	4/627 (0.64%)	8	2/618 (0.32%)	2
Urinary retention † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	2/627 (0.32%)	2	2/618 (0.32%)	2
Acute respiratory failure † 1	1/627 (0.16%)	1	6/618 (0.97%)	6
Aspiration † 1	2/627 (0.32%)	2	0/618 (0.00%)	0
Atelectasis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Bronchospasm † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Catarrh † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Chronic obstructive pulmonary disease † 1	5/627 (0.80%)	7	4/618 (0.65%)	6
Cough † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Dyspnoea † 1	11/627 (1.75%)	12	26/618 (4.21%)	32
Epistaxis † 1	1/627 (0.16%)	2	1/618 (0.16%)	1
Haemoptysis † 1	7/627 (1.12%)	9	6/618 (0.97%)	7
Haemothorax † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Hiccups † 1	1/627 (0.16%)	2	1/618 (0.16%)	1
Hydrothorax † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Hypoxia † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Interstitial lung disease † 1	0/627 (0.00%)	0	3/618 (0.49%)	3
Lung infiltration † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Oropharyngeal pain † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Pleural effusion † 1	9/627 (1.44%)	10	21/618 (3.40%)	23
Pneumomediastinum † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pneumonia aspiration † 1	1/627 (0.16%)	1	1/618 (0.16%)	2
Pneumonitis † 1	2/627 (0.32%)	2	3/618 (0.49%)	3
Pneumothorax † 1	5/627 (0.80%)	5	3/618 (0.49%)	3
Pneumothorax spontaneous † 1	2/627 (0.32%)	2	2/618 (0.32%)	2
Pulmonary bulla † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pulmonary congestion † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pulmonary embolism † 1	8/627 (1.28%)	8	12/618 (1.94%)	13
Pulmonary haemorrhage † 1	4/627 (0.64%)	4	4/618 (0.65%)	5
Pulmonary oedema † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Respiratory acidosis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Respiratory arrest † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Respiratory disorder † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Respiratory distress † 1	0/627 (0.00%)	0	2/618 (0.32%)	2
Respiratory failure † 1	3/627 (0.48%)	3	9/618 (1.46%)	10
Respiratory tract haemorrhage † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Tachypnoea † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Pruritus † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Psoriasis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Rash † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Subcutaneous emphysema † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Urticaria † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Surgical and medical procedures
Hospitalisation † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Lung lobectomy † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Vascular disorders
Aortic aneurysm rupture † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Deep vein thrombosis † 1	2/627 (0.32%)	3	2/618 (0.32%)	2
Hypertension † 1	1/627 (0.16%)	1	1/618 (0.16%)	1
Hypotension † 1	3/627 (0.48%)	3	4/618 (0.65%)	5
Iliac artery occlusion † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Jugular vein thrombosis † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Orthostatic hypotension † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Peripheral arterial occlusive disease † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Peripheral artery aneurysm † 1	1/627 (0.16%)	1	0/618 (0.00%)	0
Superior vena cava syndrome † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
Venous thrombosis limb † 1	0/627 (0.00%)	0	1/618 (0.16%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ramucirumab and Docetaxel		Placebo and Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	601/627 (95.85%)		583/618 (94.34%)
Blood and lymphatic system disorders
Anaemia † 1	135/627 (21.53%)	306	174/618 (28.16%)	399
Leukopenia † 1	79/627 (12.60%)	259	68/618 (11.00%)	151
Neutropenia † 1	228/627 (36.36%)	547	188/618 (30.42%)	415
Thrombocytopenia † 1	51/627 (8.13%)	114	27/618 (4.37%)	48
Eye disorders
Lacrimation increased † 1	85/627 (13.56%)	100	29/618 (4.69%)	31
Gastrointestinal disorders
Abdominal pain † 1	56/627 (8.93%)	69	35/618 (5.66%)	41
Constipation † 1	107/627 (17.07%)	135	110/618 (17.80%)	132
Diarrhoea † 1	200/627 (31.90%)	338	175/618 (28.32%)	226
Dyspepsia † 1	37/627 (5.90%)	47	18/618 (2.91%)	25
Nausea † 1	170/627 (27.11%)	236	173/618 (27.99%)	256
Stomatitis † 1	143/627 (22.81%)	245	81/618 (13.11%)	104
Vomiting † 1	88/627 (14.04%)	117	86/618 (13.92%)	119
General disorders
Asthenia † 1	72/627 (11.48%)	178	65/618 (10.52%)	127
Fatigue † 1	287/627 (45.77%)	623	260/618 (42.07%)	524
Mucosal inflammation † 1	103/627 (16.43%)	167	43/618 (6.96%)	53
Oedema peripheral † 1	107/627 (17.07%)	149	55/618 (8.90%)	86
Pain † 1	35/627 (5.58%)	40	33/618 (5.34%)	37
Pyrexia † 1	100/627 (15.95%)	148	79/618 (12.78%)	114
Investigations
Neutrophil count decreased † 1	112/627 (17.86%)	281	89/618 (14.40%)	193
Platelet count decreased † 1	36/627 (5.74%)	104	9/618 (1.46%)	20
Weight decreased † 1	67/627 (10.69%)	84	49/618 (7.93%)	56
White blood cell count decreased † 1	58/627 (9.25%)	148	50/618 (8.09%)	219
Metabolism and nutrition disorders
Decreased appetite † 1	189/627 (30.14%)	290	163/618 (26.38%)	221
Dehydration † 1	39/627 (6.22%)	47	24/618 (3.88%)	31
Hyperglycaemia † 1	39/627 (6.22%)	83	25/618 (4.05%)	49
Musculoskeletal and connective tissue disorders
Arthralgia † 1	71/627 (11.32%)	110	51/618 (8.25%)	86
Back pain † 1	73/627 (11.64%)	113	56/618 (9.06%)	83
Bone pain † 1	31/627 (4.94%)	40	36/618 (5.83%)	57
Myalgia † 1	79/627 (12.60%)	123	65/618 (10.52%)	110
Pain in extremity † 1	50/627 (7.97%)	60	26/618 (4.21%)	31
Nervous system disorders
Dizziness † 1	43/627 (6.86%)	54	46/618 (7.44%)	52
Dysgeusia † 1	69/627 (11.00%)	83	46/618 (7.44%)	55
Headache † 1	66/627 (10.53%)	88	65/618 (10.52%)	78
Paraesthesia † 1	38/627 (6.06%)	49	36/618 (5.83%)	46
Peripheral sensory neuropathy † 1	74/627 (11.80%)	121	60/618 (9.71%)	102
Psychiatric disorders
Insomnia † 1	69/627 (11.00%)	78	54/618 (8.74%)	55
Respiratory, thoracic and mediastinal disorders
Cough † 1	137/627 (21.85%)	194	131/618 (21.20%)	169
Dysphonia † 1	38/627 (6.06%)	49	23/618 (3.72%)	23
Dyspnoea † 1	150/627 (23.92%)	220	148/618 (23.95%)	207
Epistaxis † 1	116/627 (18.50%)	149	41/618 (6.63%)	45
Haemoptysis † 1	36/627 (5.74%)	38	31/618 (5.02%)	37
Oropharyngeal pain † 1	49/627 (7.81%)	65	30/618 (4.85%)	39
Productive cough † 1	40/627 (6.38%)	61	34/618 (5.50%)	41
Skin and subcutaneous tissue disorders
Alopecia † 1	163/627 (26.00%)	192	156/618 (25.24%)	176
Nail discolouration † 1	41/627 (6.54%)	45	27/618 (4.37%)	27
Rash † 1	44/627 (7.02%)	56	36/618 (5.83%)	51
Vascular disorders
Hypertension † 1	67/627 (10.69%)	129	29/618 (4.69%)	107
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1

