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A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02711553
Collaborator
(none)
309
Enrollment
92
Locations
4
Arms
79.4
Anticipated Duration (Months)
3.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to evaluate the efficacy and safety of ramucirumab or merestinib or placebo plus cisplatin and gemcitabine in participants with advanced or metastatic biliary tract cancer.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
309 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo Plus Cisplatin and Gemcitabine as First-Line Treatment in Patients With Advanced or Metastatic Biliary Tract Cancer
Actual Study Start Date :
May 19, 2016
Actual Primary Completion Date :
Feb 16, 2018
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).

Drug: Ramucirumab
Administered IV
Other Names:
  • LY3009806

    • Drug: Cisplatin
    Administered IV

    Drug: Gemcitabine
    Administered IV
    Other Names:
  • LY188011

    		•
    Placebo Comparator: Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

    Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).

    Drug: Cisplatin
    Administered IV

    Drug: Gemcitabine
    Administered IV
    Other Names:
  • LY188011

    • Drug: Placebo IV
    Administered IV
    Experimental: 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

    Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).

    Drug: Merestinib
    Administered orally
    Other Names:
  • LY2801653

    • Drug: Cisplatin
    Administered IV

    Drug: Gemcitabine
    Administered IV
    Other Names:
  • LY188011

    		•
    Placebo Comparator: Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

    Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).

    Drug: Cisplatin
    Administered IV

    Drug: Gemcitabine
    Administered IV
    Other Names:
  • LY188011

    • Drug: Placebo Oral
    Administered orally

    Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival (PFS) [Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months)]

      PFS time was measured from the date of randomization until the first radiographic documentation of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was 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. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.

    Secondary Outcome Measures

    1. Overall Survival (OS) [Randomization to Date of Death from Any Cause (Up To 48 Months)]

      OS defined as the time from from randomization to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.

    2. Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [Randomization to Disease Progression (Up To 30 Months)]

      ORR was the number of participants who achieve a best overall response of CR or PR divided by the total number of participants randomized to the corresponding treatment arm as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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 longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. 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.

    3. Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) [Randomization to Disease Progression (Up To 30 Months)]

      Disease Control Rate (DCR) was the number of participants who achieve a best overall response of CR, PR, or SD divided by the total number of participants randomized to the corresponding treatment arm as per RECIST v1.1. 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. 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.

    4. Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [C1 D8, C2 D1, C3 D1, C4 D1,C5 D1,C7 D1, C9 D1 and C13 D1: Within 3 days Prior to Infusion(PTI)]

      PK was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D).

    5. PK: Plasma Concentration of Merestinib [C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning]

      PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced.

    6. Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies [Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months)]

      Number of participants with positive treatment emergent anti-ramucirumab antibodies (ADA) was summarized by treatment group.

    7. Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) [Baseline, Follow Up (Up To 48 Months)]

      FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72. The Trial Outcomes Index (TOI) is the sum of the PWB, FWB and Hep subscales with a scores range of 0 to 128. The Total FACT-Hep score was the sum of all questions with a scores range of 0 to 180.Total FACT-G score was the sum of the 27 questions in the PWB, SFWB, EWB and FWB with a scores range of 0 to 108. The FACT-Hep Symptoms Index with 8 key questions and scores range of 0 to 32 from the Hep Subscale. Higher score in sub-score or total score indicates better QOL and better health state. Participants were classified as "Improved" if they had positive change from baseline, "Worsened" if they had negative change from baseline, and "Stable" otherwise.

    8. Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [Baseline, Follow Up (Up To 48 Months)]

      EQ-5D-5L is a 2-part questionnaire that assesses general health status for 'today'. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using country-specific algorithms, with scores ranging from less than 0 (where zero is a health state equivalent to death; negative values are valued as worse than dead) to 1 (perfect health). Index values were calculated using the US algorithm (-0.109 to 1). A higher score indicates better health state.

    9. Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score [Baseline, Follow Up (Up To 48 Months)]

      EQ-5D-5L is a 2-part questionnaire that assesses general health status 'today'. The second part is assessed using a VAS on which the patient rates their perceived health state, ranging from 0 (the worst health you can imagine) to 100 (the best health you can imagine).

    Eligibility Criteria

    Criteria

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

    • Have an Eastern Cooperative Oncology Group performance status of 0 or 1.

    • Have a histologically or cytologically confirmed diagnosis of non-resectable, recurrent, or metastatic biliary tract adenocarcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or Ampulla of Vater) .

    • Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).

    • Have adequate biliary drainage.

    • Have adequate organ function.

    • Males and females are sterile, postmenopausal, or compliant with a highly effective contraceptive method.

    • Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose.

    • Are willing to provide blood/serum/plasma and tumor tissue samples for research purposes. Submission of blood/serum/plasma and tumor tissue samples is mandatory for participation in this study, unless restricted per local regulations.

    Exclusion Criteria:

    • Previous systemic therapy for locally advanced or metastatic disease is not allowed.

    • Have a history of or have current hepatic encephalopathy of any grade, or ascites of Grade >1, or cirrhosis with Child-Pugh Stage B or higher.

    • Have ongoing or recent (≤6 months) hepatorenal syndrome.

    • Have had a major surgical procedure or significant traumatic injury including nonhealing wound, peptic ulcer, or bone fracture ≤28 days prior to randomization.

    • Anticipate having a major surgical procedure during the course of the study.

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

    • Within 6 months prior to randomization, have had any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.

    • Have an uncontrolled arterial hypertension with systolic blood pressure ≥150 or diastolic blood pressure ≥90 millimeters of mercury (mm Hg) despite standard medical management.

    • Have a previous malignancy within 5 years of study entry or a concurrent malignancy.

    • Have a history of gastrointestinal perforation and/or fistulae within 6 months prior to randomization.

    • Have a known allergy or hypersensitivity reaction to any of the treatment components.

    • Have a history of uncontrolled hereditary or acquired thrombotic disorder.

    • Have uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain.

    • Have mixed hepatocellular biliary tract cancer histology.

