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A Study of Ramucirumab in Participants With Gastric or Gastroesophageal Junction Adenocarcinoma

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT02539225
Collaborator
(none)
191
Enrollment
34
Locations
2
Arms
65.1
Actual Duration (Months)
5.6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to evaluate the effectiveness of S-1 and oxaliplatin with or without ramucirumab as first line therapy in participants with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
191 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of S-1 and Oxaliplatin With or Without Ramucirumab as First-line Therapy Followed by Paclitaxel With Ramucirumab as Second-line Therapy in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma
Actual Study Start Date :
Oct 5, 2015
Actual Primary Completion Date :
Oct 25, 2017
Actual Study Completion Date :
Mar 10, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: S-1/Oxaliplatin + Ramucirumab

(Part A) Ramucirumab intravenously (IV) on day 1 and day 8 along with S-1 by mouth (PO) on days 1-14 and oxaliplatin IV on day 1 of each 21 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met then move to Part B. (Part B) Ramucirumab IV on day 1 and day 15 along with paclitaxel IV on day 1, 8, and 15 of each 28 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.

Drug: Ramucirumab
Administered IV
Other Names:
  • LY3009806
  • IMC-1121B
  • Cyramza

    • Drug: S-1
    Administered PO

    Drug: Oxaliplatin
    Administered IV

    Drug: Paclitaxel
    Administered IV
    Active Comparator: S-1/Oxaliplatin + Placebo

    (Part A) Placebo IV on day 1 and day 8 along with S-1 PO on days 1-14 and oxaliplatin IV on day 1 of each 21 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met then move to Part B. (Part B) Ramucirumab IV on day 1 and day 15 along with paclitaxel IV on day 1, 8, and 15 of each 28 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.

    Drug: Ramucirumab
    Administered IV
    Other Names:
  • LY3009806
  • IMC-1121B
  • Cyramza

    • Drug: Placebo
    Administered IV

    Drug: S-1
    Administered PO

    Drug: Oxaliplatin
    Administered IV

    Drug: Paclitaxel
    Administered IV

    Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival (PFS) [Randomization to Radiographic Documentation of Progression or Death Due to Any Cause (Up to 25 Months)]

      PFS is defined as the time from the date of randomization until the date of objectively determined progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or death from any cause, whichever is first. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 millimeter (mm) or the appearance of ≥1 new lesions was progression. Participants who did not progress, were lost to follow-up were censored at the day of their last adequate tumor assessment.

    Secondary Outcome Measures

    1. Progression-free Survival to the Second Disease Progression (PFS 2) [Randomization to Second Radiographic Documentation of Progression or Death Due to Any Cause (Up to 31 Months)]

      Progression-free survival 2 (PFS2) is defined as the time from the date of randomization to second disease progression (defined as the date of first tumor assessment observing PD defined by RECIST v.1.1, after the start of second-line therapy using the last tumor assessment before starting the second-line therapy (RAM+PTX) as the baseline assessment), or death of any cause, whichever occurs first. If the second-line therapy was not started, the OS will be substituted for PFS2. If a post-discontinuation therapy was started before observing PD after the start of second-line therapy. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. PFS2 will be censored at the date of the last adequate tumor assessment on or before staring the post-discontinuation therapy.

    2. Overall Survival (OS) [Randomization to Death Due to Any Cause (Up to 31 Months)]

      Overall survival is defined as time from the date of randomization to the date of death from any cause. If the patient was alive at the cut-off for analysis (or lost to follow-up), OS data were censored for analysis on the last date the patient was known to be alive.

    3. Percentage of Participants With Objective Response Rate (ORR) [Randomization to Disease Progression (Up to 25 Months)]

      The ORR is the number of all participants with Partial Response (PR) or Complete Response (CR) according to RECIST v1.1 from the start of the treatment until disease progression/recurrence. CR is defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 mm. PR is defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm or the appearance of ≥1 new lesions was progression.

    4. Disease Control Rate (DCR) [Randomization to Disease Progression (Up to 25 Months)]

      Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm or the appearance of ≥1 new lesions was progression.

    5. Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part A [Cycle 1 Day 1 & 8 Predose, Cycle 2 Day 1 Predose, Cycle 3 Day 1 Predose, Cycle 5 Day 1 Predose, Cycle 9 Day 1 Predose]

      Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part A.

    6. Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part B [Cycle 1 Day 1 predose, Cycle 2 Day 1 predose]

      Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part B.

    7. Number of Participants With Anti-Ramucirumab Antibodies [Baseline through 25 months]

      Participant is considered as treatment emergent anti-drug antibody (TE ADA) positive if the participant has at least one post baseline titer that is a 4-fold or greater increase in titer from baseline measurement. If baseline result is ADA Not Present, then the participant is TE ADA+ if there is at least one post baseline result of ADA Present with titer >= 20.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    20 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Have a histopathologically or cytologically confirmed diagnosis of metastatic gastric or GEJ adenocarcinoma. Participants with esophageal cancer are not eligible.

    • Have not received any prior first-line systemic therapy for gastric or GEJ adenocarcinoma (prior adjuvant or neoadjuvant therapy is permitted). Participants whose disease has progressed after >24 weeks following the last dose of systemic treatment in the adjuvant/neoadjuvant setting are eligible.

    • Have measurable or nonmeasurable but evaluable disease determined using guidelines in Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v.1.1).

    • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale at baseline.

    • Have adequate organ function.

    • Have an estimated life expectancy of ≥12 weeks in the judgment of the investigator.

    • Eligible participants of reproductive potential (both sexes) must agree to use contraception (hormonal or barrier methods) during the study period and at least 6 months after the last dose of study treatment or longer if required per local regulations.

    • Are willing to provide a blood sample for research purposes. Submission of a blood sample is mandatory for participation in this study unless restricted by local regulations or ethical review boards (ERBs); submission of a tumor tissue sample is optional.

    Exclusion Criteria:

    • Participants with human epidermal growth factor receptor 2 (HER2)-positive status as determined per local standards. Participants with a negative test or having an indeterminate result due to any reason are eligible, provided these participants are not eligible for treatment directed against tumors which overexpress HER2.

    • Have radiation therapy within 14 days prior to randomization. Any lesion requiring palliative radiation or which has been previously irradiated cannot be considered for response assessment.

    • Have documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.

    • Have undergone major surgery within 28 days prior to randomization.

