Pemetrexed and Best Supportive Care Versus Placebo and Best Supportive Care in Non-Small Cell Lung Cancer (NSCLC)

• ClinicalTrials.gov Identifier: NCT00102804
• Recruitment Status: Completed
• First Posted: February 2, 2005
• Results First Posted: December 29, 2014
• Last Update Posted: December 29, 2014
• 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: Drug: Pemetrexed; Drug: Placebo; Other: Best Supportive Care
• Enrollment: 663

Participant Flow

Recruitment Details
Pre-assignment Details	Participants who signed the informed consent form (ICF) and completed the randomized process are presented in the participant flow by the treatment arm to which they were randomized. Participants who did not sign the ICF or complete the randomization process were removed from the database and excluded from all analyses.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description	Pemetrexed: 500 milligrams per square meter (mg/m^2), intravenous (IV) administration, every (q) 21 days, until disease progression. Best Supportive Care (BSC): Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Period Title: Overall Study
Started	441	222
Received at Least 1 Dose of Study Drug	434	222 [1]
Completed	0	0
Not Completed	441	222
Reason Not Completed
Progressive Disease (PD)	307	196
Withdrawal by Subject	46	7
Adverse Event	37	3
Physician Decision	24	6
Death	5	6
Enrollment Criteria Not Met	6	0
Lost to Follow-up	4	1
Protocol Violation	2	1
Satisfactory Response	2	0
Sponsor Decision	1	0
Alive, Receiving Treatment	7	2
[1] Four participants randomized to placebo received pemetrexed.

Baseline Characteristics

Arm/Group Title		Pemetrexed and BSC	Placebo and BSC	Total
Arm/Group Description		Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Total of all reporting groups
Overall Number of Baseline Participants		441	222	663
Baseline Analysis Population Description		Participants who signed the ICF and completed the randomized process are reported according to the treatment arm to which they were randomized.
Age, Continuous; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	441 participants	222 participants	663 participants
		60.6; (54.3 to 67.5)	60.4; (53.8 to 67.0)	60.6; (54.1 to 67.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	222 participants	663 participants
	Female	119 27.0%	61 27.5%	180 27.1%
	Male	322 73.0%	161 72.5%	483 72.9%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	441 participants	222 participants	663 participants
Aboriginal		0	1	1
African		6	0	6
Caucasian		279	149	428
East Asian		104	50	154
Hispanic		13	6	19
West Asian		39	16	55
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	441 participants	222 participants	663 participants
United States		20	12	32
Taiwan		5	4	9
Greece		18	9	27
Spain		30	19	49
Turkey		7	4	11
Austria		2	2	4
Italy		18	16	34
India		39	16	55
Hungary		8	6	14
Czech Republic		5	2	7
Poland		25	11	36
Brazil		24	10	34
Croatia		10	3	13
Romania		51	26	77
Australia		19	8	27
Bulgaria		11	8	19
Netherlands		10	4	14
Germany		40	16	56
China		62	37	99
Korea, Republic of		37	9	46

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Time
Description	PFS time was the elapsed time from the date of randomization to the first date of objective progression of disease or death from any cause. PFS was censored at the date of the participant's last tumor assessment for participants who were not known to have died or to have PD as of the data-inclusion cut-off date for analysis. PD, defined using Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0), was at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.
Time Frame	Randomization to measured PD or death from any cause (up to 41 months)

Outcome Measure Data

Analysis Population Description

Participants who signed the ICF and completed the randomized process are reported according to the treatment arm to which they were randomized. Participants censored: N = 123, 36 participants in the pemetrexed and placebo treatment arms, respectively.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description:	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Overall Number of Participants Analyzed	441	222
Median (95% Confidence Interval); Unit of Measure: months
	4.27; (4.07 to 4.73)	2.60; (1.68 to 2.83)

2. Secondary Outcome

Title	Overall Survival (OS) Time
Description	OS time was the elapsed time from the date of randomization to the date of death from any cause. OS was censored at the last date of contact for participants who were not known to have died as of the data-inclusion cut-off date for analysis.
Time Frame	Randomization to date of death from any cause (up to 41 months)

Outcome Measure Data

Analysis Population Description

Participants who signed the ICF and completed the randomized process are reported according to the treatment arm to which they were randomized. Participants censored: N = 138, 48 participants in the pemetrexed and placebo treatment arms, respectively.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description:	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Overall Number of Participants Analyzed	441	222
Median (95% Confidence Interval); Unit of Measure: months
	13.37; (11.93 to 15.87)	10.58; (8.74 to 12.02)

3. Secondary Outcome

Title	Time to Objective Progressive Disease (TPD)
Description	TPD was the elapsed time from the date of randomization to the first date of objective PD. TPD was censored at the date of the participant's last tumor assessment for participants who were not known to have PD as of the data-inclusion cut-off date for analysis or who died without objective PD. PD, defined using RECIST v1.0, was at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.
Time Frame	Randomization to measured PD (up to 41 months)