    • Have a corrected QT interval >470 milliseconds as calculated by the Fridericia equation.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arizona Cancer Center Tucson Arizona United States 85724
    2 USC Norris Cancer Hospital Los Angeles California United States 90003
    3 USC Norris Cancer Hospital Los Angeles California United States 90033
    4 University of California, San Francisco San Francisco California United States 94143
    5 Georgetown University Medical Center Washington District of Columbia United States 20007
    6 Florida Cancer Specialists Fort Myers Florida United States 33916
    7 University of Southern Florida School of Medicine Gainesville Florida United States 33612
    8 Florida Cancer Specialists Saint Petersburg Florida United States 33705
    9 Loyola University Medical Center Maywood Illinois United States 60153
    10 Karmanos Cancer Institute Detroit Michigan United States 48201
    11 Washington University Medical Center Saint Louis Missouri United States 63110
    12 SUNY At Stony Brook Stony Brook New York United States 11794
    13 Thomas Jefferson University Philadelphia Pennsylvania United States 19107
    14 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111-2497
    15 Hasbro Children's Hospital Providence Rhode Island United States 02903
    16 Sarah Cannon Cancer Center Nashville Tennessee United States 37203
    17 Tennessee Oncology PLLC Nashville Tennessee United States 37203
    18 Vanderbilt University Medical Center Nashville Tennessee United States 37232
    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. Buenos Aires Argentina 1426
    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. Capital Federal Argentina C1264AAA
    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. Ciudad de Buenos Aires Argentina 1093
    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. La Rioja Argentina 5300
    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. San Juan Argentina J5402DIL
    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. San Miguel de Tucumán Argentina T4000IAK
    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. San Salvador de Jujuy Argentina Y4600APW
    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. Viedma Argentina 8500
    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. Adelaide Australia 5000
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    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. Heidelberg Australia 3084
    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. Newcastle Australia Newcastle
    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. Salzburg Austria 5020
    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. Wiener Neustadt Austria 2700
    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. Wien Austria 1020
    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. Brussels Belgium 1200
    35 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. Gent Belgium 9000
    36 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. Leuven Belgium 3000
    37 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. Liege Belgium 4000
    38 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. Brno Czechia 656 53
    39 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. Hradec Kralove Czechia 500 05
    40 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. Praha 5 Czechia 150 06
    41 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. Aarhus C Denmark 8000
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    43 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. Besancon Cedex France 25030
    44 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. Bordeaux Cedex France 33000
    45 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. Lille France 59037
    46 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. Lyon Cedex 08 France 69373
    47 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. Montpellier Cedex 5 France 34295
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    50 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. Strasbourg France 67000
    51 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. Villejuif Cedex France 94805
    52 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. Berlin Germany 13125
    53 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. Erlangen Germany 91054
    54 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. Hamburg Germany 20246
    55 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. Hannover Germany 30625
    56 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. Tübingen Germany 72076
    57 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. Ulm Germany 89081
    58 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. Budapest Hungary 1097
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    60 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 277 8577
    61 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. Tokyo Japan 104-0045
    62 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
    63 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
    64 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
    65 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
    66 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. Mexico City Mexico 14080
    67 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. Mexico Mexico 06700
    68 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. San Luis Potosi Mexico 78213
    69 Arkhangelsk Regional Clinical Oncology Dispensary Arkhangelsk Russian Federation 163045
    70 Blokhin Cancer Research Center Moscow Russian Federation 115478
    71 Central Roentgenoradiological Research Institute MZ RF St. Petersburg Russian Federation 197758
    72 Hospital Clínico Universitario de Valencia Barcelona Spain 46010
    73 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. Hospitalet De Llobregat Spain 08908
    74 Hospital 12 De Octubre Madrid Spain 28041
    75 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. Danderyd Sweden 182 88
    76 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. Lund Sweden 22185
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    78 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
    79 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
    80 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
    81 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. Taoyuan City Taiwan 33305
    82 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. Adana Turkey 1250
    83 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. Ankara Turkey 06100
    84 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. Antalya Turkey 07059
    85 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. Edirne Turkey 22030
    86 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. Istanbul Turkey 34098
    87 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. Acton United Kingdom W12 0HS
    88 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. London United Kingdom NW1 2BU
    89 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. London United Kingdom SE1 9RT
    90 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. Manchester United Kingdom M20 4BX
    91 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. Merseyside United Kingdom CH63 4JY
    92 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. Sutton United Kingdom SM2 5PT

    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:
    NCT02711553
    Other Study ID Numbers:
    • 16329
    • I3O-MC-JSBF
    • 2015-004699-31
    First Posted:
    Mar 17, 2016
    Last Update Posted:
    Oct 1, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Biliary Tract Neoplasms
    Gemcitabine
    Ramucirumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail In the Participant Flow, participants who completed were those who died due to any cause or were alive and on study at conclusion but off treatment.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Period Title: Overall Study
    STARTED 106 52 102 49
    Received at Least 1 Dose of Study Drug 104 52 102 48
    COMPLETED 100 47 92 45
    NOT COMPLETED 6 5 10 4

    Baseline Characteristics

    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Total
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). Total of all reporting groups
    Overall Participants 106 52 102 49 309
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    63.49
    (9.76)
    57.06
    (11.67)
    60.95
    (9.14)
    62.00
    (9.14)
    61.33
    (10.01)
    Sex: Female, Male (Count of Participants)
    Female
    60
    56.6%
    26
    50%
    54
    52.9%
    22
    44.9%
    162
    52.4%
    Male
    46
    43.4%
    26
    50%
    48
    47.1%
    27
    55.1%
    147
    47.6%
    Female
    59
    55.7%
    26
    50%
    54
    52.9%
    21
    42.9%
    160
    51.8%
    Male
    45
    42.5%
    26
    50%
    48
    47.1%
    27
    55.1%
    146
    47.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    106
    100%
    52
    100%
    102
    100%
    49
    100%
    309
    100%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    1
    1%
    0
    0%
    1
    0.3%
    Asian
    20
    18.9%
    11
    21.2%
    26
    25.5%
    9
    18.4%
    66
    21.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    0.9%
    1
    1.9%
    1
    1%
    1
    2%
    4
    1.3%
    White
    78
    73.6%
    35
    67.3%
    70
    68.6%
    38
    77.6%
    221
    71.5%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    7
    6.6%
    5
    9.6%
    4
    3.9%
    1
    2%
    17
    5.5%
    Region of Enrollment (Count of Participants)
    Argentina
    11
    10.4%
    3
    5.8%
    8
    7.8%
    3
    6.1%
    25
    8.1%
    Hungary
    5
    4.7%
    7
    13.5%
    4
    3.9%
    1
    2%
    17
    5.5%
    United States
    12
    11.3%
    3
    5.8%
    6
    5.9%
    4
    8.2%
    25
    8.1%
    Czechia
    2
    1.9%
    2
    3.8%
    5
    4.9%
    2
    4.1%
    11
    3.6%
    United Kingdom
    4
    3.8%
    2
    3.8%
    5
    4.9%
    3
    6.1%
    14
    4.5%
    Russia
    9
    8.5%
    2
    3.8%
    4
    3.9%
    6
    12.2%
    21
    6.8%
    Spain
    8
    7.5%
    3
    5.8%
    10
    9.8%
    1
    2%
    22
    7.1%
    Austria
    3
    2.8%
    2
    3.8%
    1
    1%
    0
    0%
    6
    1.9%
    South Korea
    8
    7.5%
    6
    11.5%
    12
    11.8%
    4
    8.2%
    30
    9.7%
    Sweden
    1
    0.9%
    0
    0%
    3
    2.9%
    2
    4.1%
    6
    1.9%
    Turkey
    6
    5.7%
    7
    13.5%
    7
    6.9%
    3
    6.1%
    23
    7.4%
    Belgium
    6
    5.7%
    1
    1.9%
    3
    2.9%
    4
    8.2%
    14
    4.5%
    Taiwan
    9
    8.5%
    5
    9.6%
    13
    12.7%
    4
    8.2%
    31
    10%
    Denmark
    1
    0.9%
    1
    1.9%
    3
    2.9%
    1
    2%
    6
    1.9%
    Mexico
    4
    3.8%
    0
    0%
    3
    2.9%
    0
    0%
    7
    2.3%
    Australia
    6
    5.7%
    2
    3.8%
    2
    2%
    4
    8.2%
    14
    4.5%
    France
    8
    7.5%
    5
    9.6%
    5
    4.9%
    2
    4.1%
    20
    6.5%
    Germany
    3
    2.8%
    1
    1.9%
    8
    7.8%
    5
    10.2%
    17
    5.5%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival (PFS)
    Description PFS time was measured from the date of randomization until the first radiographic documentation of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was 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. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
    Time Frame Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants. Censored participants: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 29; 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 34; Pooled Placebo = 25. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Pooled Placebo
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 106 102 101
    Median (Inter-Quartile Range) [Months]
    6.47
    6.97
    6.64
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4821
    Comments p-value is 2-sided.
    Method Log Rank
    Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.123
    Confidence Interval (2-Sided) 80%
    0.904 to 1.395
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6417
    Comments p-value is 2-sided.
    Method Log Rank
    Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.920
    Confidence Interval (2-Sided) 80%
    0.734 to 1.153
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    2. Secondary Outcome
    Title Overall Survival (OS)
    Description OS defined as the time from from randomization to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.
    Time Frame Randomization to Date of Death from Any Cause (Up To 48 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants. Censored participants: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 29; 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 34; Pooled Placebo = 25. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Pooled Placebo
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 106 102 101
    Median (Inter-Quartile Range) [Months]
    10.45
    14.03
    13.04
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0870
    Comments
    Method Log Rank
    Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.336
    Confidence Interval (2-Sided) 95%
    0.959 to 1.862
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7599
    Comments
    Method Log Rank
    Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.948
    Confidence Interval (2-Sided) 95%
    0.669 to 1.342
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
    3. Secondary Outcome
    Title Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
    Description ORR was the number of participants who achieve a best overall response of CR or PR divided by the total number of participants randomized to the corresponding treatment arm as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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 longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. 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.
    Time Frame Randomization to Disease Progression (Up To 30 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Pooled Placebo
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 106 102 101
    Number (95% Confidence Interval) [Percentage of participants]
    31.1
    29.3%
    19.6
    37.7%
    32.7
    32.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.878
    Comments
    Method Exact Cochran-Mantel-Haenszel
    Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.0
    Confidence Interval (2-Sided) 95%
    0.6 to 1.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method Exact Cochran-Mantel-Haenszel
    Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.5
    Confidence Interval (2-Sided) 95%
    0.2 to 0.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    4. Secondary Outcome
    Title Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)
    Description Disease Control Rate (DCR) was the number of participants who achieve a best overall response of CR, PR, or SD divided by the total number of participants randomized to the corresponding treatment arm as per RECIST v1.1. 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. 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.
    Time Frame Randomization to Disease Progression (Up To 30 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Pooled Placebo
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 106 102 101
    Number (95% Confidence Interval) [Percentage of participants]
    81.1
    76.5%
    83.3
    160.2%
    78.2
    76.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.680
    Comments
    Method Exact Cochran-Mantel-Haenszel
    Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.2
    Confidence Interval (2-Sided) 95%
    0.6 to 2.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.499
    Comments
    Method Exact Cochran-Mantel-Haenszel
    Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.3
    Confidence Interval (2-Sided) 95%
    0.6 to 2.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
    5. Secondary Outcome
    Title Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab
    Description PK was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D).
    Time Frame C1 D8, C2 D1, C3 D1, C4 D1,C5 D1,C7 D1, C9 D1 and C13 D1: Within 3 days Prior to Infusion(PTI)