    • Are currently enrolled in, or discontinued study drug within the last 28 days from, a clinical trial involving an investigational product or non-approved use of a drug or device (other than the study drug used in this study), or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Participants participating in surveys or observational studies are eligible to participate in this study.

    • Are pregnant or breast feeding. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to first dose of study treatment.

    • Have any prior malignancies.

    • Have any condition (eg, psychological, geographical, or medical) that does not permit compliance with the study and follow-up procedures or suggest that the participant is, in the investigator's opinion, not an appropriate candidate for the study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Akashi Japan 673-8558
    2 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Bunkyo-Ku Japan 113-8677
    3 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Chiba Japan 260-8717
    4 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Gifu Japan 501-1194
    5 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kochi Japan 781-8555
    6 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Koto-ku Japan 135-8550
    7 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Koto-ku Japan 135-8577
    8 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kumamoto Japan 860-8556
    9 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nagoya Japan 464-8681
    10 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nagoya Japan 466-8560
    11 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Osaka Japan 534-0021
    12 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Osaka Japan 541-8567
    13 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Osaka Japan 558-8558
    14 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Sagamihara Japan 252-0375
    15 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Sakai Japan 593-8304
    16 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Sapporo Japan 060-8648
    17 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Shinjuku-Ku Japan 160-8582
    18 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Suita-shi Japan 565-0871
    19 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Takatsuki Japan 569-8686
    20 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician Toyonaka Japan 560-8565
    21 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Utsunomiya Japan 320-0834
    22 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Yokohama Japan 224-8503
    23 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Yokohama Japan 241-8515
    24 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Seoul Korea, Republic of 03080
    25 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Seoul Korea, Republic of 03722
    26 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Seoul Korea, Republic of 05505
    27 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Seoul Korea, Republic of 06273
    28 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Seoul Korea, Republic of 06351
    29 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ulsan-si Korea, Republic of 44033
    30 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kuei Shan Hsiang Taiwan 33305
    31 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Taichung Taiwan 40447
    32 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tainan Taiwan 70403
    33 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Taipei Taiwan 10048
    34 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Taipei Taiwan 11217

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT02539225
    Other Study ID Numbers:
    • 15461
    • I4T-JE-JVCW
    First Posted:
    Sep 2, 2015
    Last Update Posted:
    Mar 8, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Adenocarcinoma
    Esophageal Neoplasms
    Paclitaxel
    Oxaliplatin
    Ramucirumab

    Study Results

    Participant Flow

    Recruitment Details Completers are defined as participants who died or those who were alive and off treatment at study completion.
    Pre-assignment Detail
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Period Title: Part A
    STARTED 97 94
    Received Any Quantity of Study Drug 96 93
    COMPLETED 77 78
    NOT COMPLETED 20 16
    Period Title: Part A
    STARTED 63 66
    COMPLETED 58 64
    NOT COMPLETED 5 2
    Period Title: Part A
    STARTED 58 64
    COMPLETED 54 48
    NOT COMPLETED 4 16

    Baseline Characteristics

    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin Total
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Total of all reporting groups
    Overall Participants 96 93 189
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    59.2
    (12.35)
    61.3
    (11.53)
    60.2
    (11.97)
    Sex: Female, Male (Count of Participants)
    Female
    39
    40.6%
    29
    31.2%
    68
    36%
    Male
    57
    59.4%
    64
    68.8%
    121
    64%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    96
    100%
    93
    100%
    189
    100%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    96
    100%
    93
    100%
    189
    100%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    0
    0%
    0
    0%
    0
    0%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    South Korea
    20
    20.8%
    20
    21.5%
    40
    21.2%
    Japan
    65
    67.7%
    64
    68.8%
    129
    68.3%
    Taiwan
    11
    11.5%
    9
    9.7%
    20
    10.6%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival (PFS)
    Description PFS is defined as the time from the date of randomization until the date of objectively determined progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or death from any cause, whichever is first. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 millimeter (mm) or the appearance of ≥1 new lesions was progression. Participants who did not progress, were lost to follow-up were censored at the day of their last adequate tumor assessment.
    Time Frame Randomization to Radiographic Documentation of Progression or Death Due to Any Cause (Up to 25 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received any quantity of study drug in Part A. Censored participants: Ramucirumab + S-1 + Oxaliplatin = 23; Placebo + S-1 + Oxaliplatin = 19.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Measure Participants 96 93
    Median (80% Confidence Interval) [Months]
    6.34
    6.74
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + S-1 + Oxaliplatin, Placebo + S-1 + Oxaliplatin
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.698
    Comments
    Method Stratified Log Rank
    Comments
    2. Secondary Outcome
    Title Progression-free Survival to the Second Disease Progression (PFS 2)
    Description Progression-free survival 2 (PFS2) is defined as the time from the date of randomization to second disease progression (defined as the date of first tumor assessment observing PD defined by RECIST v.1.1, after the start of second-line therapy using the last tumor assessment before starting the second-line therapy (RAM+PTX) as the baseline assessment), or death of any cause, whichever occurs first. If the second-line therapy was not started, the OS will be substituted for PFS2. If a post-discontinuation therapy was started before observing PD after the start of second-line therapy. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. PFS2 will be censored at the date of the last adequate tumor assessment on or before staring the post-discontinuation therapy.
    Time Frame Randomization to Second Radiographic Documentation of Progression or Death Due to Any Cause (Up to 31 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received any quantity of study drug. Censored participants: Ramucirumab + S-1 + Oxaliplatin = 26; Placebo + S-1 + Oxaliplatin = 26.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Measure Participants 96 93
    Median (80% Confidence Interval) [Months]
    10.94
    11.99
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + S-1 + Oxaliplatin, Placebo + S-1 + Oxaliplatin
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.549
    Comments
    Method Log Rank Stratified
    Comments
    3. Secondary Outcome
    Title Overall Survival (OS)
    Description Overall survival is defined as time from the date of randomization to the date of death from any cause. If the patient was alive at the cut-off for analysis (or lost to follow-up), OS data were censored for analysis on the last date the patient was known to be alive.
    Time Frame Randomization to Death Due to Any Cause (Up to 31 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug. Censored participants: Ramucirumab + S-1 + Oxaliplatin = 27; Placebo + S-1 + Oxaliplatin = 30.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Measure Participants 96 93
    Median (80% Confidence Interval) [Months]
    14.65
    14.26
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + S-1 + Oxaliplatin, Placebo + S-1 + Oxaliplatin
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.548
    Comments
    Method Log Rank Stratified
    Comments
    4. Secondary Outcome
    Title Percentage of Participants With Objective Response Rate (ORR)
    Description The ORR is the number of all participants with Partial Response (PR) or Complete Response (CR) according to RECIST v1.1 from the start of the treatment until disease progression/recurrence. CR is defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 mm. PR is defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm or the appearance of ≥1 new lesions was progression.
    Time Frame Randomization to Disease Progression (Up to 25 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received any quantity of study drug in Part A with measurable disease.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Measure Participants 55 54
    Number (80% Confidence Interval) [percentage of participants]
    58.2
    60.6%
    50.0
    53.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + S-1 + Oxaliplatin, Placebo + S-1 + Oxaliplatin
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.402
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.374
    Confidence Interval (2-Sided) 80%
    0.844 to 2.236
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Disease Control Rate (DCR)
    Description Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm or the appearance of ≥1 new lesions was progression.
    Time Frame Randomization to Disease Progression (Up to 25 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received any quantity of study drug in Part A with measurable disease.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Measure Participants 55 54
    Number (80% Confidence Interval) [percentage of participants]
    90.9
    94.7%
    87
    93.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + S-1 + Oxaliplatin, Placebo + S-1 + Oxaliplatin
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.501
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.527
    Confidence Interval (2-Sided) 80%
    0.680 to 3.433
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part A
    Description Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part A.
    Time Frame Cycle 1 Day 1 & 8 Predose, Cycle 2 Day 1 Predose, Cycle 3 Day 1 Predose, Cycle 5 Day 1 Predose, Cycle 9 Day 1 Predose

