Clincosm LogoSign in Get a demo

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

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT02435433
Collaborator
(none)
403
Enrollment
131
Locations
5
Arms
76
Actual Duration (Months)
3.1
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of ramucirumab in participants with hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein. Participants will be randomized to ramucirumab or placebo in a 2:1 ratio (Main Global Cohort and China Maximized Extended Enrollment [ME2] Cohort). Participants may also receive ramucirumab if eligible to be enrolled in Open-Label Expansion (OLE) Cohort.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
403 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-Line Therapy With Sorafenib
Actual Study Start Date :
Jul 20, 2015
Actual Primary Completion Date :
Mar 15, 2018
Actual Study Completion Date :
Nov 19, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ramucirumab

8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.

Drug: Ramucirumab
Administered IV
Other Names:
  • Cyramza
  • LY3009806

    		•
    Placebo Comparator: Placebo

    Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.

    Drug: Ramucirumab
    Administered IV
    Other Names:
  • Cyramza
  • LY3009806

    • Drug: Placebo
    Administered IV
    Experimental: Open Label Ramucirumab

    8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.

    Drug: Ramucirumab
    Administered IV
    Other Names:
  • Cyramza
  • LY3009806

    		•
    Experimental: Ramucirumab ME2 Cohort

    8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.

    Drug: Ramucirumab
    Administered IV
    Other Names:
  • Cyramza
  • LY3009806

    		•
    Placebo Comparator: Placebo ME2 Cohort

    Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.

    Drug: Ramucirumab
    Administered IV
    Other Names:
  • Cyramza
  • LY3009806

    • Drug: Placebo
    Administered IV

    Outcome Measures

    Primary Outcome Measures

    1. Overall Survival (OS) [From Date of Randomization to Death from Any Cause (Up to 28 Months)]

      OS time was measured from date of randomization to date of death from any cause. Participants who were not known to have died on or before the date of data cut-off, OS data was censored on the last date (on or before the cut-off date) the participant was known to be alive.

    Secondary Outcome Measures

    1. Progression Free Survival (PFS) [From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months)]

      Progression-free survival is defined as time from the date of randomization to the date of first observation of objective progression or death from any cause. Progressive disease (PD) is referenced as the smallest measurements recorded since the treatment started.

    2. Time to Radiographic Progression [From Randomization to Objective Progression (Up to 28 Months)]

      Time to radiographic progression is defined as the time from the date of randomization to the date of first observation of objective progression. Progressive disease (PD) is referenced as the smallest measurements recorded since the treatment started.

    3. Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [From Randomization to Objective Progression (Up to 28 Months)]

      Objective response rate is defined as the percentage of participants who achieve a best overall response of complete response (CR) + partial response (PR). ORR = CR + PR. CR is the disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.

    4. Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) Before 2nd, 4th, 7th, and 10th Infusion [Predose, Weeks 2, 6, 12 and 18, Day 1; Up to 3 Days Before Infusion (14-Day Cycles)]

      PK Cmin of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.

    5. PK: Serum Concentration Maximum (Cmax) After 1st, 2nd, 4th, 7th and 10th Ram Infusion [Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles)]

      PK Cmax of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.

    6. Percentage of Participants With Anti-Ramucirumab Antibodies [Predose Cycle 1: 7 Days prior to First Infusion, Cycle 4: 3 Days Prior to Infusion, Cycle 7 through Follow Up (Up to 28 Months)]

      Percentage of participants with positive treatment emergent anti-drug antibodies was summarized by treatment group. A treatment-emergent ADA (TEADA) was defined as: having a negative ADA at baseline and an ADA titer greater than or equal to 1:20 (that is (i.e.), greater than 2-fold from the minimal required dilution of 1:10) any time post baseline (i.e., treatment-induced); or a 4-fold or greater change in ADA titer from baseline for participants that had a detectable ADA titer at baseline (i.e., treatment boosted).

    7. Time to Deterioration of Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) [From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months)]

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

    8. Change From Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire [From Randomization through End of Study (Up to 28 Months)]

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

    9. Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) [From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months)]

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

    Eligibility Criteria

    Criteria

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

    • A diagnosis of HCC based on histopathologic findings, or a diagnosis of cirrhosis and a tumor with classical HCC imaging characteristics.

    • Sorafenib was the only systemic therapy for HCC and was discontinued for disease progression or intolerance (Main Global and ME2 Cohorts only).

    • The participant received ≤2 prior systemic therapy regimen, excluding prior sorafenib or chemotherapy, for the treatment of HCC (OLE Cohort only).

    • ≥1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 that has not been previously treated with locoregional therapy. A participant with a lesion(s) that has previously been treated with locoregional therapy is also eligible, if the lesion has documented progression after locoregional treatment and is measureable.