Outcome Measure Data

Analysis Population Description

Participants who signed the ICF and completed the randomized process are reported according to the treatment arm to which they were randomized. Participants censored: N = 145, 40 participants in the pemetrexed and placebo treatment arms, respectively.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description:	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Overall Number of Participants Analyzed	441	222
Median (95% Confidence Interval); Unit of Measure: months
	4.27; (4.11 to 4.73)	2.60; (1.68 to 2.83)

4. Secondary Outcome

Title	Time to Worsening of Symptoms (TWS)
Description	TWS was the elapsed time from the date of randomization to the first date of worsening [defined as a 15-millimeter (mm) increase from baseline based on a 100-mm scale] of each symptom and summary item in the Lung Cancer Symptom Scale (LCSS). The participant-reported LCSS was a 9-item questionnaire. Six items were symptom-specific measures for lung cancer (loss of appetite, fatigue, cough, dyspnea, hemoptysis, and pain), and 3 summation items described total symptomatic distress, interference with activity level, and global quality of life. Participant (pt) responses to each item were measured using visual analogue scales (VAS) from 0 (for best outcome) to 100 (for worst outcome). TWS was censored at the date of the last LCSS assessment for pts who were not known to have LCSS worsening.
Time Frame	Randomization to worsening of each LCSS item (up to 39 months)

Outcome Measure Data

Analysis Population Description

Pts who signed ICF and completed randomization, according to treatment randomized. Pts censored: Loss of appetite 236,140; fatigue 237,130; cough 274,146; dyspnea 271,143, hemoptysis 404,198; pain 271,135; symptom distress 247,141; interference with activity level 267,141, global quality of life 262,137 pts in pemetrexed, placebo arm, respectively.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description:	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Overall Number of Participants Analyzed	441	222
Median (95% Confidence Interval); Unit of Measure: months
Loss of appetite	3.78; (2.86 to 4.44)	4.40; (2.96 to 15.61)
Fatigue	3.06; (2.63 to 5.29)	3.09; (2.43 to 3.98)
Cough	6.05; (4.21 to 7.82)	4.67; (3.06 to 15.61)
Dyspnea	5.36; (4.21 to 10.87)	4.40; (2.83 to 15.61)
Hemoptysis	NA [1]; (NA to NA)	NA [1]; (NA to NA)
Pain	6.11; (4.57 to 9.56)	4.63; (3.32 to 5.98)
Symptomatic distress	4.21; (3.58 to 5.55)	3.78; (2.99 to 18.53)
Interference with activity level	6.51; (4.34 to 8.18)	3.98; (2.83 to 15.61)
Global quality of life	5.75; (4.37 to 8.41)	3.71; (2.99 to 5.49)

[1]

Median (95% confidence interval) TWS for hemoptysis was not calculated due to the high level of censoring.

5. Secondary Outcome

Title	Percentage of Participants With a Complete Response (CR) or Partial Response (PR) (Objective Tumor Response Rate)
Description	Response was defined using RECIST v1.0 criteria. CR was defined as the disappearance of all target lesions. PR was defined either A) at least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LDs or B) complete disappearance of target lesions, with persistence (but not worsening) of 1 or more nontarget lesions. In either case, no new lesions may have appeared. The percentage of participants with CR or PR=(Number of participants with CR or PR)/(Number of participants assessed)*100.
Time Frame	Baseline to measured PD (up to 41 months)

Outcome Measure Data

Analysis Population Description

Participants who signed the ICF and completed the randomized process are reported according to the treatment arm to which they were randomized.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description:	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Overall Number of Participants Analyzed	441	222
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	6.8; (5 to 10)	1.8; (0 to 5)

6. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	Clinically significant events were defined as serious adverse events (SAEs) and other non-serious AEs regardless of causality. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time Frame	Baseline to study completion (up to 41 Months)

Outcome Measure Data

Analysis Population Description

Participants who signed the ICF, completed the randomized process and received at least 1 dose of study drug are reported according to the treatment to which they were received.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description:	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Overall Number of Participants Analyzed	438	218
Measure Type: Number; Unit of Measure: participants
SAEs	83	31
Other Non-Serious AEs	386	178

7. Secondary Outcome

Title	Maximum Improvement Over Baseline in Individual Symptom Scores and Quality of Life Using the LCSS
Description	The participant-reported LCSS was a 9-item questionnaire. Six items were symptom-specific measures for lung cancer (loss of appetite, fatigue, cough, dyspnea, hemoptysis, and pain), and 3 summation items described total symptomatic distress, interference with activity level, and global quality of life. Participant responses to each item were measured using VAS from 0 (for best outcome) to 100 (for worst outcome). The average symptom burden index (ASBI) was the mean of the 6 symptom-specific items. The LCSS total score was the mean of the 9 items.
Time Frame	Baseline through 30 days post discontinuation of study treatment (up to 39 Months)

Outcome Measure Data

Analysis Population Description

Participants who signed the ICF, completed the randomization process, had LCSS data at baseline and at least once postdose are reported according to the treatment arm to which they were randomized.