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of ramucirumab in part A and had evaluable PK samples.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin - Part A
    Arm/Group Description Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met.
    Measure Participants 96
    Cycle 1 Day 1
    NA
    (NA)
    Cycle 1 Day 8
    42.6
    (32)
    Cycle 2 Day 1
    41.4
    (40)
    Cycle 3 Day 1
    59.4
    (51)
    Cycle 5 Day 1
    83.6
    (37)
    Cycle 9 Day 1
    94.6
    (38)
    7. Secondary Outcome
    Title Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part B
    Description Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab in Part B.
    Time Frame Cycle 1 Day 1 predose, Cycle 2 Day 1 predose

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of ramucirumab in part B and had evaluable PK samples.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Part B Placebo + S-1 + Oxaliplatin - Part B
    Arm/Group Description Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Measure Participants 58 64
    Cycle 1 Day 1
    52.0
    (65)
    NA
    (NA)
    Cycle 2 Day 1
    58.1
    (40)
    41.0
    (45)
    8. Secondary Outcome
    Title Number of Participants With Anti-Ramucirumab Antibodies
    Description Participant is considered as treatment emergent anti-drug antibody (TE ADA) positive if the participant has at least one post baseline titer that is a 4-fold or greater increase in titer from baseline measurement. If baseline result is ADA Not Present, then the participant is TE ADA+ if there is at least one post baseline result of ADA Present with titer >= 20.
    Time Frame Baseline through 25 months

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received any quantity of study drug in part A and had at least one baseline & post baseline antibody (ADA) measurement.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin Placebo + S-1 + Oxaliplatin
    Arm/Group Description Part A: Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Part A: Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Part B:Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    Measure Participants 92 90
    Count of Participants [Participants]
    1
    1%
    3
    3.2%

