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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02711553
Recruitment Status : Active, not recruiting
First Posted : March 17, 2016
Results First Posted : February 26, 2021
Last Update Posted : October 20, 2022
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Biliary Tract Cancer
Metastatic Cancer
Advanced Cancer
Interventions Drug: Ramucirumab
Drug: Merestinib
Drug: Cisplatin
Drug: Gemcitabine
Drug: Placebo Oral
Drug: Placebo IV
Enrollment 309
Recruitment Details  
Pre-assignment Details 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
Hide 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
Reason Not Completed
Withdrawal by Subject             2             1             1             0
Lost to Follow-up             3             3             6             3
On Study Treatment at Study Conclusion             1             1             3             1
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
Hide 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 Number of Baseline Participants 106 52 102 49 309
Hide Baseline Analysis Population Description
All randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
63.49  (9.76) 57.06  (11.67) 60.95  (9.14) 62.00  (9.14) 61.33  (10.01)
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
All randomized participants Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
Female 60 26 54 22 162
Male 46 26 48 27 147
All randomized participants who received at least 1 dose of study drug Number Analyzed 104 participants 52 participants 102 participants 48 participants 306 participants
Female 59 26 54 21 160
Male 45 26 48 27 146
[1]
Measure Analysis Population Description: All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
Hispanic or Latino 0 0 0 0 0
Not Hispanic or Latino 0 0 0 0 0
Unknown or Not Reported 106 52 102 49 309
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
American Indian or Alaska Native 0 0 1 0 1
Asian 20 11 26 9 66
Native Hawaiian or Other Pacific Islander 0 0 0 0 0
Black or African American 1 1 1 1 4
White 78 35 70 38 221
More than one race 0 0 0 0 0
Unknown or Not Reported 7 5 4 1 17
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Argentina Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
11 3 8 3 25
Hungary Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
5 7 4 1 17
United States Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
12 3 6 4 25
Czechia Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
2 2 5 2 11
United Kingdom Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
4 2 5 3 14
Russia Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
9 2 4 6 21
Spain Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
8 3 10 1 22
Austria Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
3 2 1 0 6
South Korea Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
8 6 12 4 30
Sweden Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
1 0 3 2 6
Turkey Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
6 7 7 3 23
Belgium Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
6 1 3 4 14
Taiwan Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
9 5 13 4 31
Denmark Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
1 1 3 1 6
Mexico Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
4 0 3 0 7
Australia Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
6 2 2 4 14
France Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
8 5 5 2 20
Germany Number Analyzed 106 participants 52 participants 102 participants 49 participants 309 participants
3 1 8 5 17
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 106 102 101
Median (Inter-Quartile Range)
Unit of Measure: Months
6.47
(3.68 to 8.51)
6.97
(4.34 to 9.79)
6.64
(4.11 to 9.72)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
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
Estimation Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
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
Estimation Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
2.Secondary Outcome
Title Overall Survival (OS)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 106 102 101
Median (Inter-Quartile Range)
Unit of Measure: Months
10.45
(8.48 to 11.76)
14.03
(11.96 to 16.36)
13.04
(11.40 to 15.31)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0870
Comments [Not Specified]
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
Estimation Comments Stratified by geographical region, pathological diagnosis, metastatic disease.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7599
Comments [Not Specified]
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
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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 106 102 101
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
31.1
(22.3 to 39.9)
19.6
(11.9 to 27.3)
32.7
(23.5 to 41.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.878
Comments [Not Specified]
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
Estimation Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.023
Comments [Not Specified]
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
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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 106 102 101
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
81.1
(73.7 to 88.6)
83.3
(76.1 to 90.6)
78.2
(70.2 to 86.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.680
Comments [Not Specified]
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
Estimation Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine, Pooled Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.499
Comments [Not Specified]
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
Estimation Comments Stratified by randomization strata Geographical Region, Pathological Diagnosis, Metastatic Disease.