Arm/Group Title	Pemetrexed and BSC	Placebo and BSC
Arm/Group Description:	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.	Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
Overall Number of Participants Analyzed	403	197
Mean (Standard Deviation); Unit of Measure: units on a scale
Loss of appetite (n=403, 197)	7.3 (25.90)	10.6 (25.25)
Fatigue (n=403, 197)	10.2 (27.10)	10.4 (23.92)
Cough (n=402, 197)	7.6 (20.09)	6.7 (23.81)
Dyspnea (n=400, 196)	7.6 (22.50)	5.4 (20.44)
Pain (n=401, 197)	5.4 (20.96)	4.3 (21.93)
Hemoptysis (n=402, 196)	1.5 (9.41)	2.1 (9.23)
Symptom distress (n=401, 196)	6.5 (21.13)	8.2 (22.5)
Interference with activity level (n=400, 197)	10.8 (27.08)	9.3 (25.50)
Global quality of life (n=401, 195)	10.7 (24.94)	10.5 (22.98)
ASBI (n=392, 195)	3.7 (12.34)	3.8 (13.24)
Total LCSS (n=388, 193)	4.07 (12.76)	4.04 (13.03)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Participants are reported under the treatment to which they received.
Arm/Group Title	Pemetrexed and BSC		Placebo and BSC
Arm/Group Description	Pemetrexed: 500 mg/m^2, IV administration, q 21 days, until disease progression. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.		Placebo: IV administration, q 21 days. BSC: Treatment without a specific antineoplastic regimen, given with the intent to maximize quality of life, as judged by the treating physician.
All-Cause Mortality
	Pemetrexed and BSC		Placebo and BSC
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Pemetrexed and BSC		Placebo and BSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/438 (18.95%)		31/218 (14.22%)
Blood and lymphatic system disorders
Anaemia † 1	6/438 (1.37%)	7	0/218 (0.00%)	0
Anaemia of malignant disease † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Febrile neutropenia † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Leukopenia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Neutropenia † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Thrombocytopenia † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Cardiac disorders
Acute myocardial infarction † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Atrial fibrillation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Cardiac failure † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Cardio-respiratory arrest † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Myocardial infarction † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Myocardial ischaemia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pericardial effusion † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Sinus tachycardia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Ear and labyrinth disorders
Vertigo † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Gastrointestinal disorders
Abdominal pain † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Constipation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Dysphagia † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Haematemesis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Large intestine perforation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Nausea † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Reflux oesophagitis † 1	1/438 (0.23%)	2	0/218 (0.00%)	0
Vomiting † 1	0/438 (0.00%)	0	2/218 (0.92%)	2
General disorders
Asthenia † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Chest pain † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Death † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Fatigue † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
General physical health deterioration † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Mucosal inflammation † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Multi-organ failure † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Performance status decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pyrexia † 1	4/438 (0.91%)	5	1/218 (0.46%)	1
Infections and infestations
Bronchitis † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Bronchopneumonia † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Cellulitis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Erysipelas † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Gastrointestinal infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Herpes zoster † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Oral candidiasis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pneumonia † 1	10/438 (2.28%)	10	3/218 (1.38%)	3
Pulmonary sepsis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Respiratory tract infection † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Sepsis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Skin infection † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Urinary tract infection † 1	3/438 (0.68%)	3	1/218 (0.46%)	1
Urosepsis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Viral upper respiratory tract infection † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Injury, poisoning and procedural complications
Femur fracture † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Rib fracture † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Investigations
Weight decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Metabolism and nutrition disorders
Anorexia † 1	4/438 (0.91%)	5	0/218 (0.00%)	0
Dehydration † 1	1/438 (0.23%)	2	0/218 (0.00%)	0
Diabetic ketoacidosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypercalcaemia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypercholesterolaemia † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Hypoglycaemia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Back pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Bone pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Intervertebral disc degeneration † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Joint effusion † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Muscle contracture † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Muscular weakness † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Myalgia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pain in extremity † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Metastases to central nervous system † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tumour pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Nervous system disorders
Convulsion † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Dizziness † 1	0/438 (0.00%)	0	2/218 (0.92%)	2
Epilepsy † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Headache † 1	1/438 (0.23%)	1	1/218 (0.46%)	2
Hemiparesis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypoaesthesia † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Ischaemic stroke † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Paraparesis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Paraplegia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Partial seizures † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Spinal cord compression † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Transient ischaemic attack † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Psychiatric disorders