    Adverse Events

    Time Frame Up to 31 Months
    Adverse Event Reporting Description All randomized participants who received at least one dose of study drug. Adverse events data for pre-treatment Part B were included in part A. There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
    Arm/Group Title Ramucirumab + S-1 + Oxaliplatin - Part A Placebo + S-1 + Oxaliplatin - Part A Ramucirumab + S-1 + Oxaliplatin Part B Placebo + S-1 + Oxaliplatin - Part B
    Arm/Group Description Participants received 8 milligram per kilogram (mg/kg) Ramucirumab by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Participants received placebo by intravenous (IV) infusion on day 1 and day 8 of 21 days cycle in combination with oral dose of 80-120 mg/day S-1 on days 1 to14 and 100 milligram per square meter (mg/m^2) Oxaliplatin administered by IV infusion on day 1 until disease progression or any other discontinuation criteria is met. Participants received 8 mg/kg Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met. Participants received Ramucirumab by intravenous infusion on day 1 and day 15 of 28 days cycle in combination with 80 mg/m^2 Paclitaxel on day 1, 8 and 15 by intravenous infusion until disease progression or any other discontinuation criteria is met.
    All Cause Mortality
    Ramucirumab + S-1 + Oxaliplatin - Part A Placebo + S-1 + Oxaliplatin - Part A Ramucirumab + S-1 + Oxaliplatin Part B Placebo + S-1 + Oxaliplatin - Part B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/96 (2.1%) 1/93 (1.1%) 1/58 (1.7%) 0/64 (0%)
    Serious Adverse Events
    Ramucirumab + S-1 + Oxaliplatin - Part A Placebo + S-1 + Oxaliplatin - Part A Ramucirumab + S-1 + Oxaliplatin Part B Placebo + S-1 + Oxaliplatin - Part B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 29/96 (30.2%) 24/93 (25.8%) 16/58 (27.6%) 14/64 (21.9%)
    Blood and lymphatic system disorders
    Anaemia 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Disseminated intravascular coagulation 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Febrile neutropenia 1/96 (1%) 1 0/93 (0%) 0 3/58 (5.2%) 3 4/64 (6.3%) 4
    Haemolytic uraemic syndrome 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Gastrointestinal disorders
    Abdominal pain 1/96 (1%) 1 3/93 (3.2%) 3 1/58 (1.7%) 1 0/64 (0%) 0
    Ascites 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Diarrhoea 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Duodenal stenosis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Dysphagia 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Enterocolitis 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Gastric perforation 1/96 (1%) 1 1/93 (1.1%) 1 3/58 (5.2%) 3 0/64 (0%) 0
    Gastric stenosis 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Gastrointestinal perforation 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Gastrooesophageal reflux disease 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Gingival bleeding 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Ileal perforation 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Ileus 1/96 (1%) 1 1/93 (1.1%) 1 1/58 (1.7%) 2 1/64 (1.6%) 1
    Intestinal obstruction 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Intussusception 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Large intestinal obstruction 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Obstruction gastric 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Prepyloric stenosis 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Small intestinal perforation 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 1/64 (1.6%) 1
    Upper gastrointestinal haemorrhage 3/96 (3.1%) 3 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Vomiting 3/96 (3.1%) 3 2/93 (2.2%) 2 0/58 (0%) 0 1/64 (1.6%) 1
    General disorders
    Pyrexia 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Hepatobiliary disorders
    Bile duct obstruction 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Bile duct stenosis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Bile duct stone 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Cholecystitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Cholecystocholangitis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Jaundice 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Jaundice cholestatic 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Portal vein thrombosis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Immune system disorders
    Hypersensitivity 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Infections and infestations
    Abdominal abscess 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Anal abscess 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Appendicitis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Arthritis infective 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Bronchitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Cellulitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Mycobacterial infection 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Peritonitis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Pneumonia 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 1/64 (1.6%) 1
    Pneumonia staphylococcal 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Pyelonephritis 0/96 (0%) 0 0/93 (0%) 0 2/58 (3.4%) 3 0/64 (0%) 0
    Sepsis 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Urinary tract infection 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Wound infection 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Foot fracture 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Fracture 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Infusion related reaction 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Ligament injury 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Road traffic accident 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Spinal fracture 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Subarachnoid haemorrhage 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Aspartate aminotransferase increased 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Blood bilirubin increased 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Platelet count decreased 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 2/96 (2.1%) 2 1/93 (1.1%) 1 1/58 (1.7%) 1 1/64 (1.6%) 1
    Dehydration 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Diabetes mellitus 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Hypercalcaemia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hyponatraemia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hypophagia 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 2 0/64 (0%) 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Musculoskeletal pain 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Nervous system disorders
    Cerebral infarction 1/96 (1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Dizziness 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Loss of consciousness 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Psychiatric disorders
    Delirium 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Renal and urinary disorders
    Hydronephrosis 2/96 (2.1%) 2 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Renal impairment 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Urinary tract obstruction 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Chronic obstructive pulmonary disease 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Dyspnoea 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Pneumonia aspiration 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Pneumonitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Pneumothorax 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Other (Not Including Serious) Adverse Events