Limitations and Caveats

Three participants randomized to placebo and docetaxel received 1 dose of ramucirumab in error. They are included in the placebo and docetaxel arm in the ITT population and are included in the ramucirumab and docetaxel arm in the Safety population.

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.

Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.

Results Point of Contact

• Name/Title: Chief Medical Officer
• Organization: Eli Lilly and Company
• Phone: 800-545-5979

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

Rolfo C, Hess LM, Jen MH, Peterson P, Li X, Liu H, Lai Y, Sugihara T, Kiiskinen U, Vickers A, Summers Y. External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer. ESMO Open. 2022 Aug;7(4):100551. doi: 10.1016/j.esmoop.2022.100551. Epub 2022 Aug 2.

Garon EB, Scagliotti GV, Gautschi O, Reck M, Thomas M, Iglesias Docampo L, Kalofonos H, Kim JH, Gans S, Brustugun OT, Orlov SV, Cuyun Carter G, Zimmermann AH, Oton AB, Alexandris E, Lee P, Wolff K, Stefaniak VJ, Socinski MA, Perol M. Exploratory analysis of front-line therapies in REVEL: a randomised phase 3 study of ramucirumab plus docetaxel versus docetaxel for the treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy. ESMO Open. 2020 Jan;5(1):e000567. doi: 10.1136/esmoopen-2019-000567.

Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Perol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. doi: 10.1016/S0140-6736(14)60845-X. Epub 2014 Jun 2.

Garon EB, Cao D, Alexandris E, John WJ, Yurasov S, Perol M. A randomized, double-blind, phase III study of Docetaxel and Ramucirumab versus Docetaxel and placebo in the treatment of stage IV non-small-cell lung cancer after disease progression after 1 previous platinum-based therapy (REVEL): treatment rationale and study design. Clin Lung Cancer. 2012 Nov;13(6):505-9. doi: 10.1016/j.cllc.2012.06.007. Epub 2012 Jul 31.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01168973
• Other Study ID Numbers: 13852; I4T-MC-JVBA ( Other Identifier: Eli Lilly and Company ); 2010-021297-11 ( EudraCT Number ); CP12-1027 ( Other Identifier: ImClone Trial Number ); CTRI/2011/08/001942 ( Registry Identifier: Clinical Trials Registry India )
• First Submitted: July 16, 2010
• First Posted: July 23, 2010
• Results First Submitted: December 17, 2014
• Results First Posted: December 29, 2014
• Last Update Posted: September 25, 2019