Confusional state † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Renal and urinary disorders
Dysuria † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Nephrolithiasis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Renal failure † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Renal failure acute † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Urinary retention † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Reproductive system and breast disorders
Balanitis † 1	1/321 (0.31%)	1	0/158 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Bronchial obstruction † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Cough † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Dyspnoea † 1	14/438 (3.20%)	14	6/218 (2.75%)	6
Haemoptysis † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Hypoxia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pleural effusion † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Pneumonia aspiration † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pneumonitis † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Pulmonary embolism † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pulmonary fibrosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Respiratory failure † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Vascular disorders
Deep vein thrombosis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Pelvic venous thrombosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Superior vena caval occlusion † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 11.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Pemetrexed and BSC		Placebo and BSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	386/438 (88.13%)		178/218 (81.65%)
Blood and lymphatic system disorders
Anaemia † 1	65/438 (14.84%)	97	12/218 (5.50%)	15
Anaemia of malignant disease † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Febrile neutropenia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Leukocytosis † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Leukopenia † 1	25/438 (5.71%)	64	5/218 (2.29%)	8
Lymph node pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Lymphadenopathy † 1	3/438 (0.68%)	4	0/218 (0.00%)	0
Lymphopenia † 1	3/438 (0.68%)	3	1/218 (0.46%)	1
Neutropenia † 1	21/438 (4.79%)	66	5/218 (2.29%)	5
Neutrophilia † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Thrombocythaemia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Thrombocytopenia † 1	17/438 (3.88%)	29	2/218 (0.92%)	3
Cardiac disorders
Arrhythmia † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Arrhythmia supraventricular † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Atrial fibrillation † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Atrial tachycardia † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Bradycardia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Cyanosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Myocardial ischaemia † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Palpitations † 1	1/438 (0.23%)	2	3/218 (1.38%)	3
Pericardial effusion † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Sinus tachycardia † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Tachycardia † 1	3/438 (0.68%)	4	1/218 (0.46%)	1
Ear and labyrinth disorders
Cerumen impaction † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Deafness † 1	2/438 (0.46%)	3	0/218 (0.00%)	0
Ear discomfort † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Ear pain † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypoacusis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Motion sickness † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tinnitus † 1	5/438 (1.14%)	5	1/218 (0.46%)	1
Vertigo † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Endocrine disorders
Goitre † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hyperthyroidism † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypothyroidism † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Eye disorders
Blepharitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Cataract † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Conjunctivitis † 1	20/438 (4.57%)	24	1/218 (0.46%)	1
Conjunctivitis allergic † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Dry eye † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Eye pain † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Eye swelling † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Eyelid oedema † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Keratoconjunctivitis sicca † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Lacrimation increased † 1	20/438 (4.57%)	21	0/218 (0.00%)	0
Ocular surface disease † 1	3/438 (0.68%)	5	1/218 (0.46%)	2
Photophobia † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Pterygium † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Vision blurred † 1	8/438 (1.83%)	10	1/218 (0.46%)	1
Visual acuity reduced † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Visual disturbance † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Gastrointestinal disorders
Abdominal distension † 1	4/438 (0.91%)	4	2/218 (0.92%)	2
Abdominal pain † 1	18/438 (4.11%)	18	8/218 (3.67%)	8
Abdominal pain lower † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Abdominal pain upper † 1	7/438 (1.60%)	7	3/218 (1.38%)	11
Aphthous stomatitis † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Ascites † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Constipation † 1	59/438 (13.47%)	85	17/218 (7.80%)	22
Dental caries † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Diarrhoea † 1	52/438 (11.87%)	88	15/218 (6.88%)	17
Dry mouth † 1	10/438 (2.28%)	10	3/218 (1.38%)	3
Dyspepsia † 1	13/438 (2.97%)	18	6/218 (2.75%)	21
Dysphagia † 1	4/438 (0.91%)	5	1/218 (0.46%)	2
Faecal incontinence † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Faecaloma † 1	0/438 (0.00%)	0	2/218 (0.92%)	2
Flatulence † 1	4/438 (0.91%)	7	0/218 (0.00%)	0
Gastric disorder † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Gastritis † 1	4/438 (0.91%)	5	1/218 (0.46%)	1
Gastrointestinal pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Gastrooesophageal reflux disease † 1	1/438 (0.23%)	1	2/218 (0.92%)	2
Gingival pain † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Gingivitis † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Haemorrhoids † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hiatus hernia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Ileus † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Inflammatory bowel disease † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Lip ulceration † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Mouth ulceration † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Nausea † 1	102/438 (23.29%)	209	22/218 (10.09%)	24