    • Child-Pugh score <7 (Child-Pugh Class A).

    • Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy.

    • Baseline AFP ≥400 nanograms/milliliter.

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

    • Resolution of all clinically significant toxic effects of prior therapy.

    • Total bilirubin ≤1.5 times upper limit of normal value (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤5 × ULN.

    • Creatinine clearance ≥60 milliliters/minute.

    • Urinary protein is ≤1+ on dipstick or routine urinalysis or 24-hour urine demonstrating <1 gram of protein.

    • Absolute neutrophil count ≥1.0 × 109/Liter, hemoglobin ≥9 grams/deciliter, and platelets ≥75 × 109/Liter.

    • International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) ≤5 seconds above the ULN.

    • Surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method.

    • If a woman of childbearing potential, a negative serum pregnancy test prior to randomization.

    • Willing to provide blood for research. The participant has provided signed informed consent prior to any study specific procedures and is amenable to compliance with protocol schedules and testing.

    Exclusion Criteria:

    • Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.

    • Concurrent malignancy. Participants with carcinoma in situ of any origin and participants with prior malignancies in remission may be eligible with sponsor approval.

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

    • History of or current hepatic encephalopathy or clinically meaningful ascites.

    • Ongoing or recent hepatorenal syndrome.

    • Liver transplant (Main Global and ME2 cohorts only; Participants with prior liver transplant may be eligible for OLE cohort).

    • Hepatic locoregional therapy following prior systemic therapy or within 28 days prior to randomization.

    • Major surgical procedure, traumatic injury, non-healing wound, or peptic ulcer ≤28 days prior to randomization.

    • Received radiation to any nonhepatic (for example, bone) site within 14 days prior to randomization.

    • Placement of a subcutaneous venous access device within 7 days prior to the first dose of study treatment unless the procedure is judged of low risk of bleeding.

    • Enrolled in a clinical trial involving an investigational product or unapproved use of a drug or in medical research judged not to be scientifically or medically compatible with this study.

    • Discontinued from study treatment from another clinical trial within 28 days prior to randomization.

    • Known allergy to any of the treatment components.

    • Uncontrolled hypertension.

    • Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, <6 months prior to randomization.

    • Any bleeding episode considered life-threatening, or any Grade 3 or 4 gastrointestinal bleeding episode in the 3 months prior to randomization requiring intervention.

    • Esophageal or gastric varices that require intervention or represent high bleeding risk. Participants with evidence of portal hypertension or prior bleeding must have had endoscopic evaluation within 3 months prior to randomization.

    • Gastrointestinal perforation or fistulae within 6 months prior to randomization.

    • Symptomatic congestive heart failure (New York Heart Association II-IV), unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.

    • Pregnant or breast-feeding.

    • Any medical or psychiatric condition that may increase the risk associated with study participation or may interfere with the interpretation of study results. Conditions include but are not limited to:

    • Human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.

    • Active or uncontrolled clinically serious infection. (Participants with chronic viral hepatitis are eligible.)

    • Ongoing or recent history of drug abuse.

    • Uncontrolled hereditary or acquired thrombotic or bleeding disorder.

    • Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection.

    • Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or similar agents.

    • Chronic therapy with nonsteroidal anti-inflammatory agents or other anti-platelet agents. Aspirin at doses up to 100 milligrams/day is permitted.

    • The participant received prior immunotherapy and is experiencing or has experienced any of the following (OLE cohort only):

    • Any clinically significant Grade ≥3 immune-related adverse event (irAE)