    Ramucirumab + S-1 + Oxaliplatin - Part A Placebo + S-1 + Oxaliplatin - Part A Ramucirumab + S-1 + Oxaliplatin Part B Placebo + S-1 + Oxaliplatin - Part B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 95/96 (99%) 93/93 (100%) 58/58 (100%) 64/64 (100%)
    Blood and lymphatic system disorders
    Anaemia 25/96 (26%) 37 20/93 (21.5%) 32 15/58 (25.9%) 19 11/64 (17.2%) 23
    Disseminated intravascular coagulation 1/96 (1%) 1 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Febrile neutropenia 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 1/64 (1.6%) 1
    Iron deficiency anaemia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Leukopenia 3/96 (3.1%) 7 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Neutropenia 6/96 (6.3%) 17 6/93 (6.5%) 20 3/58 (5.2%) 9 3/64 (4.7%) 4
    Thrombocytopenia 5/96 (5.2%) 13 2/93 (2.2%) 5 1/58 (1.7%) 1 2/64 (3.1%) 2
    Cardiac disorders
    Atrial fibrillation 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Palpitations 2/96 (2.1%) 4 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Sinus tachycardia 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Tachyarrhythmia 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Tachycardia 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Congenital, familial and genetic disorders
    Hydrocele 0/96 (0%) 0 0/93 (0%) 0 1/34 (2.9%) 1 0/64 (0%) 0
    Ear and labyrinth disorders
    Eustachian tube patulous 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Tinnitus 3/96 (3.1%) 3 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Vertigo 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Endocrine disorders
    Adrenal insufficiency 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Hypothyroidism 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Eye disorders
    Cataract 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Conjunctival haemorrhage 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Conjunctivitis allergic 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Corneal erosion 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Dry eye 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Eye discharge 1/96 (1%) 1 3/93 (3.2%) 3 1/58 (1.7%) 1 0/64 (0%) 0
    Eye pain 0/96 (0%) 0 2/93 (2.2%) 3 0/58 (0%) 0 0/64 (0%) 0
    Hyalosis asteroid 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Iridocyclitis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Keratitis 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Lacrimation increased 5/96 (5.2%) 5 4/93 (4.3%) 4 1/58 (1.7%) 1 0/64 (0%) 0
    Ocular hypertension 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Panophthalmitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Periorbital oedema 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Scleral haemorrhage 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Ulcerative keratitis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Vision blurred 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Vitreous floaters 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Gastrointestinal disorders
    Abdominal discomfort 6/96 (6.3%) 6 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Abdominal distension 11/96 (11.5%) 11 11/93 (11.8%) 12 2/58 (3.4%) 3 3/64 (4.7%) 6
    Abdominal pain 18/96 (18.8%) 26 21/93 (22.6%) 28 7/58 (12.1%) 7 4/64 (6.3%) 4
    Abdominal pain lower 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Abdominal pain upper 9/96 (9.4%) 11 6/93 (6.5%) 6 1/58 (1.7%) 1 5/64 (7.8%) 5
    Anal fistula 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Anal haemorrhage 1/96 (1%) 1 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Anal inflammation 1/96 (1%) 1 0/93 (0%) 0 2/58 (3.4%) 2 1/64 (1.6%) 1
    Ascites 7/96 (7.3%) 7 6/93 (6.5%) 6 2/58 (3.4%) 2 5/64 (7.8%) 5
    Cheilitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Colitis 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Constipation 33/96 (34.4%) 52 30/93 (32.3%) 32 3/58 (5.2%) 3 6/64 (9.4%) 6
    Dental caries 2/96 (2.1%) 2 1/93 (1.1%) 2 2/58 (3.4%) 2 1/64 (1.6%) 1
    Diarrhoea 49/96 (51%) 103 28/93 (30.1%) 62 10/58 (17.2%) 15 8/64 (12.5%) 10
    Dry mouth 1/96 (1%) 1 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Duodenal stenosis 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Dyspepsia 3/96 (3.1%) 4 4/93 (4.3%) 4 1/58 (1.7%) 2 1/64 (1.6%) 1
    Dysphagia 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Enterocolitis 1/96 (1%) 1 3/93 (3.2%) 3 0/58 (0%) 0 0/64 (0%) 0
    Epigastric discomfort 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Flatulence 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Gastric fistula 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Gastric haemorrhage 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Gastric stenosis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Gastric ulcer 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Gastritis 3/96 (3.1%) 3 4/93 (4.3%) 4 0/58 (0%) 0 1/64 (1.6%) 1
    Gastrointestinal pain 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Gastrointestinal perforation 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Gastrooesophageal reflux disease 2/96 (2.1%) 2 0/93 (0%) 0 1/58 (1.7%) 1 1/64 (1.6%) 1
    Gingival bleeding 4/96 (4.2%) 4 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Gingival pain 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Haematemesis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Haemorrhoidal haemorrhage 1/96 (1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Haemorrhoids 5/96 (5.2%) 5 2/93 (2.2%) 2 1/58 (1.7%) 1 0/64 (0%) 0
    Ileus 2/96 (2.1%) 3 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Ileus paralytic 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Large intestinal obstruction 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Large intestine perforation 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Lip dry 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Lip pain 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Melaena 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Mouth haemorrhage 4/96 (4.2%) 6 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Mouth ulceration 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Nausea 54/96 (56.3%) 90 37/93 (39.8%) 69 5/58 (8.6%) 5 4/64 (6.3%) 4
    Oesophageal obstruction 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Oesophageal pain 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Oral pain 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Periodontal disease 3/96 (3.1%) 3 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Pneumatosis intestinalis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Proctalgia 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Regurgitation 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Salivary gland fistula 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Small intestinal obstruction 0/96 (0%) 0 1/93 (1.1%) 2 0/58 (0%) 0 0/64 (0%) 0
    Stomatitis 27/96 (28.1%) 48 18/93 (19.4%) 25 9/58 (15.5%) 10 9/64 (14.1%) 9
    Subileus 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Tooth loss 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Toothache 4/96 (4.2%) 5 3/93 (3.2%) 3 1/58 (1.7%) 1 1/64 (1.6%) 1
    Upper gastrointestinal haemorrhage 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Vomiting 28/96 (29.2%) 49 21/93 (22.6%) 34 5/58 (8.6%) 6 7/64 (10.9%) 8
    General disorders
    Asthenia 3/96 (3.1%) 4 2/93 (2.2%) 2 0/58 (0%) 0 5/64 (7.8%) 6
    Axillary pain 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Catheter site pain 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Chest discomfort 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Chest pain 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Chills 3/96 (3.1%) 3 1/93 (1.1%) 1 2/58 (3.4%) 2 2/64 (3.1%) 2
    Face oedema 3/96 (3.1%) 3 2/93 (2.2%) 2 3/58 (5.2%) 3 2/64 (3.1%) 2
    Fatigue 28/96 (29.2%) 35 22/93 (23.7%) 35 7/58 (12.1%) 8 8/64 (12.5%) 9