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study drug and had evaluable PK data. As per protocol, Cmin of merestinib was not measured.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).
    Measure Participants 86
    Cycle 1 Day 8 (Week 1)
    46.2
    (32)
    Cycle 2 Day 1 (Week 3)
    38.1
    (42)
    Cycle 3 Day 1 (Week 6)
    54.1
    (43)
    Cycle 4 Day 1 (Week 9)
    77.3
    (50)
    Cycle 5 Day 1 (Week 12)
    82.9
    (35)
    Cycle 7 Day 1 (Week 18)
    85.6
    (39)
    Cycle 9 Day 1 (Week 24)
    82.7
    (35)
    Cycle 13 Day 1 (Week 36)
    97.7
    (23)
    6. Secondary Outcome
    Title PK: Plasma Concentration of Merestinib
    Description PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced.
    Time Frame C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning

    Outcome Measure Data

    Analysis Population Description
    Zero participants were analyzed as no data collected for summary analysis.
    Arm/Group Title 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Arm/Group Description Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).
    Measure Participants 0
    7. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies
    Description Number of participants with positive treatment emergent anti-ramucirumab antibodies (ADA) was summarized by treatment group.
    Time Frame Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study drug with both baseline and at least one post baseline ADA assessments.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 74 37
    Count of Participants [Participants]
    3
    2.8%
    0
    0%
    8. Secondary Outcome
    Title Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep)
    Description FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72. The Trial Outcomes Index (TOI) is the sum of the PWB, FWB and Hep subscales with a scores range of 0 to 128. The Total FACT-Hep score was the sum of all questions with a scores range of 0 to 180.Total FACT-G score was the sum of the 27 questions in the PWB, SFWB, EWB and FWB with a scores range of 0 to 108. The FACT-Hep Symptoms Index with 8 key questions and scores range of 0 to 32 from the Hep Subscale. Higher score in sub-score or total score indicates better QOL and better health state. Participants were classified as "Improved" if they had positive change from baseline, "Worsened" if they had negative change from baseline, and "Stable" otherwise.
    Time Frame Baseline, Follow Up (Up To 48 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study drug with baseline and one post-baseline FACT-Hep Questionnaire.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Pooled Placebo
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 97 95 95
    PWB
    -2.75
    (0.43)
    -2.88
    (0.43)
    -1.65
    (0.42)
    SWB
    -0.26
    (0.36)
    0.22
    (0.36)
    0.56
    (0.36)
    EWB
    0.23
    (0.31)
    0.64
    (0.32)
    0.93
    (0.31)
    FWB
    -2.40
    (0.44)
    -1.34
    (0.44)
    -0.75
    (0.44)
    HCS
    -3.62
    (0.63)
    -2.32
    (0.64)
    -0.68
    (0.63)
    FACT-Hep
    -1.11
    (0.37)
    -0.74
    (0.37)
    -0.09
    (0.37)
    TOI
    -8.68
    (1.31)
    -6.43
    (1.32)
    -3.01
    (1.30)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments PWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.069
    Comments p-values are from Type 3 sums of squares mixed model repeated measures (MMRM) Model.
    Method MMRM Model
    Comments Least Squares (LS) Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.10
    Confidence Interval (2-Sided) 95%
    -2.28 to 0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.60
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments PWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.042
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.23
    Confidence Interval (2-Sided) 95%
    -2.42 to -0.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.60
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Comments SWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.112
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.82
    Confidence Interval (2-Sided) 95%
    -1.83 to 0.19
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.51
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments SWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.505
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.34
    Confidence Interval (2-Sided) 95%
    -1.35 to 0.67
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.51
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments EWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.116
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.70
    Confidence Interval (2-Sided) 95%
    -1.56 to 0.17
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.44
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments EWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.521
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.29
    Confidence Interval (2-Sided) 95%
    -1.16 to 0.59
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.45
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments FWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.008
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.66
    Confidence Interval (2-Sided) 95%
    -2.87 to -0.44
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.62
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments FWB
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.335
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.60
    Confidence Interval (2-Sided) 95%
    -1.82 to 0.62
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.62
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments HCS
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -2.93
    Confidence Interval (2-Sided) 95%
    -4.69 to -1.18
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.89
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments HCS
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.068
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.64
    Confidence Interval (2-Sided) 95%
    -3.40 to 0.12
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.89
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments FACT-Hep
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.051
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.02
    Confidence Interval (2-Sided) 95%
    -2.04 to 0.00
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.52
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments FACT-Hep
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.212
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.65
    Confidence Interval (2-Sided) 95%
    -1.68 to 0.38
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.52
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments TOI
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -5.67
    Confidence Interval (2-Sided) 95%
    -9.30 to -2.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.84
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
    Comments TOI
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.066
    Comments p-values are from type 3 sums of squares MMRM model.
    Method MMRM Model
    Comments LS Mean value was adjusted for treatment, visit, baseline, treatment*visit and baseline*visit.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -3.42
    Confidence Interval (2-Sided) 95%
    -7.07 to 0.22
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.85
    Estimation Comments
    9. Secondary Outcome
    Title Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
    Description EQ-5D-5L is a 2-part questionnaire that assesses general health status for 'today'. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using country-specific algorithms, with scores ranging from less than 0 (where zero is a health state equivalent to death; negative values are valued as worse than dead) to 1 (perfect health). Index values were calculated using the US algorithm (-0.109 to 1). A higher score indicates better health state.
    Time Frame Baseline, Follow Up (Up To 48 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Pooled Placebo
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 45 42 40
    Mean (Standard Deviation) [Units on a Scale]
    0.61
    (0.31)
    0.63
    (0.29)
    0.66
    (0.27)
    10. Secondary Outcome
    Title Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score
    Description EQ-5D-5L is a 2-part questionnaire that assesses general health status 'today'. The second part is assessed using a VAS on which the patient rates their perceived health state, ranging from 0 (the worst health you can imagine) to 100 (the best health you can imagine).
    Time Frame Baseline, Follow Up (Up To 48 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Pooled Placebo
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    Measure Participants 45 42 40
    Mean (Standard Deviation) [millimeter (mm)]
    66.44
    (22.8)
    66.57
    (21.73)
    69.08
    (20.03)