    • Any grade neurologic or ocular irAE

    • Any grade immune-related pneumonitis, cardiomyopathy, or hepatitis

    • The participant received prior immunotherapy and at the time of study enrollment, requires steroids or other immunosuppressive agents (OLE cohort only).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pacific Hematology and Oncology Associates Daly City California United States 94115
    2 UCLA Medical Center Los Angeles California United States 90024
    3 Georgetown University Medical Center Washington District of Columbia United States 20007
    4 University of Iowa Hospital Iowa City Iowa United States 52242
    5 Massachusetts General Hospital Boston Massachusetts United States 02114
    6 Mount Sinai Medical Center New York New York United States 10029
    7 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    8 OREGON HEALTH and SCIENCE UNIVERSITY Portland Oregon United States 97239
    9 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kurralta Park Australia 5037
    10 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Woodville Australia 5011
    11 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Linz Austria 4020
    12 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Wien Austria 1090
    13 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Brussels Belgium 1200
    14 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Liege Belgium 4000
    15 Fundação PIO XII Barretos Brazil 14784-400
    16 "For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician." Barretos Brazil 14784700
    17 Cenantron - Centro Avançado de Tratamento Oncológico Belo Horizonte Brazil 30130-090
    18 Associação Hospital de Caridade Ijuí Ijui Brazil 98700 000
    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. Porto Alegre Brazil 90470-340
    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. São Paulo Brazil 04039-901
    21 For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician. Montreal Canada H2X 3E4
    22 For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician. Toronto Canada M5G 2M9
    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." Beijing China 100032
    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." Beijing China 100142
    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." Beijing China
    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. Beijing China
    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. Changsha China 410011
    28 "For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician." Changsha China 410013
    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." Chongqing China 400038
    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. Guangdong China 510515
    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." Guangzhou China 510080
    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." Hangzhou China 310003
    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." Hangzhou China 310009
    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." Hangzhou China 310022
    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." Hebei China 050011
    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. Hefei China 230022
    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. Heilongjiang China 150081
    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. Henan China 450008
    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. Hubei China 56456
    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. Nanjing China 210002
    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. Nanjing China 210006
    42 "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." Nanning China 530021
    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." Qingdao China 266003
    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. Shanghai China 200030
    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 Shanghai China 200127
    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." Shanghai China
    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. Shanghai China
    48 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. Shenyang China 100042
    49 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. Wu Han China 430030
    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." Xi'an China 710032
    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. Brno Czechia 656 53
    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. Praha 5 Czechia 150 06
    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. Amiens France 80054
    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. Avignon France 84918
    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. Besancon France 25030
    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. Caen France 14033
    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. Clermont-Ferrand France 63003
    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. Lyon France 69317
    59 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 France 34295
    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. Nantes France 44093
    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. Pessac France 33604
    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. Rennes France 35042
    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. Saint Etienne France 42000
    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." Bayern Germany 81377
    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. Berlin Germany 13125
    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. Essen Germany 45122
    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. Frankfurt Germany 60590
    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. Hamburg Germany 20246
    69 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
    70 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. Leipzig Germany 04103
    71 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. Magdeburg Germany 39120
    72 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. Mainz Germany 55131
    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. München Germany 81675
    74 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. Tubingen Germany 72076
    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." Hong Kong Hong Kong
    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. Hong Kong Hong Kong
    77 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 Kowloon Hong Kong
    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. ShaTin Hong Kong
    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. Tuen Mun Hong Kong
    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. Haifa Israel 3109601
    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. Tel Aviv Israel 6423906
    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. Benevento Italy 82100
    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. Bologna Italy 40138
    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. Cremona Italy 26100
    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. Padova Italy 35128
    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. Rome Italy 00168
    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." Chuo Ku Japan 104-0045
    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. Fukuoka Japan 810-8563
    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." Fukuoka Japan 811-1395
    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." Iizuka Japan 820-8505
    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. Kanazawa Japan 920-8641
    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. Kashiwa Japan 277 8577
    93 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. Kyoto Japan 606-8507
    94 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. Matsuyama Japan 791-0280
    95 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Osaka Japan 589-8511
    96 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. Shimotsuke Japan 329-0498
    97 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Suita-shi Japan 565-0871
    98 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. Sunto-Gun Japan 411-8777
    99 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 101-0062
    100 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Yokohama Japan 241-8515
    101 "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." Ōsaka Japan 541-8567
    102 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. Incheon Korea, Republic of 21565
    103 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
    104 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
    105 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
    106 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
    107 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ulsan Korea, Republic of 44033
    108 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. Gdansk Poland 80-219
    109 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. Poznan Poland 61-866
    110 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. Warszawa Poland 01-748
    111 Hospital Universitari de Girona Dr. Josep Trueta Girona Spain 17007
    112 Hospital Clínico San Carlos Madrid Spain 28040
    113 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. Santander Spain 39008
    114 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. Valencia Spain 46026
    115 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. Bern Switzerland 3010
    116 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. Kaohsiung city Taiwan 83301
    117 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. Puzi City Taiwan 61363
    118 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 40705
    119 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 704
    120 "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 71004
    121 "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 736
    122 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 city Taiwan 10048
    123 For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician. Taipei city Taiwan 11217
    124 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
    125 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
    126 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 w120hs
    127 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. Bebington United Kingdom CH63 4JY
    128 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. Birmingham United Kingdom B15 2TH
    129 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 NW3 2QG
    130 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 SE5 9RS
    131 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