Odynophagia † 1	4/438 (0.91%)	5	1/218 (0.46%)	1
Oesophageal haemorrhage † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Oesophagitis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Oral pain † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Paraesthesia oral † 1	2/438 (0.46%)	4	0/218 (0.00%)	0
Periodontal disease † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Rectal haemorrhage † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Stomatitis † 1	19/438 (4.34%)	22	1/218 (0.46%)	1
Tongue black hairy † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tongue coated † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Toothache † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Vomiting † 1	56/438 (12.79%)	88	9/218 (4.13%)	12
General disorders
Asthenia † 1	48/438 (10.96%)	74	10/218 (4.59%)	11
Axillary pain † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Catheter site erythema † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Chest discomfort † 1	3/438 (0.68%)	14	0/218 (0.00%)	0
Chest pain † 1	44/438 (10.05%)	67	16/218 (7.34%)	17
Chills † 1	7/438 (1.60%)	9	0/218 (0.00%)	0
Condition aggravated † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Cyst † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Extravasation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Face oedema † 1	6/438 (1.37%)	7	2/218 (0.92%)	2
Facial pain † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Fatigue † 1	145/438 (33.11%)	227	49/218 (22.48%)	63
Feeling abnormal † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Gait disturbance † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
General physical health deterioration † 1	7/438 (1.60%)	9	0/218 (0.00%)	0
Influenza like illness † 1	10/438 (2.28%)	17	3/218 (1.38%)	4
Injection site reaction † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Irritability † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Localised oedema † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Malaise † 1	2/438 (0.46%)	4	0/218 (0.00%)	0
Mucosal inflammation † 1	12/438 (2.74%)	19	2/218 (0.92%)	2
Obstruction † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Oedema † 1	12/438 (2.74%)	16	1/218 (0.46%)	1
Oedema peripheral † 1	27/438 (6.16%)	34	2/218 (0.92%)	3
Pain † 1	24/438 (5.48%)	28	13/218 (5.96%)	13
Peripheral coldness † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Pyrexia † 1	56/438 (12.79%)	78	25/218 (11.47%)	33
Swelling † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Visceral oedema † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hepatobiliary disorders
Cholelithiasis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hepatic pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Hepatitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hepatomegaly † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hyperbilirubinaemia † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Immune system disorders
Contrast media allergy † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypersensitivity † 1	6/438 (1.37%)	8	1/218 (0.46%)	1
Seasonal allergy † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Infections and infestations
Abscess † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Bronchitis † 1	15/438 (3.42%)	17	2/218 (0.92%)	2
Candidiasis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Cellulitis † 1	1/438 (0.23%)	2	1/218 (0.46%)	1
Cystitis † 1	2/438 (0.46%)	3	0/218 (0.00%)	0
Diverticulitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Ear infection † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Erysipelas † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Folliculitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Fungal infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Gastroenteritis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Gastroenteritis viral † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hepatic infection † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Herpes simplex † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Herpes virus infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Herpes zoster † 1	3/438 (0.68%)	3	1/218 (0.46%)	1
Infection † 1	3/438 (0.68%)	3	3/218 (1.38%)	3
Influenza † 1	10/438 (2.28%)	12	0/218 (0.00%)	0
Laryngitis † 1	0/438 (0.00%)	0	2/218 (0.92%)	2
Lower respiratory tract infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Lung infection † 1	3/438 (0.68%)	3	1/218 (0.46%)	1
Nasopharyngitis † 1	14/438 (3.20%)	17	3/218 (1.38%)	3
Oral candidiasis † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Oral herpes † 1	0/438 (0.00%)	0	2/218 (0.92%)	2
Otitis media † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Paronychia † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Parotitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pharyngitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pneumonia † 1	2/438 (0.46%)	2	2/218 (0.92%)	2
Pyothorax † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Respiratory tract infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Respiratory tract infection viral † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Rhinitis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Sinusitis † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Soft tissue infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tonsillitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tooth abscess † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tooth infection † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Upper respiratory tract infection † 1	15/438 (3.42%)	20	3/218 (1.38%)	3
Urinary tract infection † 1	5/438 (1.14%)	7	4/218 (1.83%)	4
Injury, poisoning and procedural complications
Arterial injury † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Contusion † 1	3/438 (0.68%)	3	1/218 (0.46%)	1
Fall † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Foot fracture † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Fracture † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Incision site pain † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Procedural headache † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Radiation skin injury † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Rib fracture † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Thermal burn † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Wound † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Investigations
Alanine aminotransferase † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Alanine aminotransferase decreased † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Alanine aminotransferase increased † 1	60/438 (13.70%)	87	9/218 (4.13%)	11
Aspartate aminotransferase increased † 1	52/438 (11.87%)	63	8/218 (3.67%)	10
Blood albumin decreased † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Blood alkaline phosphatase † 1	1/438 (0.23%)	1	1/218 (0.46%)	2