    Adverse Events

    Time Frame Randomization Up To 48 Months
    Adverse Event Reporting Description All randomized participants who received at least 1 dose of study drug.
    Arm/Group Title 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Arm/Group Description Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
    All Cause Mortality
    8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 84/104 (80.8%) 34/52 (65.4%) 71/102 (69.6%) 38/48 (79.2%)
    Serious Adverse Events
    8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 53/104 (51%) 25/52 (48.1%) 56/102 (54.9%) 23/48 (47.9%)
    Blood and lymphatic system disorders
    Anemia 3/104 (2.9%) 3 2/52 (3.8%) 2 2/102 (2%) 2 1/48 (2.1%) 1
    Disseminated intravascular coagulation 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Febrile neutropenia 1/104 (1%) 1 2/52 (3.8%) 2 1/102 (1%) 1 2/48 (4.2%) 2
    Neutropenia 3/104 (2.9%) 3 1/52 (1.9%) 1 5/102 (4.9%) 5 0/48 (0%) 0
    Pancytopenia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Thrombocytopenia 6/104 (5.8%) 7 3/52 (5.8%) 3 2/102 (2%) 2 3/48 (6.3%) 3
    Cardiac disorders
    Acute coronary syndrome 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Atrial fibrillation 0/104 (0%) 0 3/52 (5.8%) 3 0/102 (0%) 0 0/48 (0%) 0
    Atrial flutter 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Atrioventricular block complete 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Cardiac arrest 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Cardiac failure 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Myocardial infarction 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Supraventricular tachycardia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Tachycardia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Congenital, familial and genetic disorders
    Pyloric stenosis 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Ear and labyrinth disorders
    Hypoacusis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Vertigo 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Vestibular disorder 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Eye disorders
    Blindness unilateral 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Optic ischaemic neuropathy 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Abdominal pain 2/104 (1.9%) 2 2/52 (3.8%) 2 4/102 (3.9%) 5 0/48 (0%) 0
    Anastomotic ulcer perforation 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Ascites 3/104 (2.9%) 4 0/52 (0%) 0 2/102 (2%) 2 2/48 (4.2%) 3
    Constipation 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Diarrhoea 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Duodenal ulcer 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Duodenal ulcer haemorrhage 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Gastric haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Gastritis erosive 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Gastrooesophageal reflux disease 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Haematemesis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Ileus 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Impaired gastric emptying 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Inguinal hernia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Intestinal obstruction 2/104 (1.9%) 2 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Intestinal perforation 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Mesenteric vein thrombosis 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Nausea 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 3 0/48 (0%) 0
    Obstruction gastric 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Oesophageal ulcer 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Oesophageal varices haemorrhage 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Rectal haemorrhage 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Stomatitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Upper gastrointestinal haemorrhage 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Vomiting 3/104 (2.9%) 4 1/52 (1.9%) 1 4/102 (3.9%) 5 1/48 (2.1%) 1
    General disorders
    Catheter site extravasation 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Death 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Device related thrombosis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Fatigue 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    General physical health deterioration 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Implant site haemorrhage 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Localised oedema 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Multiple organ dysfunction syndrome 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Non-cardiac chest pain 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Oedema peripheral 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Pyrexia 5/104 (4.8%) 9 1/52 (1.9%) 1 4/102 (3.9%) 5 2/48 (4.2%) 4
    Sudden death 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hepatobiliary disorders
    Bile duct obstruction 0/104 (0%) 0 1/52 (1.9%) 1 2/102 (2%) 2 0/48 (0%) 0
    Bile duct stenosis 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Cholangitis 5/104 (4.8%) 7 0/52 (0%) 0 2/102 (2%) 2 1/48 (2.1%) 1
    Cholangitis acute 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Cholecystitis 0/104 (0%) 0 1/52 (1.9%) 2 0/102 (0%) 0 0/48 (0%) 0
    Hyperbilirubinaemia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Hypertransaminasaemia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Jaundice cholestatic 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 2/48 (4.2%) 2
    Portal vein thrombosis 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Venoocclusive liver disease 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Infections and infestations
    Abdominal infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Appendicitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Arthritis bacterial 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Bacteraemia 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Biliary tract infection 3/104 (2.9%) 6 1/52 (1.9%) 1 2/102 (2%) 3 1/48 (2.1%) 1
    Bronchitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Cellulitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Cholangitis infective 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Cholecystitis infective 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Clostridium difficile colitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Device related infection 2/104 (1.9%) 2 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Escherichia bacteraemia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hepatic infection 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Infection 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Influenza 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Klebsiella bacteraemia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Large intestine infection 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Liver abscess 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 1/48 (2.1%) 1
    Lower respiratory tract infection viral 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Lung infection 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Meningitis meningococcal 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Parotitis 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Peritonitis bacterial 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Pneumonia 1/104 (1%) 1 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 2
    Respiratory tract infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Respiratory tract infection viral 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Sepsis 4/104 (3.8%) 5 1/52 (1.9%) 2 4/102 (3.9%) 6 1/48 (2.1%) 1
    Septic shock 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Upper respiratory tract infection 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Urinary tract infection 2/104 (1.9%) 2 1/52 (1.9%) 1 2/102 (2%) 2 0/48 (0%) 0
    Urosepsis 1/104 (1%) 1 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Injury, poisoning and procedural complications
    Infusion related reaction 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Post procedural haemorrhage 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Procedural haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Blood bilirubin increased 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Blood creatinine increased 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    C-reactive protein increased 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dehydration 2/104 (1.9%) 2 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Hypercalcaemia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Hyperkalaemia 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Hypoglycaemia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hypokalaemia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hypomagnesaemia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Hyponatraemia 1/104 (1%) 1 1/52 (1.9%) 1 2/102 (2%) 2 1/48 (2.1%) 1
    Hypoproteinaemia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthritis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Back pain 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Bursitis 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Musculoskeletal pain 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Neck pain 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Pain in extremity 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Nervous system disorders