    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:
    NCT02435433
    Other Study ID Numbers:
    • 15755
    • I4T-MC-JVDE
    • 2014-005068-13
    First Posted:
    May 6, 2015
    Last Update Posted:
    Jan 14, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Eli Lilly and Company
    liver cancer
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Hepatocellular
    Ramucirumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Completers include participants who had died due to any cause or alive and on study at the end of study, but off treatment. Results for open label and maximum extended enrollment participants will be posted after the study completion.
    Arm/Group Title Ramucirumab Placebo Open Label Ramucirumab Ramucirumab ME2 Cohort Placebo ME2 Cohort
    Arm/Group Description 8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm. 8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. 8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Period Title: Overall Study
    STARTED 197 95 0 0 0
    Participants Who Received Study Drug 197 95 0 0 0
    COMPLETED 182 90 0 0 0
    NOT COMPLETED 15 5 0 0 0

    Baseline Characteristics

    Arm/Group Title Ramucirumab + BSC Placebo + Best Supportive Care (BSC) Total
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm. Total of all reporting groups
    Overall Participants 197 95 292
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    64
    64
    64
    Sex: Female, Male (Count of Participants)
    Female
    43
    21.8%
    16
    16.8%
    59
    20.2%
    Male
    154
    78.2%
    79
    83.2%
    233
    79.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    12
    6.1%
    9
    9.5%
    21
    7.2%
    Not Hispanic or Latino
    129
    65.5%
    58
    61.1%
    187
    64%
    Unknown or Not Reported
    56
    28.4%
    28
    29.5%
    84
    28.8%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    102
    51.8%
    45
    47.4%
    147
    50.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    0.5%
    1
    1.1%
    2
    0.7%
    White
    60
    30.5%
    31
    32.6%
    91
    31.2%
    More than one race
    0
    0%
    1
    1.1%
    1
    0.3%
    Unknown or Not Reported
    34
    17.3%
    17
    17.9%
    51
    17.5%
    Region of Enrollment (Count of Participants)
    Hong Kong
    6
    3%
    1
    1.1%
    7
    2.4%
    United States
    10
    5.1%
    1
    1.1%
    11
    3.8%
    Czechia
    4
    2%
    2
    2.1%
    6
    2.1%
    Japan
    41
    20.8%
    18
    18.9%
    59
    20.2%
    United Kingdom
    9
    4.6%
    2
    2.1%
    11
    3.8%
    Switzerland
    2
    1%
    2
    2.1%
    4
    1.4%
    Spain
    3
    1.5%
    2
    2.1%
    5
    1.7%
    Canada
    1
    0.5%
    1
    1.1%
    2
    0.7%
    Austria
    1
    0.5%
    1
    1.1%
    2
    0.7%
    South Korea
    24
    12.2%
    14
    14.7%
    38
    13%
    Belgium
    2
    1%
    2
    2.1%
    4
    1.4%
    China
    3
    1.5%
    1
    1.1%
    4
    1.4%
    Taiwan
    22
    11.2%
    11
    11.6%
    33
    11.3%
    Brazil
    5
    2.5%
    4
    4.2%
    9
    3.1%
    Poland
    2
    1%
    3
    3.2%
    5
    1.7%
    Italy
    13
    6.6%
    9
    9.5%
    22
    7.5%
    Israel
    1
    0.5%
    0
    0%
    1
    0.3%
    Australia
    2
    1%
    1
    1.1%
    3
    1%
    France
    34
    17.3%
    17
    17.9%
    51
    17.5%
    Germany
    12
    6.1%
    3
    3.2%
    15
    5.1%