5.Secondary Outcome
Title Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 86
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Microgram per milliliter (µg/mL)
Cycle 1 Day 8 (Week 1) Number Analyzed 86 participants
46.2
(32%)
Cycle 2 Day 1 (Week 3) Number Analyzed 74 participants
38.1
(42%)
Cycle 3 Day 1 (Week 6) Number Analyzed 53 participants
54.1
(43%)
Cycle 4 Day 1 (Week 9) Number Analyzed 48 participants
77.3
(50%)
Cycle 5 Day 1 (Week 12) Number Analyzed 32 participants
82.9
(35%)
Cycle 7 Day 1 (Week 18) Number Analyzed 19 participants
85.6
(39%)
Cycle 9 Day 1 (Week 24) Number Analyzed 9 participants
82.7
(35%)
Cycle 13 Day 1 (Week 36) Number Analyzed 7 participants
97.7
(23%)
6.Secondary Outcome
Title PK: Plasma Concentration of Merestinib
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
7.Secondary Outcome
Title Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 74 37
Measure Type: Count of Participants
Unit of Measure: Participants
3 0
8.Secondary Outcome
Title Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 97 95 95
Least Squares Mean (Standard Error)
Unit of Measure: Units on a Scale
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)
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
Hide 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 [Not Specified]
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 [Not Specified]
9.Secondary Outcome
Title Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 45 42 40
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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 millimeter (the worst health you can imagine) to 100 millimeter (the best health you can imagine).
Time Frame Baseline, Follow Up (Up To 48 Months)
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 45 42 40
Mean (Standard Deviation)
Unit of Measure: millimeter (mm)
66.44  (22.8) 66.57  (21.73) 69.08  (20.03)
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   84/104 (80.77%)      34/52 (65.38%)      71/102 (69.61%)      38/48 (79.17%)    
Hide 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 (50.96%)      25/52 (48.08%)      56/102 (54.90%)      23/48 (47.92%)    
Blood and lymphatic system disorders         
Anemia † 1  3/104 (2.88%)  3 2/52 (3.85%)  2 2/102 (1.96%)  2 1/48 (2.08%)  1
Disseminated intravascular coagulation † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Febrile neutropenia † 1  1/104 (0.96%)  1 2/52 (3.85%)  2 1/102 (0.98%)  1 2/48 (4.17%)  2
Neutropenia † 1  3/104 (2.88%)  3 1/52 (1.92%)  1 5/102 (4.90%)  5 0/48 (0.00%)  0
Pancytopenia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Thrombocytopenia † 1  6/104 (5.77%)  7 3/52 (5.77%)  3 2/102 (1.96%)  2 3/48 (6.25%)  3
Cardiac disorders         
Acute coronary syndrome † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Atrial fibrillation † 1  0/104 (0.00%)  0 3/52 (5.77%)  3 0/102 (0.00%)  0 0/48 (0.00%)  0
Atrial flutter † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Atrioventricular block complete † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Cardiac arrest † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Cardiac failure † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Myocardial infarction † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Supraventricular tachycardia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Tachycardia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Congenital, familial and genetic disorders         
Pyloric stenosis † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Ear and labyrinth disorders         
Hypoacusis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Vertigo † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Vestibular disorder † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Eye disorders         
Blindness unilateral † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Optic ischaemic neuropathy † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Gastrointestinal disorders         
Abdominal distension † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Abdominal pain † 1  2/104 (1.92%)  2 2/52 (3.85%)  2 4/102 (3.92%)  5 0/48 (0.00%)  0
Anastomotic ulcer perforation † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Ascites † 1  3/104 (2.88%)  4 0/52 (0.00%)  0 2/102 (1.96%)  2 2/48 (4.17%)  3
Constipation † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Diarrhoea † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Duodenal ulcer † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Duodenal ulcer haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Gastric haemorrhage † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Gastritis erosive † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Gastrooesophageal reflux disease † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Haematemesis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Ileus † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Impaired gastric emptying † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Inguinal hernia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Intestinal obstruction † 1  2/104 (1.92%)  2 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Intestinal perforation † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Mesenteric vein thrombosis † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Nausea † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 2/102 (1.96%)  3 0/48 (0.00%)  0
Obstruction gastric † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Oesophageal ulcer † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Oesophageal varices haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Rectal haemorrhage † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Stomatitis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Upper gastrointestinal haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Vomiting † 1  3/104 (2.88%)  4 1/52 (1.92%)  1 4/102 (3.92%)  5 1/48 (2.08%)  1
General disorders         
Catheter site extravasation † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Death † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Device related thrombosis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Fatigue † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