    Cerebral ischaemia 0/104 (0%) 0 1/52 (1.9%) 1 2/102 (2%) 2 0/48 (0%) 0
    Depressed level of consciousness 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Haemorrhage intracranial 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hemiparesis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Ischaemic stroke 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Posterior reversible encephalopathy syndrome 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Seizure 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Spinal cord compression 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Transient ischaemic attack 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Product Issues
    Device occlusion 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Stent malfunction 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Psychiatric disorders
    Confusional state 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Delirium 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Renal and urinary disorders
    Acute kidney injury 2/104 (1.9%) 2 0/52 (0%) 0 3/102 (2.9%) 3 2/48 (4.2%) 2
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Chronic obstructive pulmonary disease 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Dyspnoea 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 1/48 (2.1%) 1
    Dyspnoea exertional 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hypoxia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Pneumothorax 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Pulmonary embolism 3/104 (2.9%) 3 0/52 (0%) 0 5/102 (4.9%) 5 1/48 (2.1%) 1
    Pulmonary fibrosis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Skin and subcutaneous tissue disorders
    Dermal cyst 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Rash 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Rash generalised 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Vascular disorders
    Deep vein thrombosis 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Embolism venous 1/104 (1%) 1 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Peripheral arterial occlusive disease 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Peripheral embolism 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Venous thrombosis 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Other (Not Including Serious) Adverse Events
    8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 102/104 (98.1%) 49/52 (94.2%) 100/102 (98%) 48/48 (100%)
    Blood and lymphatic system disorders
    Anemia 52/104 (50%) 94 22/52 (42.3%) 39 40/102 (39.2%) 80 24/48 (50%) 33
    Coagulopathy 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Febrile neutropenia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Haemolytic uraemic syndrome 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Iron deficiency anaemia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Leukocytosis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Leukopenia 20/104 (19.2%) 45 9/52 (17.3%) 23 20/102 (19.6%) 46 4/48 (8.3%) 15
    Lymphopenia 3/104 (2.9%) 4 2/52 (3.8%) 3 2/102 (2%) 3 2/48 (4.2%) 5
    Neutropenia 63/104 (60.6%) 160 24/52 (46.2%) 63 52/102 (51%) 122 19/48 (39.6%) 60
    Spleen disorder 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Thrombocytopenia 56/104 (53.8%) 120 15/52 (28.8%) 31 42/102 (41.2%) 80 15/48 (31.3%) 33
    Thrombocytopenic purpura 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Thrombocytosis 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Cardiac disorders
    Angina pectoris 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Atrial fibrillation 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Atrial flutter 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Bradycardia 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Cardiac failure 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Cardiac failure congestive 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Coronary artery disease 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Palpitations 2/104 (1.9%) 2 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 1
    Sinus bradycardia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Sinus tachycardia 3/104 (2.9%) 4 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Tachycardia 2/104 (1.9%) 2 2/52 (3.8%) 2 2/102 (2%) 2 1/48 (2.1%) 1
    Ventricular arrhythmia 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Congenital, familial and genetic disorders
    Atrial septal defect 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hydrocele 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Pyloric stenosis 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Ear and labyrinth disorders
    Deafness 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Ear pain 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hypoacusis 1/104 (1%) 1 1/52 (1.9%) 1 1/102 (1%) 1 2/48 (4.2%) 2
    Presbyacusis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Tinnitus 5/104 (4.8%) 5 2/52 (3.8%) 2 2/102 (2%) 2 1/48 (2.1%) 1
    Vertigo 2/104 (1.9%) 2 1/52 (1.9%) 1 2/102 (2%) 2 3/48 (6.3%) 3
    Endocrine disorders
    Cushingoid 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Endocrine disorder 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hyperparathyroidism 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hyperthyroidism 0/104 (0%) 0 1/52 (1.9%) 3 0/102 (0%) 0 1/48 (2.1%) 1
    Hypothyroidism 2/104 (1.9%) 3 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Inappropriate antidiuretic hormone secretion 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Eye disorders
    Conjunctival haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Diplopia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dry eye 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Eye irritation 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Eye pruritus 0/104 (0%) 0 1/52 (1.9%) 2 0/102 (0%) 0 0/48 (0%) 0
    Eyelid irritation 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Eyelid oedema 3/104 (2.9%) 3 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Lacrimation increased 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Ocular hyperaemia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Optic neuropathy 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Periorbital oedema 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Vision blurred 4/104 (3.8%) 7 0/52 (0%) 0 3/102 (2.9%) 5 0/48 (0%) 0
    Visual acuity reduced 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Visual impairment 0/104 (0%) 0 1/52 (1.9%) 2 0/102 (0%) 0 0/48 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 2
    Abdominal distension 10/104 (9.6%) 13 2/52 (3.8%) 2 14/102 (13.7%) 15 2/48 (4.2%) 2
    Abdominal pain 39/104 (37.5%) 54 13/52 (25%) 27 33/102 (32.4%) 47 15/48 (31.3%) 26
    Abdominal rigidity 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Aerophagia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 3 0/48 (0%) 0
    Anal fissure 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Ascites 13/104 (12.5%) 13 2/52 (3.8%) 2 10/102 (9.8%) 11 1/48 (2.1%) 1
    Cheilitis 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Constipation 33/104 (31.7%) 49 14/52 (26.9%) 23 36/102 (35.3%) 59 13/48 (27.1%) 16
    Defaecation urgency 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dental caries 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Diarrhoea 34/104 (32.7%) 50 9/52 (17.3%) 10 29/102 (28.4%) 36 7/48 (14.6%) 13
    Dry mouth 5/104 (4.8%) 11 1/52 (1.9%) 1 2/102 (2%) 2 1/48 (2.1%) 1
    Dyspepsia 5/104 (4.8%) 8 2/52 (3.8%) 6 4/102 (3.9%) 5 4/48 (8.3%) 6
    Dysphagia 0/104 (0%) 0 0/52 (0%) 0 4/102 (3.9%) 4 0/48 (0%) 0
    Epigastric discomfort 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Faeces discoloured 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Flatulence 3/104 (2.9%) 3 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Food poisoning 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Gastric haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Gastric ulcer 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Gastritis 0/104 (0%) 0 0/52 (0%) 0 3/102 (2.9%) 3 1/48 (2.1%) 1
    Gastritis erosive 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Gastroduodenal haemorrhage 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Gastrooesophageal reflux disease 2/104 (1.9%) 2 0/52 (0%) 0 4/102 (3.9%) 5 1/48 (2.1%) 1
    Gingival bleeding 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Gingival pain 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Haematochezia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 2/48 (4.2%) 2
    Haemorrhoidal haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Haemorrhoids 4/104 (3.8%) 4 1/52 (1.9%) 1 4/102 (3.9%) 4 2/48 (4.2%) 2
    Ileus 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 2 0/48 (0%) 0
    Ileus paralytic 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Impaired gastric emptying 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Inguinal hernia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 2 0/48 (0%) 0