    Outcome Measures

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

    Outcome Measure Data

    Analysis Population Description
    All randomized participants. Participants were censored in Ramucirumab arm = 50 and Placebo arm = 21. All randomized participants (including the censored participants) were included in the analyses.
    Arm/Group Title Ramucirumab + Best Supportive Care (BSC) Placebo + BSC
    Arm/Group Description 8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 197 95
    Median (95% Confidence Interval) [Months]
    8.51
    7.29
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + Best Supportive Care (BSC), Placebo + BSC
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0199
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.710
    Confidence Interval (2-Sided) 95%
    0.531 to 0.949
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Progression Free Survival (PFS)
    Description Progression-free survival is defined as time from the date of randomization to the date of first observation of objective progression or death from any cause. Progressive disease (PD) is referenced as the smallest measurements recorded since the treatment started.
    Time Frame From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants. Participants were censored in the Ramucirumab arm = 25 and in the Placebo arm = 9. All randomized participants (including the censored participants) were included in the analyses.
    Arm/Group Title Ramucirumab + BSC Placebo + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an intravenous IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 197 95
    Median (95% Confidence Interval) [Months]
    2.83
    1.61
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + Best Supportive Care (BSC), Placebo + BSC
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.452
    Confidence Interval (2-Sided) 95%
    0.339 to 0.603
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Time to Radiographic Progression
    Description Time to radiographic progression is defined as the time from the date of randomization to the date of first observation of objective progression. Progressive disease (PD) is referenced as the smallest measurements recorded since the treatment started.
    Time Frame From Randomization to Objective Progression (Up to 28 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants.
    Arm/Group Title Ramucirumab + BSC Placebo + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 197 95
    Median (95% Confidence Interval) [Months]
    3.02
    1.61
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + Best Supportive Care (BSC), Placebo + BSC
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.427
    Confidence Interval (2-Sided) 95%
    0.313 to 0.582
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
    Description Objective response rate is defined as the percentage of participants who achieve a best overall response of complete response (CR) + partial response (PR). ORR = CR + PR. CR is the disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.
    Time Frame From Randomization to Objective Progression (Up to 28 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants.
    Arm/Group Title Ramucirumab + BSC Placebo + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 197 95
    Number [percentage of participants]
    4.6
    2.3%
    1.1
    1.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + Best Supportive Care (BSC), Placebo + BSC
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1697
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.6
    Confidence Interval (2-Sided) 95%
    0.6 to 37.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) Before 2nd, 4th, 7th, and 10th Infusion
    Description PK Cmin of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.
    Time Frame Predose, Weeks 2, 6, 12 and 18, Day 1; Up to 3 Days Before Infusion (14-Day Cycles)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug.
    Arm/Group Title Ramucirumab + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
    Measure Participants 195
    Week 0
    NA
    (NA)
    Week 2
    23.5
    (57)
    Week 6
    44.1
    (60)
    Week 12
    60.2
    (46)
    Week 18
    63.2
    (40)
    6. Secondary Outcome
    Title PK: Serum Concentration Maximum (Cmax) After 1st, 2nd, 4th, 7th and 10th Ram Infusion
    Description PK Cmax of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.
    Time Frame Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who had received at least one dose of study drug.
    Arm/Group Title Ramucirumab + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
    Measure Participants 195
    Week 0
    156
    (22)
    Week 2
    181
    (24)
    Week 6
    205
    (24)
    Week 12
    221
    (24)
    Week 18
    228
    (22)
    7. Secondary Outcome
    Title Percentage of Participants With Anti-Ramucirumab Antibodies
    Description Percentage of participants with positive treatment emergent anti-drug antibodies was summarized by treatment group. A treatment-emergent ADA (TEADA) was defined as: having a negative ADA at baseline and an ADA titer greater than or equal to 1:20 (that is (i.e.), greater than 2-fold from the minimal required dilution of 1:10) any time post baseline (i.e., treatment-induced); or a 4-fold or greater change in ADA titer from baseline for participants that had a detectable ADA titer at baseline (i.e., treatment boosted).
    Time Frame Predose Cycle 1: 7 Days prior to First Infusion, Cycle 4: 3 Days Prior to Infusion, Cycle 7 through Follow Up (Up to 28 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and had evaluable anti-ramucirumab data.
    Arm/Group Title Ramucirumab + BSC Placebo + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 161 76
    Number [percentage of participants]
    5.0
    2.5%
    9.2
    9.7%
    8. Secondary Outcome
    Title Time to Deterioration of Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)
    Description The FACT Hepatobiliary Symptom Index (FHSI-8) is a instrument with specific focus regarding the most frequent and concerning symptoms experienced by participants with hepatobiliary malignancies, including lack of energy, nausea, pain, weight loss, pain in back, fatigue, jaundice, stomach pain or discomfort. The (FHSI-8) questionnaire was used to assess the time to deterioration of FSHI-8 total score issued from the date of randomization to the first date observing deterioration, with the deterioration threshold defined as a decrease ≥ 3-points from baseline. In case of no deterioration, the participants were censored at the time of the last FSHI-8 item recording. FHSI-8 total score ranges from 0 to 32 where "0" is a severely symptomatic participant and the highest score indicates an asymptomatic participant. Kaplan-Meier method Hazard ratio was used to estimate (Ramucirumab versus Placebo) and 95% Confidence Interval (CI) (Wald) were estimated from un-stratified/stratified Cox model.
    Time Frame From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who had evaluable FHSI-8 data.
    Arm/Group Title Ramucirumab + BSC Placebo + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 197 95
    Median (95% Confidence Interval) [Months]
    3.71
    2.79
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab + Best Supportive Care (BSC), Placebo + BSC
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2382
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.799
    Confidence Interval (2-Sided) 95%
    0.545 to 1.171
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Change From Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
    Description The EQ-5D-5L is a nonspecific and standardized instrument for use as a measure of self-reported health status (EuroQol Group 1990; Herdman et al. 2011). Participants completed the 5-level (no problems, slight problems, moderate problems, severe problems, and extreme problems), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. A unique EQ-5D-5L health state scale ranges from 0 to 100 and is defined by combining 1 level from each of the 5 dimensions. Participants indicated their current health status by marking on a continuum ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).
    Time Frame From Randomization through End of Study (Up to 28 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants and had evaluable EQ-5D-5L data.
    Arm/Group Title Ramucirumab + BSC Placebo + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 197 95
    Mean (Standard Deviation) [units on a scale]
    -0.105
    (0.201)
    -0.099
    (0.170)
    10. Secondary Outcome
    Title Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS)
    Description Time to deterioration in ECOG PS is defined as the time from the date of randomization to the first date observing ECOG PS 2 (ie, deterioration from baseline status of 0 [fully active] or 1 [restricted in physically strenuous activity but ambulatory and able to carry out light work]). Participants without PS deterioration were censored at their last documented assessments of 0 or 1. Assessments included ECOG Performance Status (PS): 2- Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours, 3 -Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours, 4 -Completely disabled, cannot carry on any self-care. Totally confined to bed or chair, 5- Dead.
    Time Frame From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants and had evaluable ECOG data. Censored participants without any post baseline assessments at randomization date were in the Ramucirumab + BSC arm = 141 and the Placebo + BSC arm =75. All randomized participants (including the censored participants) were included in the analyses.
    Arm/Group Title Ramucirumab + BSC Placebo + BSC
    Arm/Group Description 8 mg/kg ramucirumab administered as an IV injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    Measure Participants 197 95
    Median (95% Confidence Interval) [Months]
    NA
    NA