General physical health deterioration † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Implant site haemorrhage † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Localised oedema † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Multiple organ dysfunction syndrome † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Non-cardiac chest pain † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Oedema peripheral † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Pyrexia † 1  5/104 (4.81%)  9 1/52 (1.92%)  1 4/102 (3.92%)  5 2/48 (4.17%)  4
Sudden death † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Hepatobiliary disorders         
Bile duct obstruction † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 2/102 (1.96%)  2 0/48 (0.00%)  0
Bile duct stenosis † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 1/48 (2.08%)  1
Cholangitis † 1  5/104 (4.81%)  7 0/52 (0.00%)  0 2/102 (1.96%)  2 1/48 (2.08%)  1
Cholangitis acute † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Cholecystitis † 1  0/104 (0.00%)  0 1/52 (1.92%)  2 0/102 (0.00%)  0 0/48 (0.00%)  0
Hyperbilirubinaemia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Hypertransaminasaemia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Jaundice cholestatic † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 2/48 (4.17%)  2
Portal vein thrombosis † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Venoocclusive liver disease † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Infections and infestations         
Abdominal infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Appendicitis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Arthritis bacterial † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Bacteraemia † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Biliary tract infection † 1  3/104 (2.88%)  6 1/52 (1.92%)  1 2/102 (1.96%)  3 1/48 (2.08%)  1
Bronchitis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Cellulitis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Cholangitis infective † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Cholecystitis infective † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Clostridium difficile colitis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Device related infection † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Escherichia bacteraemia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Hepatic infection † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Infection † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Influenza † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Klebsiella bacteraemia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Large intestine infection † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Liver abscess † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 2/102 (1.96%)  2 1/48 (2.08%)  1
Lower respiratory tract infection viral † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Lung infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Meningitis meningococcal † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Parotitis † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Peritonitis bacterial † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Pneumonia † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 1/102 (0.98%)  1 1/48 (2.08%)  2
Respiratory tract infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Respiratory tract infection viral † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Sepsis † 1  4/104 (3.85%)  5 1/52 (1.92%)  2 4/102 (3.92%)  6 1/48 (2.08%)  1
Septic shock † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Upper respiratory tract infection † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Urinary tract infection † 1  2/104 (1.92%)  2 1/52 (1.92%)  1 2/102 (1.96%)  2 0/48 (0.00%)  0
Urosepsis † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Injury, poisoning and procedural complications         
Infusion related reaction † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Post procedural haemorrhage † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Procedural haemorrhage † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Investigations         
Alanine aminotransferase increased † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Blood bilirubin increased † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Blood creatinine increased † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
C-reactive protein increased † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Metabolism and nutrition disorders         
Decreased appetite † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Dehydration † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 1/102 (0.98%)  1 1/48 (2.08%)  1
Hypercalcaemia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Hyperkalaemia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Hypoglycaemia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Hypokalaemia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Hypomagnesaemia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Hyponatraemia † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 2/102 (1.96%)  2 1/48 (2.08%)  1
Hypoproteinaemia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Arthritis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Back pain † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Bursitis † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Musculoskeletal pain † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Neck pain † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Pain in extremity † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Tumour associated fever † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Nervous system disorders         
Cerebral ischaemia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 2/102 (1.96%)  2 0/48 (0.00%)  0
Depressed level of consciousness † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Haemorrhage intracranial † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Hemiparesis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Ischaemic stroke † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Posterior reversible encephalopathy syndrome † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Seizure † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Spinal cord compression † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Transient ischaemic attack † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Product Issues         