    Intestinal obstruction 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Intra-abdominal haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Large intestinal haemorrhage 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Melaena 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Mouth ulceration 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Nausea 52/104 (50%) 92 21/52 (40.4%) 39 58/102 (56.9%) 97 15/48 (31.3%) 24
    Obstruction gastric 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Odynophagia 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Oesophageal varices haemorrhage 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 3 0/48 (0%) 0
    Oral dysaesthesia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Oral pain 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Pancreatic failure 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Pancreatitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Periodontal disease 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Proctalgia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Rectal haemorrhage 1/104 (1%) 2 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Reflux gastritis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Regurgitation 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 3
    Salivary hypersecretion 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Stomatitis 11/104 (10.6%) 15 5/52 (9.6%) 7 4/102 (3.9%) 6 2/48 (4.2%) 2
    Toothache 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Upper gastrointestinal haemorrhage 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Vomiting 34/104 (32.7%) 130 12/52 (23.1%) 18 34/102 (33.3%) 93 12/48 (25%) 26
    General disorders
    Catheter site pain 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Chest discomfort 2/104 (1.9%) 2 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Chest pain 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Chills 8/104 (7.7%) 18 1/52 (1.9%) 1 5/102 (4.9%) 8 2/48 (4.2%) 2
    Device related thrombosis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Early satiety 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Face oedema 5/104 (4.8%) 7 1/52 (1.9%) 1 7/102 (6.9%) 10 2/48 (4.2%) 2
    Fatigue 61/104 (58.7%) 94 17/52 (32.7%) 22 53/102 (52%) 90 22/48 (45.8%) 34
    Gait disturbance 1/104 (1%) 2 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    General physical health deterioration 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Generalised oedema 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Impaired healing 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Influenza like illness 2/104 (1.9%) 3 2/52 (3.8%) 2 3/102 (2.9%) 4 0/48 (0%) 0
    Infusion site extravasation 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Infusion site thrombosis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Injection site haemorrhage 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Injection site rash 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Injection site reaction 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Localised oedema 1/104 (1%) 1 1/52 (1.9%) 1 3/102 (2.9%) 3 0/48 (0%) 0
    Malaise 3/104 (2.9%) 3 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Mucosal inflammation 0/104 (0%) 0 0/52 (0%) 0 3/102 (2.9%) 3 2/48 (4.2%) 2
    Non-cardiac chest pain 1/104 (1%) 1 1/52 (1.9%) 1 3/102 (2.9%) 3 1/48 (2.1%) 2
    Oedema 2/104 (1.9%) 2 0/52 (0%) 0 4/102 (3.9%) 4 0/48 (0%) 0
    Oedema peripheral 33/104 (31.7%) 46 7/52 (13.5%) 10 18/102 (17.6%) 22 6/48 (12.5%) 9
    Pain 5/104 (4.8%) 5 2/52 (3.8%) 2 1/102 (1%) 1 3/48 (6.3%) 3
    Peripheral swelling 2/104 (1.9%) 2 0/52 (0%) 0 1/102 (1%) 2 1/48 (2.1%) 1
    Pyrexia 25/104 (24%) 46 6/52 (11.5%) 12 26/102 (25.5%) 52 9/48 (18.8%) 11
    Secretion discharge 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hepatobiliary disorders
    Bile duct obstruction 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 1
    Bile duct stenosis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Biliary colic 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Cholangitis 3/104 (2.9%) 6 1/52 (1.9%) 1 3/102 (2.9%) 3 4/48 (8.3%) 4
    Hepatic failure 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Hepatic infarction 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hepatic pain 0/104 (0%) 0 1/52 (1.9%) 1 2/102 (2%) 3 0/48 (0%) 0
    Hepatocellular injury 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Hepatomegaly 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hyperbilirubinaemia 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 2/48 (4.2%) 2
    Hypertransaminasaemia 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Jaundice 2/104 (1.9%) 2 0/52 (0%) 0 1/102 (1%) 1 2/48 (4.2%) 2
    Jaundice cholestatic 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Portal vein stenosis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Portal vein thrombosis 2/104 (1.9%) 2 0/52 (0%) 0 3/102 (2.9%) 3 0/48 (0%) 0
    Immune system disorders
    Allergy to arthropod sting 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Contrast media allergy 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Drug hypersensitivity 0/104 (0%) 0 0/52 (0%) 0 3/102 (2.9%) 3 0/48 (0%) 0
    Hypersensitivity 3/104 (2.9%) 4 1/52 (1.9%) 1 2/102 (2%) 2 0/48 (0%) 0
    Seasonal allergy 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Infections and infestations
    Abdominal infection 1/104 (1%) 1 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Acute sinusitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Bacteraemia 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Biliary sepsis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Biliary tract infection 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 2 0/48 (0%) 0
    Bronchitis 0/104 (0%) 0 2/52 (3.8%) 3 0/102 (0%) 0 0/48 (0%) 0
    Candida infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Cellulitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Cholecystitis infective 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Clostridium difficile colitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Cystitis 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Device related infection 4/104 (3.8%) 4 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Diverticulitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Ear infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Enterococcal infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Escherichia infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Fungaemia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Fungal infection 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Gastroenteritis viral 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Gingivitis 4/104 (3.8%) 4 1/52 (1.9%) 2 3/102 (2.9%) 3 1/48 (2.1%) 1
    Helicobacter infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hepatic infection 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Herpes zoster 0/104 (0%) 0 2/52 (3.8%) 2 0/102 (0%) 0 0/48 (0%) 0
    Hordeolum 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Infection 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Influenza 4/104 (3.8%) 6 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Laryngitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Liver abscess 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Lower respiratory tract infection 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Lung infection 0/104 (0%) 0 1/52 (1.9%) 2 0/102 (0%) 0 1/48 (2.1%) 1
    Mastitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Mucosal infection 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Nail infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Nasopharyngitis 4/104 (3.8%) 5 2/52 (3.8%) 2 3/102 (2.9%) 4 3/48 (6.3%) 3
    Oral candidiasis 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 2/48 (4.2%) 2
    Oral fungal infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Otitis externa 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Otitis media 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Paronychia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Periodontitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Peritonitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Peritonitis bacterial 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Pharyngitis 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Pharyngotonsillitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Pneumonia 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 2 1/48 (2.1%) 1
    Post procedural infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Respiratory tract infection 4/104 (3.8%) 4 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Rhinitis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Sepsis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Sinusitis 1/104 (1%) 1 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 1
    Skin infection 2/104 (1.9%) 2 1/52 (1.9%) 1 4/102 (3.9%) 5 0/48 (0%) 0
    Staphylococcal infection 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Streptococcal bacteraemia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Subcutaneous abscess 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Tooth abscess 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Tooth infection 3/104 (2.9%) 3 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Upper respiratory tract infection 7/104 (6.7%) 8 4/52 (7.7%) 7 7/102 (6.9%) 8 2/48 (4.2%) 2
    Urinary tract infection 11/104 (10.6%) 17 2/52 (3.8%) 2 8/102 (7.8%) 9 2/48 (4.2%) 4