    Adverse Events

    Time Frame Up to 28 Months
    Adverse Event Reporting Description
    Arm/Group Title Ramucirumab Placebo
    Arm/Group Description 8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.
    All Cause Mortality
    Ramucirumab Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 147/195 (75.4%) 74/95 (77.9%)
    Serious Adverse Events
    Ramucirumab Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 68/197 (34.5%) 28/95 (29.5%)
    Blood and lymphatic system disorders
    Neutropenia 1/197 (0.5%) 1 0/95 (0%) 0
    Splenic infarction 1/197 (0.5%) 1 0/95 (0%) 0
    Cardiac disorders
    Angina pectoris 1/197 (0.5%) 1 0/95 (0%) 0
    Myocardial infarction 1/197 (0.5%) 1 1/95 (1.1%) 1
    Gastrointestinal disorders
    Abdominal hernia 1/197 (0.5%) 1 0/95 (0%) 0
    Abdominal pain 3/197 (1.5%) 3 0/95 (0%) 0
    Abdominal pain upper 1/197 (0.5%) 1 0/95 (0%) 0
    Ascites 6/197 (3%) 6 0/95 (0%) 0
    Colitis 1/197 (0.5%) 1 0/95 (0%) 0
    Constipation 0/197 (0%) 0 1/95 (1.1%) 1
    Enterocolitis 0/197 (0%) 0 1/95 (1.1%) 1
    Gastric haemorrhage 1/197 (0.5%) 1 0/95 (0%) 0
    Gastric perforation 1/197 (0.5%) 1 0/95 (0%) 0
    Gastric ulcer 1/197 (0.5%) 1 0/95 (0%) 0
    Gastroduodenal ulcer 1/197 (0.5%) 1 0/95 (0%) 0
    Gastrointestinal haemorrhage 0/197 (0%) 0 1/95 (1.1%) 1
    Lower gastrointestinal haemorrhage 1/197 (0.5%) 1 0/95 (0%) 0
    Melaena 0/197 (0%) 0 1/95 (1.1%) 1
    Nausea 0/197 (0%) 0 1/95 (1.1%) 1
    Oesophageal haemorrhage 1/197 (0.5%) 1 0/95 (0%) 0
    Oesophageal varices haemorrhage 2/197 (1%) 2 1/95 (1.1%) 1
    Rectal haemorrhage 1/197 (0.5%) 1 0/95 (0%) 0
    Upper gastrointestinal haemorrhage 1/197 (0.5%) 1 0/95 (0%) 0
    Varices oesophageal 1/197 (0.5%) 1 0/95 (0%) 0
    General disorders
    Asthenia 1/197 (0.5%) 1 0/95 (0%) 0
    General physical health deterioration 1/197 (0.5%) 1 0/95 (0%) 0
    Generalised oedema 1/197 (0.5%) 1 0/95 (0%) 0
    Multiple organ dysfunction syndrome 1/197 (0.5%) 1 0/95 (0%) 0
    Oedema peripheral 2/197 (1%) 2 0/95 (0%) 0
    Pyrexia 2/197 (1%) 2 1/95 (1.1%) 1
    Hepatobiliary disorders
    Acute hepatic failure 1/197 (0.5%) 1 0/95 (0%) 0
    Cholestasis 0/197 (0%) 0 1/95 (1.1%) 1
    Hepatorenal syndrome 2/197 (1%) 3 0/95 (0%) 0
    Jaundice 1/197 (0.5%) 1 1/95 (1.1%) 1
    Immune system disorders
    Anaphylactic reaction 1/197 (0.5%) 1 0/95 (0%) 0
    Infections and infestations
    Anal abscess 1/197 (0.5%) 1 0/95 (0%) 0
    Appendicitis 1/197 (0.5%) 1 1/95 (1.1%) 1
    Gastroenteritis 1/197 (0.5%) 1 0/95 (0%) 0
    Infection 0/197 (0%) 0 1/95 (1.1%) 2
    Influenza 2/197 (1%) 2 0/95 (0%) 0
    Lower respiratory tract infection 2/197 (1%) 2 0/95 (0%) 0
    Lung infection 0/197 (0%) 0 1/95 (1.1%) 1
    Peritonitis 1/197 (0.5%) 1 2/95 (2.1%) 2