    Feeling cold 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Feeling hot 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Gait disturbance 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Impaired healing 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Influenza like illness 2/96 (2.1%) 3 2/93 (2.2%) 4 1/58 (1.7%) 1 0/64 (0%) 0
    Infusion site extravasation 1/96 (1%) 1 3/93 (3.2%) 3 1/58 (1.7%) 1 1/64 (1.6%) 1
    Infusion site pain 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Injection site pain 2/96 (2.1%) 2 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Injection site reaction 6/96 (6.3%) 10 8/93 (8.6%) 17 1/58 (1.7%) 1 0/64 (0%) 0
    Injury associated with device 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Localised oedema 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Malaise 26/96 (27.1%) 35 20/93 (21.5%) 25 9/58 (15.5%) 11 7/64 (10.9%) 9
    Medical device site pain 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Mucosal inflammation 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Nodule 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Non-cardiac chest pain 2/96 (2.1%) 4 0/93 (0%) 0 1/58 (1.7%) 1 1/64 (1.6%) 1
    Oedema 4/96 (4.2%) 4 1/93 (1.1%) 1 0/58 (0%) 0 2/64 (3.1%) 3
    Oedema peripheral 26/96 (27.1%) 31 19/93 (20.4%) 24 8/58 (13.8%) 8 8/64 (12.5%) 8
    Pain 8/96 (8.3%) 9 4/93 (4.3%) 4 1/58 (1.7%) 1 1/64 (1.6%) 1
    Peripheral swelling 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Pyrexia 22/96 (22.9%) 28 22/93 (23.7%) 43 7/58 (12.1%) 9 11/64 (17.2%) 15
    Sensation of foreign body 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Tenderness 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hepatobiliary disorders
    Bile duct obstruction 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Cholangitis 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Cholelithiasis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hepatic failure 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hepatic function abnormal 2/96 (2.1%) 3 5/93 (5.4%) 5 2/58 (3.4%) 2 1/64 (1.6%) 1
    Hepatic steatosis 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hepatobiliary disease 0/96 (0%) 0 0/93 (0%) 0 2/58 (3.4%) 2 1/64 (1.6%) 1
    Jaundice 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Jaundice cholestatic 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Liver disorder 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Immune system disorders
    Contrast media allergy 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Seasonal allergy 1/96 (1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Infections and infestations
    Actinomycosis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Anal abscess 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Angular cheilitis 2/96 (2.1%) 2 2/93 (2.2%) 5 1/58 (1.7%) 3 0/64 (0%) 0
    Bacteraemia 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Cellulitis 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Conjunctivitis 3/96 (3.1%) 3 0/93 (0%) 0 1/58 (1.7%) 1 2/64 (3.1%) 2
    Cystitis 2/96 (2.1%) 2 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Enterococcal infection 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Eye infection 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Folliculitis 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 2/64 (3.1%) 2
    Gastroenteritis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Gingivitis 0/96 (0%) 0 0/93 (0%) 0 2/58 (3.4%) 2 0/64 (0%) 0
    Herpes ophthalmic 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Herpes simplex 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Herpes zoster 1/96 (1%) 1 1/93 (1.1%) 1 1/58 (1.7%) 1 3/64 (4.7%) 3
    Infection 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Influenza 1/96 (1%) 1 2/93 (2.2%) 2 1/58 (1.7%) 1 0/64 (0%) 0
    Lip infection 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Localised infection 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Lung infection 0/96 (0%) 0 3/93 (3.2%) 5 0/58 (0%) 0 2/64 (3.1%) 2
    Mucosal infection 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Mycobacterial infection 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Nail infection 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Nasopharyngitis 5/96 (5.2%) 5 3/93 (3.2%) 4 4/58 (6.9%) 4 1/64 (1.6%) 1
    Oral candidiasis 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Oral herpes 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Paronychia 2/96 (2.1%) 3 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Periodontitis 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Peritonitis 0/96 (0%) 0 0/93 (0%) 0 3/58 (5.2%) 3 2/64 (3.1%) 2
    Pharyngitis 3/96 (3.1%) 4 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Pneumonia 2/96 (2.1%) 2 1/93 (1.1%) 1 2/58 (3.4%) 2 2/64 (3.1%) 2
    Purulence 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Pyoderma 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Rhinitis 1/96 (1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Sepsis 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Sinusitis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Skin infection 0/96 (0%) 0 3/93 (3.2%) 3 0/58 (0%) 0 1/64 (1.6%) 1
    Tinea infection 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Tinea pedis 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Tracheitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Upper respiratory tract infection 8/96 (8.3%) 11 6/93 (6.5%) 7 3/58 (5.2%) 3 2/64 (3.1%) 2
    Urethritis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Urinary tract infection 3/96 (3.1%) 4 3/93 (3.2%) 6 2/58 (3.4%) 2 2/64 (3.1%) 2
    Wound infection 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Injury, poisoning and procedural complications
    Anastomotic stenosis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Animal bite 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Arthropod sting 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Contusion 1/96 (1%) 1 3/93 (3.2%) 3 2/58 (3.4%) 2 0/64 (0%) 0
    Fall 0/96 (0%) 0 6/93 (6.5%) 13 1/58 (1.7%) 1 1/64 (1.6%) 1
    Fracture 0/96 (0%) 0 1/93 (1.1%) 3 0/58 (0%) 0 0/64 (0%) 0
    Gastrointestinal stoma complication 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Head injury 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Infusion related reaction 1/96 (1%) 6 3/93 (3.2%) 4 0/58 (0%) 0 0/64 (0%) 0
    Laceration 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Limb injury 1/96 (1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Post procedural discomfort 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Procedural pain 1/96 (1%) 2 2/93 (2.2%) 2 0/58 (0%) 0 1/64 (1.6%) 1
    Skin abrasion 0/96 (0%) 0 2/93 (2.2%) 2 1/58 (1.7%) 1 1/64 (1.6%) 1
    Spinal fracture 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Stoma site discharge 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Thermal burn 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Vascular access complication 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Wound complication 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Wound dehiscence 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Wound secretion 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Investigations
    Alanine aminotransferase increased 21/96 (21.9%) 32 12/93 (12.9%) 18 4/58 (6.9%) 6 3/64 (4.7%) 4
    Amylase increased 1/96 (1%) 1 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Aspartate aminotransferase increased 25/96 (26%) 45 15/93 (16.1%) 26 5/58 (8.6%) 7 3/64 (4.7%) 4
    Blood alkaline phosphatase increased 10/96 (10.4%) 11 7/93 (7.5%) 8 5/58 (8.6%) 8 4/64 (6.3%) 4
    Blood bilirubin increased 2/96 (2.1%) 3 9/93 (9.7%) 11 3/58 (5.2%) 3 3/64 (4.7%) 5
    Blood creatine phosphokinase increased 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Blood creatinine increased 3/96 (3.1%) 5 0/93 (0%) 0 2/58 (3.4%) 2 1/64 (1.6%) 1