    Wound infection 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Injury, poisoning and procedural complications
    Arthropod bite 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Burn oral cavity 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Contusion 3/104 (2.9%) 3 1/52 (1.9%) 1 1/102 (1%) 2 0/48 (0%) 0
    Fall 2/104 (1.9%) 4 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Febrile nonhaemolytic transfusion reaction 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Infusion related reaction 4/104 (3.8%) 4 1/52 (1.9%) 1 2/102 (2%) 2 1/48 (2.1%) 1
    Ligament sprain 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Muscle strain 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Patella fracture 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Post procedural bile leak 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Procedural haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Procedural pain 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Rib fracture 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Skin abrasion 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Skin injury 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Sunburn 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Thermal burn 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Transfusion reaction 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Urinary retention postoperative 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Wound complication 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Alanine aminotransferase increased 12/104 (11.5%) 18 6/52 (11.5%) 9 32/102 (31.4%) 55 7/48 (14.6%) 11
    Amylase increased 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Aspartate aminotransferase increased 14/104 (13.5%) 19 9/52 (17.3%) 11 26/102 (25.5%) 38 8/48 (16.7%) 10
    Bacterial test 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Blood alkaline phosphatase increased 9/104 (8.7%) 12 8/52 (15.4%) 12 10/102 (9.8%) 13 3/48 (6.3%) 3
    Blood bilirubin increased 15/104 (14.4%) 16 4/52 (7.7%) 4 11/102 (10.8%) 14 5/48 (10.4%) 5
    Blood creatinine increased 10/104 (9.6%) 16 4/52 (7.7%) 4 11/102 (10.8%) 19 3/48 (6.3%) 3
    Blood lactate dehydrogenase increased 0/104 (0%) 0 1/52 (1.9%) 2 1/102 (1%) 2 2/48 (4.2%) 2
    Blood urea increased 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    C-reactive protein increased 2/104 (1.9%) 2 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Computerised tomogram abnormal 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Creatinine renal clearance decreased 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Eastern cooperative oncology group performance status worsened 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Endoscopic retrograde cholangiopancreatography 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 3 0/48 (0%) 0
    Gamma-glutamyltransferase increased 6/104 (5.8%) 6 6/52 (11.5%) 8 6/102 (5.9%) 7 1/48 (2.1%) 1
    Glomerular filtration rate decreased 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Haemoglobin increased 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Heart rate increased 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    International normalised ratio increased 3/104 (2.9%) 4 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 1
    Lipase increased 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Paracentesis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Prothrombin time prolonged 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Transaminases increased 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 2 0/48 (0%) 0
    Urine output decreased 2/104 (1.9%) 3 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Wall motion score index abnormal 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Weight decreased 16/104 (15.4%) 18 3/52 (5.8%) 3 14/102 (13.7%) 15 7/48 (14.6%) 7
    Weight increased 2/104 (1.9%) 2 0/52 (0%) 0 5/102 (4.9%) 5 0/48 (0%) 0
    Metabolism and nutrition disorders
    Acidosis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Decreased appetite 39/104 (37.5%) 47 14/52 (26.9%) 14 26/102 (25.5%) 41 14/48 (29.2%) 17
    Dehydration 1/104 (1%) 1 0/52 (0%) 0 4/102 (3.9%) 4 0/48 (0%) 0
    Fluid intake reduced 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Gout 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hypercalcaemia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 2/48 (4.2%) 2
    Hyperglycaemia 7/104 (6.7%) 12 3/52 (5.8%) 3 3/102 (2.9%) 4 2/48 (4.2%) 2
    Hyperkalaemia 4/104 (3.8%) 7 1/52 (1.9%) 1 5/102 (4.9%) 5 3/48 (6.3%) 3
    Hyperlipidaemia 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Hypermagnesaemia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hypernatraemia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hyperuricaemia 1/104 (1%) 2 2/52 (3.8%) 2 1/102 (1%) 1 1/48 (2.1%) 1
    Hypoalbuminaemia 10/104 (9.6%) 14 6/52 (11.5%) 7 11/102 (10.8%) 15 2/48 (4.2%) 2
    Hypocalcaemia 4/104 (3.8%) 6 1/52 (1.9%) 1 8/102 (7.8%) 9 2/48 (4.2%) 2
    Hypochloraemia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Hypoglycaemia 2/104 (1.9%) 3 0/52 (0%) 0 3/102 (2.9%) 3 0/48 (0%) 0
    Hypokalaemia 7/104 (6.7%) 15 3/52 (5.8%) 3 9/102 (8.8%) 12 3/48 (6.3%) 4
    Hypomagnesaemia 20/104 (19.2%) 32 8/52 (15.4%) 11 10/102 (9.8%) 11 7/48 (14.6%) 7
    Hyponatraemia 11/104 (10.6%) 17 4/52 (7.7%) 5 4/102 (3.9%) 7 4/48 (8.3%) 5
    Hypophagia 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hypophosphataemia 2/104 (1.9%) 3 1/52 (1.9%) 1 4/102 (3.9%) 7 0/48 (0%) 0
    Hypoproteinaemia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Malnutrition 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Vitamin d deficiency 3/104 (2.9%) 3 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 6/104 (5.8%) 7 2/52 (3.8%) 2 6/102 (5.9%) 6 0/48 (0%) 0
    Arthritis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Back pain 15/104 (14.4%) 19 8/52 (15.4%) 9 9/102 (8.8%) 10 7/48 (14.6%) 8
    Bone pain 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Bursitis 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Flank pain 2/104 (1.9%) 3 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Gouty arthritis 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Groin pain 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Joint swelling 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Muscle atrophy 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Muscle spasms 1/104 (1%) 1 0/52 (0%) 0 5/102 (4.9%) 5 1/48 (2.1%) 1
    Muscle swelling 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Muscular weakness 4/104 (3.8%) 4 0/52 (0%) 0 3/102 (2.9%) 4 1/48 (2.1%) 2
    Musculoskeletal chest pain 1/104 (1%) 2 0/52 (0%) 0 3/102 (2.9%) 4 1/48 (2.1%) 1
    Musculoskeletal pain 2/104 (1.9%) 2 0/52 (0%) 0 3/102 (2.9%) 3 2/48 (4.2%) 2
    Myalgia 8/104 (7.7%) 10 2/52 (3.8%) 5 5/102 (4.9%) 5 1/48 (2.1%) 1
    Neck pain 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Pain in extremity 3/104 (2.9%) 3 1/52 (1.9%) 4 7/102 (6.9%) 7 1/48 (2.1%) 1
    Tendon disorder 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma 1/104 (1%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Lentigo maligna 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Malignant melanoma 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Metastases to meninges 1/104 (1%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Tumour pain 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Nervous system disorders
    Allodynia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Amnesia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Aphonia 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 1
    Cerebral ischaemia 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Cognitive disorder 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Disturbance in attention 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Dizziness 10/104 (9.6%) 17 4/52 (7.7%) 5 12/102 (11.8%) 14 0/48 (0%) 0
    Dysarthria 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dysgeusia 12/104 (11.5%) 15 1/52 (1.9%) 1 8/102 (7.8%) 10 4/48 (8.3%) 4
    Dyskinesia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Encephalopathy 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Headache 16/104 (15.4%) 21 8/52 (15.4%) 12 14/102 (13.7%) 18 1/48 (2.1%) 1
    Hyperaesthesia 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Lethargy 3/104 (2.9%) 3 1/52 (1.9%) 1 3/102 (2.9%) 3 0/48 (0%) 0
    Migraine 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Migraine with aura 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Neuropathy 16/104 (15.4%) 21 5/52 (9.6%) 7 23/102 (22.5%) 32 5/48 (10.4%) 5
    Neurotoxicity 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Peripheral motor neuropathy 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Piriformis syndrome 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Presyncope 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Restless legs syndrome 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Syncope 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 2 0/48 (0%) 0
    Taste disorder 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Tremor 7/104 (6.7%) 10 0/52 (0%) 0 2/102 (2%) 2 3/48 (6.3%) 3
    Product Issues
    Device malfunction 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Device occlusion 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Psychiatric disorders