    Pleural infection 1/197 (0.5%) 1 0/95 (0%) 0
    Pneumonia 5/197 (2.5%) 5 2/95 (2.1%) 3
    Post procedural infection 1/197 (0.5%) 1 0/95 (0%) 0
    Respiratory tract infection 0/197 (0%) 0 1/95 (1.1%) 1
    Sepsis 3/197 (1.5%) 3 3/95 (3.2%) 3
    Septic shock 0/197 (0%) 0 1/95 (1.1%) 1
    Urinary tract infection 1/197 (0.5%) 1 0/95 (0%) 0
    Injury, poisoning and procedural complications
    Ankle fracture 0/197 (0%) 0 1/95 (1.1%) 1
    Fall 1/197 (0.5%) 1 0/95 (0%) 0
    Hip fracture 1/197 (0.5%) 1 0/95 (0%) 0
    Infusion related reaction 0/197 (0%) 0 1/95 (1.1%) 1
    Investigations
    Aspiration pleural cavity 1/197 (0.5%) 1 0/95 (0%) 0
    Blood bilirubin increased 0/197 (0%) 0 1/95 (1.1%) 1
    General physical condition abnormal 1/197 (0.5%) 2 0/95 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 1/197 (0.5%) 1 0/95 (0%) 0
    Hypercalcaemia 0/197 (0%) 0 1/95 (1.1%) 2
    Musculoskeletal and connective tissue disorders
    Back pain 1/197 (0.5%) 1 0/95 (0%) 0
    Muscular weakness 1/197 (0.5%) 1 0/95 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Liver carcinoma ruptured 0/197 (0%) 0 1/95 (1.1%) 1
    Metastases to bone 1/197 (0.5%) 1 0/95 (0%) 0
    Metastases to spine 1/197 (0.5%) 1 1/95 (1.1%) 1
    Tumour haemorrhage 1/197 (0.5%) 1 0/95 (0%) 0
    Tumour pain 1/197 (0.5%) 1 0/95 (0%) 0
    Tumour rupture 1/197 (0.5%) 1 0/95 (0%) 0
    Nervous system disorders
    Cerebral ischaemia 1/197 (0.5%) 1 0/95 (0%) 0
    Cerebrovascular accident 1/197 (0.5%) 1 0/95 (0%) 0
    Coma hepatic 1/197 (0.5%) 1 0/95 (0%) 0
    Epilepsy 1/197 (0.5%) 1 0/95 (0%) 0
    Hepatic encephalopathy 3/197 (1.5%) 3 0/95 (0%) 0
    Somnolence 1/197 (0.5%) 1 0/95 (0%) 0
    Psychiatric disorders
    Anxiety 0/197 (0%) 0 1/95 (1.1%) 1
    Confusional state 1/197 (0.5%) 1 0/95 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 3/197 (1.5%) 3 0/95 (0%) 0
    Nephrotic syndrome 1/197 (0.5%) 1 0/95 (0%) 0
    Renal failure 1/197 (0.5%) 1 0/95 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 3/197 (1.5%) 3 3/95 (3.2%) 3
    Epistaxis 1/197 (0.5%) 1 0/95 (0%) 0
    Haemothorax 1/197 (0.5%) 1 0/95 (0%) 0
    Lung disorder 0/197 (0%) 0 1/95 (1.1%) 1
    Pleural effusion 0/197 (0%) 0 1/95 (1.1%) 1
    Pulmonary oedema 0/197 (0%) 0 1/95 (1.1%) 1
    Vascular disorders
    Deep vein thrombosis 0/197 (0%) 0 1/95 (1.1%) 1
    Haemorrhage 0/197 (0%) 0 1/95 (1.1%) 1
    Hypertensive crisis 1/197 (0.5%) 1 0/95 (0%) 0
    Trousseau's syndrome 1/197 (0.5%) 1 0/95 (0%) 0
    Other (Not Including Serious) Adverse Events
    Ramucirumab Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 189/197 (95.9%) 77/95 (81.1%)
    Blood and lymphatic system disorders
    Anaemia 17/197 (8.6%) 26 6/95 (6.3%) 7
    Gastrointestinal disorders
    Abdominal distension 15/197 (7.6%) 17 5/95 (5.3%) 6