Blood alkaline phosphatase increased † 1	12/438 (2.74%)	16	4/218 (1.83%)	4
Blood bicarbonate decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood bilirubin increased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood calcium decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood creatinine decreased † 1	3/438 (0.68%)	10	1/218 (0.46%)	1
Blood creatinine increased † 1	21/438 (4.79%)	30	4/218 (1.83%)	4
Blood fibrinogen increased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood glucose increased † 1	1/438 (0.23%)	3	0/218 (0.00%)	0
Blood iron decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood lactate dehydrogenase increased † 1	9/438 (2.05%)	15	1/218 (0.46%)	1
Blood potassium decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood potassium increased † 1	1/438 (0.23%)	2	0/218 (0.00%)	0
Blood sodium decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood sodium increased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Blood uric acid increased † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
C-reactive protein increased † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Creatinine renal clearance decreased † 1	18/438 (4.11%)	28	2/218 (0.92%)	2
Forced expiratory volume decreased † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Gamma-glutamyltransferase increased † 1	6/438 (1.37%)	7	5/218 (2.29%)	5
Glomerular filtration rate † 1	1/438 (0.23%)	3	0/218 (0.00%)	0
Glomerular filtration rate decreased † 1	5/438 (1.14%)	10	0/218 (0.00%)	0
Granulocyte count decreased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Granulocyte count increased † 1	0/438 (0.00%)	0	1/218 (0.46%)	2
Haemoglobin † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Haemoglobin decreased † 1	19/438 (4.34%)	30	2/218 (0.92%)	2
Neutrophil count decreased † 1	11/438 (2.51%)	16	1/218 (0.46%)	1
Neutrophil count increased † 1	3/438 (0.68%)	4	0/218 (0.00%)	0
Platelet count † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Platelet count decreased † 1	5/438 (1.14%)	5	2/218 (0.92%)	2
Platelet count increased † 1	1/438 (0.23%)	1	2/218 (0.92%)	3
Red blood cell count decreased † 1	2/438 (0.46%)	5	1/218 (0.46%)	1
Red blood cell microcytes present † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Renal function test abnormal † 1	1/438 (0.23%)	3	0/218 (0.00%)	0
Sensory level † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Total bile acids increased † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Transaminases increased † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Troponin t † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Weight decreased † 1	17/438 (3.88%)	20	3/218 (1.38%)	3
Weight increased † 1	5/438 (1.14%)	5	1/218 (0.46%)	1
White blood cell count decreased † 1	4/438 (0.91%)	5	0/218 (0.00%)	0
White blood cell count increased † 1	1/438 (0.23%)	1	2/218 (0.92%)	3
Metabolism and nutrition disorders
Acidosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Alcohol intolerance † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Alkalosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Anorexia † 1	124/438 (28.31%)	238	40/218 (18.35%)	43
Dehydration † 1	7/438 (1.60%)	8	1/218 (0.46%)	1
Diabetes mellitus † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Fluid retention † 1	2/438 (0.46%)	3	0/218 (0.00%)	0
Glucose tolerance impaired † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypercalcaemia † 1	3/438 (0.68%)	3	2/218 (0.92%)	3
Hypercholesterolaemia † 1	1/438 (0.23%)	2	1/218 (0.46%)	1
Hypercreatininaemia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hyperglycaemia † 1	18/438 (4.11%)	20	6/218 (2.75%)	7
Hyperkalaemia † 1	4/438 (0.91%)	6	1/218 (0.46%)	1
Hyperlipidaemia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypernatraemia † 1	2/438 (0.46%)	3	0/218 (0.00%)	0
Hypertriglyceridaemia † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Hyperuricaemia † 1	1/438 (0.23%)	1	3/218 (1.38%)	3
Hypoalbuminaemia † 1	2/438 (0.46%)	3	1/218 (0.46%)	1
Hypocalcaemia † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Hypokalaemia † 1	4/438 (0.91%)	4	1/218 (0.46%)	2
Hyponatraemia † 1	7/438 (1.60%)	7	0/218 (0.00%)	0
Hypophosphataemia † 1	0/438 (0.00%)	0	1/218 (0.46%)	2
Increased appetite † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	12/438 (2.74%)	16	7/218 (3.21%)	7
Arthritis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Back pain † 1	41/438 (9.36%)	48	8/218 (3.67%)	8
Bone pain † 1	14/438 (3.20%)	14	10/218 (4.59%)	10
Flank pain † 1	1/438 (0.23%)	2	1/218 (0.46%)	1
Muscle spasms † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Muscular weakness † 1	5/438 (1.14%)	6	2/218 (0.92%)	2
Musculoskeletal chest pain † 1	8/438 (1.83%)	8	5/218 (2.29%)	5
Musculoskeletal discomfort † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Musculoskeletal pain † 1	12/438 (2.74%)	14	5/218 (2.29%)	6
Myalgia † 1	15/438 (3.42%)	17	5/218 (2.29%)	7
Neck pain † 1	3/438 (0.68%)	5	5/218 (2.29%)	6
Pain in extremity † 1	11/438 (2.51%)	14	9/218 (4.13%)	11
Pain in jaw † 1	2/438 (0.46%)	7	0/218 (0.00%)	0
Scleroderma † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tendonitis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Angiolipoma † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Cancer pain † 1	11/438 (2.51%)	11	4/218 (1.83%)	4
Metastatic pain † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Neoplasm † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Oesophageal carcinoma † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tumour pain † 1	5/438 (1.14%)	5	5/218 (2.29%)	5
Nervous system disorders
Ageusia † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Aphasia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Aphonia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Ataxia † 1	5/438 (1.14%)	6	0/218 (0.00%)	0
Balance disorder † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Brain injury † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Burning sensation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Cerebral ischaemia † 1	0/438 (0.00%)	0	2/218 (0.92%)	2
Cognitive disorder † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Coma † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Convulsion † 1	3/438 (0.68%)	3	1/218 (0.46%)	1
Depressed level of consciousness † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Disturbance in attention † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Dizziness † 1	34/438 (7.76%)	39	7/218 (3.21%)	7
Dysaesthesia † 1	1/438 (0.23%)	2	1/218 (0.46%)	1
Dysgeusia † 1	10/438 (2.28%)	14	1/218 (0.46%)	1
Dysphasia † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Formication † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Headache † 1	51/438 (11.64%)	62	19/218 (8.72%)	26
Hemicephalalgia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hemiparesis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hypoaesthesia † 1	5/438 (1.14%)	6	3/218 (1.38%)	3