    Blood lactate dehydrogenase increased 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Blood thyroid stimulating hormone increased 1/96 (1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Creatinine renal clearance decreased 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Endoscopic retrograde cholangiopancreatography 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Gamma-glutamyltransferase increased 7/96 (7.3%) 9 5/93 (5.4%) 5 2/58 (3.4%) 2 0/64 (0%) 0
    Hepatic enzyme increased 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    International normalised ratio increased 0/96 (0%) 0 0/93 (0%) 0 2/58 (3.4%) 2 0/64 (0%) 0
    Lipase increased 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Lymphocyte count decreased 1/96 (1%) 1 3/93 (3.2%) 7 2/58 (3.4%) 5 0/64 (0%) 0
    Neutrophil count decreased 48/96 (50%) 156 32/93 (34.4%) 79 33/58 (56.9%) 85 36/64 (56.3%) 108
    Neutrophil count increased 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Peritoneal effluent erythrocyte count increased 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Platelet count decreased 33/96 (34.4%) 67 28/93 (30.1%) 62 4/58 (6.9%) 4 4/64 (6.3%) 6
    Weight decreased 11/96 (11.5%) 13 9/93 (9.7%) 18 3/58 (5.2%) 5 7/64 (10.9%) 8
    Weight increased 1/96 (1%) 1 2/93 (2.2%) 2 2/58 (3.4%) 2 0/64 (0%) 0
    White blood cell count decreased 24/96 (25%) 74 18/93 (19.4%) 58 19/58 (32.8%) 49 24/64 (37.5%) 59
    Metabolism and nutrition disorders
    Acidosis 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Decreased appetite 53/96 (55.2%) 78 57/93 (61.3%) 90 9/58 (15.5%) 9 12/64 (18.8%) 12
    Dehydration 1/96 (1%) 2 2/93 (2.2%) 4 1/58 (1.7%) 1 0/64 (0%) 0
    Glucose tolerance impaired 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Gout 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Hypercalcaemia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hyperglycaemia 2/96 (2.1%) 11 7/93 (7.5%) 12 0/58 (0%) 0 0/64 (0%) 0
    Hyperkalaemia 6/96 (6.3%) 11 3/93 (3.2%) 5 3/58 (5.2%) 3 1/64 (1.6%) 1
    Hypermagnesaemia 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Hypernatraemia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hypertriglyceridaemia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hyperuricaemia 0/96 (0%) 0 3/93 (3.2%) 4 1/58 (1.7%) 4 0/64 (0%) 0
    Hypoalbuminaemia 11/96 (11.5%) 14 11/93 (11.8%) 12 6/58 (10.3%) 10 10/64 (15.6%) 10
    Hypocalcaemia 3/96 (3.1%) 6 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Hypoglycaemia 1/96 (1%) 1 1/93 (1.1%) 2 0/58 (0%) 0 0/64 (0%) 0
    Hypokalaemia 4/96 (4.2%) 8 2/93 (2.2%) 4 5/58 (8.6%) 6 2/64 (3.1%) 3
    Hypomagnesaemia 0/96 (0%) 0 2/93 (2.2%) 2 1/58 (1.7%) 1 0/64 (0%) 0
    Hyponatraemia 1/96 (1%) 1 5/93 (5.4%) 5 6/58 (10.3%) 7 4/64 (6.3%) 4
    Hypophagia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hypophosphataemia 6/96 (6.3%) 13 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 4/96 (4.2%) 4 7/93 (7.5%) 9 3/58 (5.2%) 3 4/64 (6.3%) 5
    Arthritis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Back pain 8/96 (8.3%) 8 10/93 (10.8%) 11 3/58 (5.2%) 5 2/64 (3.1%) 2
    Bone pain 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Flank pain 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 2 1/64 (1.6%) 1
    Gouty arthritis 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Joint swelling 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Muscle spasms 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Muscular weakness 2/96 (2.1%) 2 3/93 (3.2%) 3 0/58 (0%) 0 2/64 (3.1%) 2
    Musculoskeletal chest pain 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Musculoskeletal pain 2/96 (2.1%) 3 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Musculoskeletal stiffness 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Myalgia 4/96 (4.2%) 5 5/93 (5.4%) 6 4/58 (6.9%) 4 7/64 (10.9%) 15
    Neck pain 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Pain in extremity 6/96 (6.3%) 7 4/93 (4.3%) 5 1/58 (1.7%) 1 0/64 (0%) 0
    Periarthritis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Rotator cuff syndrome 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Spinal osteoarthritis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 2/64 (3.1%) 2
    Cervix carcinoma 1/39 (2.6%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Haemangioma 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Metastases to meninges 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Metastatic gastric cancer 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Ovarian neoplasm 0/96 (0%) 0 1/29 (3.4%) 1 0/58 (0%) 0 0/64 (0%) 0
    Pyogenic granuloma 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Rectal cancer 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Skin papilloma 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Tumour haemorrhage 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Tumour pain 3/96 (3.1%) 3 7/93 (7.5%) 7 5/58 (8.6%) 5 4/64 (6.3%) 4
    Uterine leiomyoma 0/96 (0%) 0 1/29 (3.4%) 1 0/58 (0%) 0 0/64 (0%) 0
    Nervous system disorders
    Dizziness 7/96 (7.3%) 8 6/93 (6.5%) 7 2/58 (3.4%) 2 1/64 (1.6%) 1
    Dysaesthesia 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Dysgeusia 21/96 (21.9%) 24 20/93 (21.5%) 20 5/58 (8.6%) 5 3/64 (4.7%) 3
    Headache 16/96 (16.7%) 29 12/93 (12.9%) 21 1/58 (1.7%) 1 4/64 (6.3%) 5
    Hepatic encephalopathy 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Hypersomnia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hypoaesthesia 5/96 (5.2%) 6 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 2
    Neuralgia 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Neuropathy peripheral 7/96 (7.3%) 13 4/93 (4.3%) 4 3/58 (5.2%) 3 1/64 (1.6%) 1
    Paraesthesia 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Paralysis 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Parosmia 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Peripheral motor neuropathy 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Peripheral sensory neuropathy 56/96 (58.3%) 88 70/93 (75.3%) 120 8/58 (13.8%) 8 14/64 (21.9%) 14
    Somnolence 1/96 (1%) 2 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Tremor 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Psychiatric disorders
    Anxiety 2/96 (2.1%) 2 1/93 (1.1%) 1 1/58 (1.7%) 1 1/64 (1.6%) 1
    Delirium 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 2/64 (3.1%) 2
    Hallucination 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Insomnia 10/96 (10.4%) 10 10/93 (10.8%) 11 6/58 (10.3%) 6 4/64 (6.3%) 4
    Restlessness 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Chronic kidney disease 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Cystitis noninfective 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Dysuria 1/96 (1%) 1 3/93 (3.2%) 4 1/58 (1.7%) 1 0/64 (0%) 0
    Haematuria 5/96 (5.2%) 7 5/93 (5.4%) 5 0/58 (0%) 0 1/64 (1.6%) 2
    Hydronephrosis 3/96 (3.1%) 3 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Nephrolithiasis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Pollakiuria 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Proteinuria 25/96 (26%) 40 14/93 (15.1%) 25 6/58 (10.3%) 14 7/64 (10.9%) 10
    Ureteric stenosis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Ureterolithiasis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Urinary incontinence 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Urinary retention 1/96 (1%) 1 2/93 (2.2%) 3 0/58 (0%) 0 0/64 (0%) 0
    Urinary tract obstruction 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 1/57 (1.8%) 1 1/64 (1.6%) 1 0/58 (0%) 0 0/64 (0%) 0
    Oedema genital 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Penile oedema 1/57 (1.8%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Penile pain 1/57 (1.8%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Uterine haemorrhage 1/39 (2.6%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Vaginal haemorrhage 0/96 (0%) 0 1/29 (3.4%) 3 0/58 (0%) 0 0/64 (0%) 0