    Abdominal pain 36/197 (18.3%) 46 12/95 (12.6%) 16
    Ascites 34/197 (17.3%) 46 7/95 (7.4%) 7
    Constipation 27/197 (13.7%) 32 18/95 (18.9%) 19
    Diarrhoea 32/197 (16.2%) 43 14/95 (14.7%) 18
    Nausea 37/197 (18.8%) 47 10/95 (10.5%) 12
    Vomiting 20/197 (10.2%) 23 7/95 (7.4%) 7
    General disorders
    Asthenia 17/197 (8.6%) 41 3/95 (3.2%) 6
    Chills 0/197 (0%) 0 5/95 (5.3%) 6
    Fatigue 54/197 (27.4%) 78 16/95 (16.8%) 23
    Influenza like illness 10/197 (5.1%) 10 1/95 (1.1%) 1
    Malaise 14/197 (7.1%) 15 5/95 (5.3%) 6
    Oedema peripheral 50/197 (25.4%) 67 13/95 (13.7%) 13
    Pyrexia 18/197 (9.1%) 21 3/95 (3.2%) 3
    Infections and infestations
    Urinary tract infection 10/197 (5.1%) 17 1/95 (1.1%) 2
    Investigations
    Alanine aminotransferase increased 7/197 (3.6%) 12 5/95 (5.3%) 6
    Aspartate aminotransferase increased 16/197 (8.1%) 27 10/95 (10.5%) 15
    Blood bilirubin increased 21/197 (10.7%) 39 8/95 (8.4%) 16
    Gamma-glutamyltransferase increased 2/197 (1%) 2 5/95 (5.3%) 6
    Neutrophil count decreased 12/197 (6.1%) 28 0/95 (0%) 0
    Platelet count decreased 22/197 (11.2%) 60 2/95 (2.1%) 3
    Weight decreased 19/197 (9.6%) 22 6/95 (6.3%) 7
    Metabolism and nutrition disorders
    Decreased appetite 46/197 (23.4%) 57 19/95 (20%) 19
    Hyperkalaemia 13/197 (6.6%) 21 3/95 (3.2%) 3
    Hypoalbuminaemia 20/197 (10.2%) 28 4/95 (4.2%) 4
    Hyponatraemia 11/197 (5.6%) 16 1/95 (1.1%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 20/197 (10.2%) 23 7/95 (7.4%) 8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain 4/197 (2%) 4 8/95 (8.4%) 9
    Nervous system disorders
    Dizziness 9/197 (4.6%) 10 8/95 (8.4%) 8
    Headache 28/197 (14.2%) 36 5/95 (5.3%) 5
    Psychiatric disorders
    Insomnia 21/197 (10.7%) 24 6/95 (6.3%) 8
    Renal and urinary disorders
    Proteinuria 40/197 (20.3%) 66 4/95 (4.2%) 4
    Respiratory, thoracic and mediastinal disorders
    Cough 18/197 (9.1%) 21 6/95 (6.3%) 7
    Dysphonia 10/197 (5.1%) 10 1/95 (1.1%) 1
    Dyspnoea 15/197 (7.6%) 18 8/95 (8.4%) 9
    Epistaxis 26/197 (13.2%) 30 3/95 (3.2%) 3
    Skin and subcutaneous tissue disorders
    Pruritus 15/197 (7.6%) 16 5/95 (5.3%) 5
    Rash 13/197 (6.6%) 18 5/95 (5.3%) 5
    Vascular disorders
    Hypertension 48/197 (24.4%) 75 12/95 (12.6%) 13

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

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

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone (800) 545-5979
    Email ClinicalTrials.gov@Lilly.com
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT02435433
    Other Study ID Numbers:
    • 15755
    • I4T-MC-JVDE
    • 2014-005068-13
    First Posted:
    May 6, 2015
    Last Update Posted:
    Jan 14, 2022
    Last Verified:
    Jan 1, 2022