Memory impairment † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Neuralgia † 1	4/438 (0.91%)	4	1/218 (0.46%)	1
Neuropathy peripheral † 1	10/438 (2.28%)	11	2/218 (0.92%)	2
Neurotoxicity † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Paraesthesia † 1	27/438 (6.16%)	29	11/218 (5.05%)	12
Peripheral motor neuropathy † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Peripheral sensory neuropathy † 1	22/438 (5.02%)	22	6/218 (2.75%)	6
Poor quality sleep † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Somnolence † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Speech disorder † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Stupor † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Syncope † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Syncope vasovagal † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Transient ischaemic attack † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tremor † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Psychiatric disorders
Abnormal behaviour † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Agitation † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Anxiety † 1	5/438 (1.14%)	5	1/218 (0.46%)	1
Confusional state † 1	4/438 (0.91%)	4	0/218 (0.00%)	0
Depressed mood † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Depression † 1	9/438 (2.05%)	9	1/218 (0.46%)	1
Insomnia † 1	28/438 (6.39%)	31	8/218 (3.67%)	8
Suicidal ideation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tic † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Renal and urinary disorders
Bladder spasm † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Calculus bladder † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Dysuria † 1	3/438 (0.68%)	8	0/218 (0.00%)	0
Glycosuria † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Haematuria † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Haemorrhage urinary tract † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Incontinence † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Micturition urgency † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Nocturia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pollakiuria † 1	3/438 (0.68%)	4	0/218 (0.00%)	0
Renal failure † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Urinary hesitation † 1	1/438 (0.23%)	3	0/218 (0.00%)	0
Urinary incontinence † 1	1/438 (0.23%)	1	2/218 (0.92%)	2
Urinary retention † 1	5/438 (1.14%)	5	0/218 (0.00%)	0
Reproductive system and breast disorders
Balanitis † 1	1/321 (0.31%)	1	0/158 (0.00%)	0
Breast swelling † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Pelvic pain † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Testicular disorder † 1	1/321 (0.31%)	1	0/158 (0.00%)	0
Testicular pain † 1	1/321 (0.31%)	1	0/158 (0.00%)	0
Vaginal haemorrhage † 1	2/117 (1.71%)	2	0/60 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Bronchial obstruction † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Cough † 1	95/438 (21.69%)	118	47/218 (21.56%)	50
Dysphonia † 1	2/438 (0.46%)	2	4/218 (1.83%)	4
Dyspnoea † 1	98/438 (22.37%)	118	43/218 (19.72%)	45
Dyspnoea exertional † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Epistaxis † 1	5/438 (1.14%)	8	1/218 (0.46%)	1
Haemoptysis † 1	24/438 (5.48%)	26	10/218 (4.59%)	11
Hiccups † 1	9/438 (2.05%)	17	3/218 (1.38%)	3
Hypoxia † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Pharyngolaryngeal pain † 1	10/438 (2.28%)	11	5/218 (2.29%)	5
Pleural effusion † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Pleurisy † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pleuritic pain † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pneumonitis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Postnasal drip † 1	3/438 (0.68%)	5	0/218 (0.00%)	0
Productive cough † 1	11/438 (2.51%)	15	3/218 (1.38%)	3
Pulmonary embolism † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Pulmonary haemorrhage † 1	0/438 (0.00%)	0	3/218 (1.38%)	3
Rales † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Rhinitis allergic † 1	4/438 (0.91%)	7	1/218 (0.46%)	1
Rhinorrhoea † 1	6/438 (1.37%)	6	0/218 (0.00%)	0
Rhonchi † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Wheezing † 1	4/438 (0.91%)	4	1/218 (0.46%)	1
Skin and subcutaneous tissue disorders
Acne † 1	1/438 (0.23%)	2	2/218 (0.92%)	2
Alopecia † 1	21/438 (4.79%)	23	1/218 (0.46%)	1
Dermal cyst † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Dermatitis acneiform † 1	2/438 (0.46%)	6	4/218 (1.83%)	4
Dermatitis exfoliative † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Dermatosis † 1	1/438 (0.23%)	2	0/218 (0.00%)	0
Dry skin † 1	5/438 (1.14%)	6	1/218 (0.46%)	1
Erythema † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Hyperhidrosis † 1	12/438 (2.74%)	15	0/218 (0.00%)	0
Madarosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Nail disorder † 1	0/438 (0.00%)	0	1/218 (0.46%)	1
Night sweats † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Pain of skin † 1	0/438 (0.00%)	0	2/218 (0.92%)	2
Periorbital oedema † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Petechiae † 1	2/438 (0.46%)	5	0/218 (0.00%)	0
Photosensitivity reaction † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pigmentation disorder † 1	4/438 (0.91%)	7	0/218 (0.00%)	0
Pruritus † 1	18/438 (4.11%)	22	7/218 (3.21%)	8
Pruritus generalised † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Psoriasis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Rash † 1	62/438 (14.16%)	81	14/218 (6.42%)	16
Rash pruritic † 1	3/438 (0.68%)	3	0/218 (0.00%)	0
Skin discolouration † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Skin exfoliation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Skin hyperpigmentation † 1	9/438 (2.05%)	9	1/218 (0.46%)	1
Skin hypopigmentation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Skin toxicity † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Swelling face † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Urticaria † 1	1/438 (0.23%)	4	0/218 (0.00%)	0
Surgical and medical procedures
Medical device implantation † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Pneumatic compression therapy † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Tumour excision † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Vascular disorders
Deep vein thrombosis † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Flushing † 1	8/438 (1.83%)	10	5/218 (2.29%)	7
Haemorrhage † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Hot flush † 1	2/438 (0.46%)	2	1/218 (0.46%)	1
Hypertension † 1	11/438 (2.51%)	11	4/218 (1.83%)	4
Hypotension † 1	6/438 (1.37%)	6	3/218 (1.38%)	3
Orthostatic hypotension † 1	1/438 (0.23%)	1	1/218 (0.46%)	1
Peripheral ischaemia † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Phlebitis † 1	2/438 (0.46%)	2	0/218 (0.00%)	0
Shock † 1	1/438 (0.23%)	1	0/218 (0.00%)	0
Superior vena caval occlusion † 1	3/438 (0.68%)	3	1/218 (0.46%)	1
Thrombosis † 1	3/438 (0.68%)	3	2/218 (0.92%)	2
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 11.0