    Vulvovaginal inflammation 1/39 (2.6%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Atelectasis 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Bronchiectasis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Cough 7/96 (7.3%) 8 10/93 (10.8%) 12 3/58 (5.2%) 3 5/64 (7.8%) 5
    Dysphonia 4/96 (4.2%) 7 0/93 (0%) 0 1/58 (1.7%) 1 1/64 (1.6%) 1
    Dyspnoea 3/96 (3.1%) 3 3/93 (3.2%) 3 2/58 (3.4%) 2 2/64 (3.1%) 2
    Epistaxis 24/96 (25%) 34 6/93 (6.5%) 7 10/58 (17.2%) 10 14/64 (21.9%) 22
    Haemoptysis 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Hiccups 6/96 (6.3%) 11 5/93 (5.4%) 6 0/58 (0%) 0 0/64 (0%) 0
    Hypoxia 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Laryngeal inflammation 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Laryngeal pain 0/96 (0%) 0 2/93 (2.2%) 3 1/58 (1.7%) 1 1/64 (1.6%) 1
    Lung infiltration 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Nasal congestion 1/96 (1%) 1 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Oropharyngeal pain 2/96 (2.1%) 2 2/93 (2.2%) 2 0/58 (0%) 0 2/64 (3.1%) 2
    Pharyngeal haemorrhage 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Pharyngeal inflammation 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Pleural adhesion 1/96 (1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Pleural effusion 1/96 (1%) 1 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Pneumonitis 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Pneumothorax 0/96 (0%) 0 0/93 (0%) 0 2/58 (3.4%) 2 0/64 (0%) 0
    Productive cough 5/96 (5.2%) 5 8/93 (8.6%) 12 2/58 (3.4%) 2 2/64 (3.1%) 2
    Pulmonary embolism 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Rhinitis allergic 2/96 (2.1%) 3 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Rhinorrhoea 5/96 (5.2%) 5 2/93 (2.2%) 5 0/58 (0%) 0 0/64 (0%) 0
    Upper respiratory tract inflammation 2/96 (2.1%) 2 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Wheezing 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 1/64 (1.6%) 1
    Skin and subcutaneous tissue disorders
    Alopecia 10/96 (10.4%) 10 2/93 (2.2%) 2 26/58 (44.8%) 26 30/64 (46.9%) 30
    Cutaneous symptom 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Decubitus ulcer 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 3/64 (4.7%) 3
    Dermal cyst 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Dermatitis acneiform 1/96 (1%) 1 4/93 (4.3%) 4 1/58 (1.7%) 1 1/64 (1.6%) 1
    Dermatitis allergic 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Dermatitis bullous 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 2/64 (3.1%) 2
    Dermatitis contact 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Dry skin 10/96 (10.4%) 10 5/93 (5.4%) 5 2/58 (3.4%) 2 4/64 (6.3%) 4
    Eczema 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Erythema 1/96 (1%) 1 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Erythema multiforme 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Erythema nodosum 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Haemorrhage subcutaneous 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Hyperkeratosis 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Nail discolouration 0/96 (0%) 0 0/93 (0%) 0 3/58 (5.2%) 3 1/64 (1.6%) 1
    Nail disorder 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 1/64 (1.6%) 1
    Nail ridging 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Night sweats 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Onychomadesis 0/96 (0%) 0 1/93 (1.1%) 1 2/58 (3.4%) 2 0/64 (0%) 0
    Pain of skin 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 15/96 (15.6%) 16 7/93 (7.5%) 7 2/58 (3.4%) 2 1/64 (1.6%) 1
    Petechiae 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Pigmentation disorder 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Pruritus 9/96 (9.4%) 10 5/93 (5.4%) 7 3/58 (5.2%) 3 6/64 (9.4%) 6
    Purpura 0/96 (0%) 0 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Rash 2/96 (2.1%) 2 8/93 (8.6%) 10 1/58 (1.7%) 1 3/64 (4.7%) 3
    Rash maculo-papular 3/96 (3.1%) 3 0/93 (0%) 0 4/58 (6.9%) 4 1/64 (1.6%) 1
    Skin disorder 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Skin exfoliation 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Skin hyperpigmentation 17/96 (17.7%) 17 15/93 (16.1%) 15 0/58 (0%) 0 1/64 (1.6%) 1
    Skin induration 1/96 (1%) 1 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Skin lesion 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Skin ulcer 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Stasis dermatitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Urticaria 1/96 (1%) 1 0/93 (0%) 0 2/58 (3.4%) 2 0/64 (0%) 0
    Xeroderma 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Surgical and medical procedures
    Abdominal cavity drainage 2/96 (2.1%) 3 1/93 (1.1%) 1 2/58 (3.4%) 2 2/64 (3.1%) 3
    Bile duct stent insertion 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Cell-free and concentrated ascites reinfusion therapy 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Central venous catheterisation 0/96 (0%) 0 2/93 (2.2%) 2 0/58 (0%) 0 0/64 (0%) 0
    Cerebrospinal fluid reservoir placement 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Colostomy 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Gastroenterostomy 0/96 (0%) 0 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Gastrointestinal tube insertion 0/96 (0%) 0 2/93 (2.2%) 4 0/58 (0%) 0 0/64 (0%) 0
    Haematoma evacuation 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hysterosalpingo-oophorectomy 0/96 (0%) 0 1/29 (3.4%) 1 0/58 (0%) 0 0/64 (0%) 0
    Ileostomy 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Laparoscopic surgery 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Laparotomy 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Limb operation 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Nephrostomy 0/96 (0%) 0 0/93 (0%) 0 1/58 (1.7%) 1 0/64 (0%) 0
    Oesophageal dilation procedure 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Omental flap operation 0/96 (0%) 0 0/93 (0%) 0 2/58 (3.4%) 2 0/64 (0%) 0
    Omental implantation 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Salpingo-oophorectomy bilateral 0/96 (0%) 0 1/29 (3.4%) 1 0/58 (0%) 0 0/64 (0%) 0
    Small intestinal intussusception reduction 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Stent placement 2/96 (2.1%) 3 3/93 (3.2%) 3 1/58 (1.7%) 1 0/64 (0%) 0
    Suture insertion 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Thoracic cavity drainage 0/96 (0%) 0 1/93 (1.1%) 1 1/58 (1.7%) 1 0/64 (0%) 0
    Tooth extraction 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Tumour excision 0/96 (0%) 0 0/93 (0%) 0 0/58 (0%) 0 1/64 (1.6%) 1
    Ureteral stent insertion 3/96 (3.1%) 3 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Vascular disorders
    Embolism 0/96 (0%) 0 1/93 (1.1%) 1 2/58 (3.4%) 2 1/64 (1.6%) 1
    Embolism venous 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Flushing 0/96 (0%) 0 2/93 (2.2%) 3 0/58 (0%) 0 0/64 (0%) 0
    Haematoma 2/96 (2.1%) 2 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Haemorrhage 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hot flush 1/96 (1%) 1 0/93 (0%) 0 0/58 (0%) 0 0/64 (0%) 0
    Hypertension 28/96 (29.2%) 28 12/93 (12.9%) 13 1/58 (1.7%) 1 10/64 (15.6%) 11
    Hypotension 2/96 (2.1%) 2 4/93 (4.3%) 6 0/58 (0%) 0 0/64 (0%) 0
    Phlebitis 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Varicose vein 0/96 (0%) 0 1/93 (1.1%) 1 0/58 (0%) 0 0/64 (0%) 0
    Vascular pain 3/96 (3.1%) 7 3/93 (3.2%) 3 0/58 (0%) 0 0/64 (0%) 0
    Vasculitis 2/96 (2.1%) 2 4/93 (4.3%) 8 0/58 (0%) 0 1/64 (1.6%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email ClinicalTrials.gov@lilly.com
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT02539225
    Other Study ID Numbers:
    • 15461
    • I4T-JE-JVCW
    First Posted:
    Sep 2, 2015
    Last Update Posted:
    Mar 8, 2022
    Last Verified:
    Feb 1, 2022