    Agitation 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Anxiety 5/104 (4.8%) 6 2/52 (3.8%) 2 0/102 (0%) 0 2/48 (4.2%) 6
    Confusional state 4/104 (3.8%) 4 1/52 (1.9%) 1 2/102 (2%) 2 0/48 (0%) 0
    Depression 4/104 (3.8%) 4 3/52 (5.8%) 4 1/102 (1%) 1 1/48 (2.1%) 1
    Disorientation 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Insomnia 7/104 (6.7%) 7 5/52 (9.6%) 6 9/102 (8.8%) 9 5/48 (10.4%) 5
    Pressure of speech 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Restlessness 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Sleep disorder 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Suicidal ideation 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 4/104 (3.8%) 4 3/52 (5.8%) 3 3/102 (2.9%) 3 0/48 (0%) 0
    Chromaturia 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Chronic kidney disease 2/104 (1.9%) 2 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Cystitis noninfective 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dysuria 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Haematuria 3/104 (2.9%) 3 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Nephropathy toxic 2/104 (1.9%) 5 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Nocturia 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Pollakiuria 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Proteinuria 13/104 (12.5%) 18 2/52 (3.8%) 2 0/102 (0%) 0 0/48 (0%) 0
    Renal failure 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Renal impairment 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 2/48 (4.2%) 2
    Urinary incontinence 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Urinary retention 3/104 (2.9%) 4 1/52 (1.9%) 1 2/102 (2%) 2 1/48 (2.1%) 1
    Urinary tract pain 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 1
    Reproductive system and breast disorders
    Adnexa uteri pain 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Benign prostatic hyperplasia 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Erectile dysfunction 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Oedema genital 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Scrotal oedema 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Vaginal haemorrhage 3/104 (2.9%) 4 0/52 (0%) 0 3/102 (2.9%) 4 2/48 (4.2%) 2
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Cough 17/104 (16.3%) 20 0/52 (0%) 0 8/102 (7.8%) 9 3/48 (6.3%) 3
    Dry throat 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Dysphonia 9/104 (8.7%) 10 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Dyspnoea 12/104 (11.5%) 15 7/52 (13.5%) 7 8/102 (7.8%) 11 10/48 (20.8%) 11
    Dyspnoea exertional 2/104 (1.9%) 3 0/52 (0%) 0 2/102 (2%) 2 1/48 (2.1%) 1
    Epistaxis 19/104 (18.3%) 27 2/52 (3.8%) 2 2/102 (2%) 2 3/48 (6.3%) 4
    Haemoptysis 3/104 (2.9%) 3 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hiccups 1/104 (1%) 1 3/52 (5.8%) 4 1/102 (1%) 2 1/48 (2.1%) 1
    Hypoxia 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Laryngeal inflammation 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Laryngeal pain 1/104 (1%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Lung infiltration 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Nasal congestion 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Nasal inflammation 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Oropharyngeal pain 3/104 (2.9%) 3 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Pharyngeal swelling 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Pleural effusion 1/104 (1%) 1 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 1
    Pleurisy 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Pneumonitis 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 2/48 (4.2%) 2
    Productive cough 3/104 (2.9%) 5 0/52 (0%) 0 2/102 (2%) 2 1/48 (2.1%) 1
    Pulmonary embolism 2/104 (1.9%) 2 0/52 (0%) 0 7/102 (6.9%) 7 6/48 (12.5%) 6
    Respiratory distress 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Rhinitis allergic 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Rhinorrhoea 2/104 (1.9%) 4 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Sinus disorder 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Sinus pain 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Upper-airway cough syndrome 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Wheezing 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 1/48 (2.1%) 2
    Skin and subcutaneous tissue disorders
    Acne 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Alopecia 13/104 (12.5%) 13 3/52 (5.8%) 3 14/102 (13.7%) 14 8/48 (16.7%) 8
    Blister 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Cold sweat 0/104 (0%) 0 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Decubitus ulcer 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dermal cyst 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Dermatitis acneiform 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dermatitis allergic 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Dermatitis bullous 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Dry skin 2/104 (1.9%) 2 0/52 (0%) 0 1/102 (1%) 1 3/48 (6.3%) 4
    Eczema 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Erythema 1/104 (1%) 1 0/52 (0%) 0 3/102 (2.9%) 3 0/48 (0%) 0
    Hyperhidrosis 1/104 (1%) 1 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Hyperkeratosis 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Nail discolouration 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Nail disorder 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Night sweats 2/104 (1.9%) 3 1/52 (1.9%) 1 1/102 (1%) 1 1/48 (2.1%) 1
    Onychomadesis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Pain of skin 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 1/48 (2.1%) 1
    Penile ulceration 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Petechiae 4/104 (3.8%) 7 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Photosensitivity reaction 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Pruritus 9/104 (8.7%) 10 2/52 (3.8%) 2 9/102 (8.8%) 9 7/48 (14.6%) 7
    Purpura 5/104 (4.8%) 5 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Rash 10/104 (9.6%) 12 1/52 (1.9%) 1 7/102 (6.9%) 19 3/48 (6.3%) 3
    Rosacea 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Skin fissures 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Skin hyperpigmentation 3/104 (2.9%) 3 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Skin ulcer 2/104 (1.9%) 2 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Swelling face 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Urticaria 3/104 (2.9%) 3 1/52 (1.9%) 1 2/102 (2%) 2 0/48 (0%) 0
    Social circumstances
    Respite care 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Surgical and medical procedures
    Bile duct stent insertion 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Catheter placement 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0
    Central venous catheterisation 2/104 (1.9%) 2 2/52 (3.8%) 2 1/102 (1%) 1 1/48 (2.1%) 1
    Cholangiostomy 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Haemorrhoid operation 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Hepatectomy 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Hernia repair 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Inguinal hernia repair 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Skin neoplasm excision 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Tooth extraction 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Vascular disorders
    Deep vein thrombosis 2/104 (1.9%) 2 1/52 (1.9%) 1 2/102 (2%) 2 3/48 (6.3%) 3
    Embolism arterial 2/104 (1.9%) 3 1/52 (1.9%) 1 4/102 (3.9%) 4 0/48 (0%) 0
    Embolism venous 3/104 (2.9%) 3 1/52 (1.9%) 1 6/102 (5.9%) 6 2/48 (4.2%) 2
    Flushing 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 3 0/48 (0%) 0
    Haematoma 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Haemorrhage 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 0/48 (0%) 0
    Hot flush 1/104 (1%) 1 0/52 (0%) 0 4/102 (3.9%) 4 0/48 (0%) 0
    Hypertension 32/104 (30.8%) 53 2/52 (3.8%) 2 6/102 (5.9%) 11 2/48 (4.2%) 2
    Hypotension 0/104 (0%) 0 0/52 (0%) 0 3/102 (2.9%) 3 1/48 (2.1%) 2
    Lymphoedema 2/104 (1.9%) 2 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Orthostatic hypotension 0/104 (0%) 0 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Peripheral coldness 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Phlebitis 0/104 (0%) 0 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Raynaud's phenomenon 1/104 (1%) 1 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Subclavian vein thrombosis 0/104 (0%) 0 0/52 (0%) 0 1/102 (1%) 1 0/48 (0%) 0
    Thrombophlebitis 1/104 (1%) 1 0/52 (0%) 0 0/102 (0%) 0 1/48 (2.1%) 1
    Thrombophlebitis superficial 1/104 (1%) 1 0/52 (0%) 0 2/102 (2%) 2 0/48 (0%) 0
    Venous thrombosis 2/104 (1.9%) 2 1/52 (1.9%) 1 1/102 (1%) 1 0/48 (0%) 0
    Venous thrombosis limb 0/104 (0%) 0 1/52 (1.9%) 1 0/102 (0%) 0 0/48 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Other disclosure agreement is maximum of 10 years restriction on the PI that the sponsor can review results communications prior to public release and can embargo communications regarding trial results. 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:
    NCT02711553
    Other Study ID Numbers:
    • 16329
    • I3O-MC-JSBF
    • 2015-004699-31
    First Posted:
    Mar 17, 2016
    Last Update Posted:
    Oct 1, 2021
    Last Verified:
    Sep 1, 2021