Limitations and Caveats

Four participants (pts) assigned to placebo received pemetrexed; pts analyzed for efficacy as randomized. Three treated pts did not sign ICF, 1 treated pt signed ICF but did not complete entire randomization process; pts excluded from all analyses.

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

• 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):

Belani CP, Brodowicz T, Ciuleanu TE, Krzakowski M, Yang SH, Franke F, Cucevic B, Madhavan J, Santoro A, Ramlau R, Liepa AM, Visseren-Grul C, Peterson P, John WJ, Zielinski CC. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol. 2012 Mar;13(3):292-9. doi: 10.1016/S1470-2045(11)70339-4. Epub 2012 Feb 14.

Gridelli C, Brodowicz T, Langer CJ, Peterson P, Islam M, Guba SC, Moore P, Visseren-Grul CM, Scagliotti G. Pemetrexed therapy in elderly patients with good performance status: analysis of two phase III trials of patients with nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2012 Sep;13(5):340-6. doi: 10.1016/j.cllc.2011.12.002. Epub 2012 Jan 23.

Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40. doi: 10.1016/S0140-6736(09)61497-5. Epub 2009 Sep 18.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00102804
• Other Study ID Numbers: 5122; H3E-MC-JMEN ( Other Identifier: Eli Lilly and Company )
• First Submitted: February 1, 2005
• First Posted: February 2, 2005
• Results First Submitted: December 17, 2014
• Results First Posted: December 29, 2014
• Last Update Posted: December 29, 2014