Device occlusion † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Stent malfunction † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Psychiatric disorders         
Confusional state † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Delirium † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Renal and urinary disorders         
Acute kidney injury † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 3/102 (2.94%)  3 2/48 (4.17%)  2
Reproductive system and breast disorders         
Benign prostatic hyperplasia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Acute respiratory distress syndrome † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Chronic obstructive pulmonary disease † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Dyspnoea † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 2/102 (1.96%)  2 1/48 (2.08%)  1
Dyspnoea exertional † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Hypoxia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Pneumothorax † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Pulmonary embolism † 1  3/104 (2.88%)  3 0/52 (0.00%)  0 5/102 (4.90%)  5 1/48 (2.08%)  1
Pulmonary fibrosis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Skin and subcutaneous tissue disorders         
Dermal cyst † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Rash † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Rash generalised † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Vascular disorders         
Deep vein thrombosis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Embolism venous † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Peripheral arterial occlusive disease † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Peripheral embolism † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Venous thrombosis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
1
Term from vocabulary, MedDRA 22.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
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 (98.08%)      49/52 (94.23%)      100/102 (98.04%)      48/48 (100.00%)    
Blood and lymphatic system disorders         
Anemia † 1  52/104 (50.00%)  94 22/52 (42.31%)  39 40/102 (39.22%)  80 24/48 (50.00%)  33
Coagulopathy † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Febrile neutropenia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Haemolytic uraemic syndrome † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Iron deficiency anaemia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Leukocytosis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Leukopenia † 1  20/104 (19.23%)  45 9/52 (17.31%)  23 20/102 (19.61%)  46 4/48 (8.33%)  15
Lymphopenia † 1  3/104 (2.88%)  4 2/52 (3.85%)  3 2/102 (1.96%)  3 2/48 (4.17%)  5
Neutropenia † 1  63/104 (60.58%)  160 24/52 (46.15%)  63 52/102 (50.98%)  122 19/48 (39.58%)  60
Spleen disorder † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Thrombocytopenia † 1  56/104 (53.85%)  120 15/52 (28.85%)  31 42/102 (41.18%)  80 15/48 (31.25%)  33
Thrombocytopenic purpura † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Thrombocytosis † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Cardiac disorders         
Angina pectoris † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Atrial fibrillation † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Atrial flutter † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Bradycardia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Cardiac failure † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Cardiac failure congestive † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Coronary artery disease † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Palpitations † 1  2/104 (1.92%)  2 1/52 (1.92%)  1 1/102 (0.98%)  1 1/48 (2.08%)  1
Sinus bradycardia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Sinus tachycardia † 1  3/104 (2.88%)  4 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Tachycardia † 1  2/104 (1.92%)  2 2/52 (3.85%)  2 2/102 (1.96%)  2 1/48 (2.08%)  1
Ventricular arrhythmia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Congenital, familial and genetic disorders         
Atrial septal defect † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Hydrocele † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Pyloric stenosis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Ear and labyrinth disorders         
Deafness † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Ear pain † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Hypoacusis † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 1/102 (0.98%)  1 2/48 (4.17%)  2
Presbyacusis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Tinnitus † 1  5/104 (4.81%)  5 2/52 (3.85%)  2 2/102 (1.96%)  2 1/48 (2.08%)  1
Vertigo † 1  2/104 (1.92%)  2 1/52 (1.92%)  1 2/102 (1.96%)  2 3/48 (6.25%)  3
Endocrine disorders         
Cushingoid † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Endocrine disorder † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Hyperparathyroidism † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Hyperthyroidism † 1  0/104 (0.00%)  0 1/52 (1.92%)  3 0/102 (0.00%)  0 1/48 (2.08%)  1
Hypothyroidism † 1  2/104 (1.92%)  3 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Inappropriate antidiuretic hormone secretion † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Eye disorders         
Conjunctival haemorrhage † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Diplopia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Dry eye † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Eye irritation † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Eye pruritus † 1  0/104 (0.00%)  0 1/52 (1.92%)  2 0/102 (0.00%)  0 0/48 (0.00%)  0
Eyelid irritation † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Eyelid oedema † 1  3/104 (2.88%)  3 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Lacrimation increased † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Ocular hyperaemia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Optic neuropathy † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Periorbital oedema † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Vision blurred † 1  4/104 (3.85%)  7 0/52 (0.00%)  0 3/102 (2.94%)  5 0/48 (0.00%)  0
Visual acuity reduced † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Visual impairment † 1  0/104 (0.00%)  0 1/52 (1.92%)  2 0/102 (0.00%)  0 0/48 (0.00%)  0
Gastrointestinal disorders         
Abdominal discomfort † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 1/48 (2.08%)  2
Abdominal distension † 1  10/104 (9.62%)  13 2/52 (3.85%)  2 14/102 (13.73%)  15 2/48 (4.17%)  2
Abdominal pain † 1  39/104 (37.50%)  54 13/52 (25.00%)  27 33/102 (32.35%)  47 15/48 (31.25%)  26
Abdominal rigidity † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Aerophagia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  3 0/48 (0.00%)  0
Anal fissure † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Ascites † 1  13/104 (12.50%)  13 2/52 (3.85%)  2 10/102 (9.80%)  11 1/48 (2.08%)  1
Cheilitis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Constipation † 1  33/104 (31.73%)  49 14/52 (26.92%)  23 36/102 (35.29%)  59 13/48 (27.08%)  16
Defaecation urgency † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Dental caries † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Diarrhoea † 1  34/104 (32.69%)  50 9/52 (17.31%)  10 29/102 (28.43%)  36 7/48 (14.58%)  13
Dry mouth † 1  5/104 (4.81%)  11 1/52 (1.92%)  1 2/102 (1.96%)  2 1/48 (2.08%)  1
Dyspepsia † 1  5/104 (4.81%)  8 2/52 (3.85%)  6 4/102 (3.92%)  5 4/48 (8.33%)  6
Dysphagia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 4/102 (3.92%)  4 0/48 (0.00%)  0
Epigastric discomfort † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Faeces discoloured † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Flatulence † 1  3/104 (2.88%)  3 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Food poisoning † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Gastric haemorrhage † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Gastric ulcer † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Gastritis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 3/102 (2.94%)  3 1/48 (2.08%)  1
Gastritis erosive † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Gastroduodenal haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Gastrooesophageal reflux disease † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 4/102 (3.92%)  5 1/48 (2.08%)  1
Gingival bleeding † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Gingival pain † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Haematochezia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 2/48 (4.17%)  2
Haemorrhoidal haemorrhage † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Haemorrhoids † 1  4/104 (3.85%)  4 1/52 (1.92%)  1 4/102 (3.92%)  4 2/48 (4.17%)  2
Ileus † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  2 0/48 (0.00%)  0
Ileus paralytic † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Impaired gastric emptying † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Inguinal hernia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  2 0/48 (0.00%)  0
Intestinal obstruction † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Intra-abdominal haemorrhage † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Large intestinal haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Melaena † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Mouth ulceration † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Nausea † 1  52/104 (50.00%)  92 21/52 (40.38%)  39 58/102 (56.86%)  97 15/48 (31.25%)  24
Obstruction gastric † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Odynophagia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Oesophageal varices haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 2/102 (1.96%)  3 0/48 (0.00%)  0
Oral dysaesthesia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Oral pain † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Pancreatic failure † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Pancreatitis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Periodontal disease † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Proctalgia † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Rectal haemorrhage † 1  1/104 (0.96%)  2 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Reflux gastritis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Regurgitation † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  3
Salivary hypersecretion † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Stomatitis † 1  11/104 (10.58%)  15 5/52 (9.62%)  7 4/102 (3.92%)  6 2/48 (4.17%)  2
Toothache † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Upper gastrointestinal haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Vomiting † 1  34/104 (32.69%)  130 12/52 (23.08%)  18 34/102 (33.33%)  93 12/48 (25.00%)  26
General disorders         
Catheter site pain † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Chest discomfort † 1  2/104 (1.92%)  2 1/52 (1.92%)  1 0/102 (0.00%)  0 1/48 (2.08%)  1
Chest pain † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 0/102 (0.00%)  0 0/48 (0.00%)  0
Chills † 1  8/104 (7.69%)  18 1/52 (1.92%)  1 5/102 (4.90%)  8 2/48 (4.17%)  2
Device related thrombosis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Early satiety † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 1/48 (2.08%)  1
Face oedema † 1  5/104 (4.81%)  7 1/52 (1.92%)  1 7/102 (6.86%)  10 2/48 (4.17%)  2
Fatigue † 1  61/104 (58.65%)  94 17/52 (32.69%)  22 53/102 (51.96%)  90 22/48 (45.83%)  34
Gait disturbance † 1  1/104 (0.96%)  2 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
General physical health deterioration † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 1/48 (2.08%)  1
Generalised oedema † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Impaired healing † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Influenza like illness † 1  2/104 (1.92%)  3 2/52 (3.85%)  2 3/102 (2.94%)  4 0/48 (0.00%)  0
Infusion site extravasation † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 1/48 (2.08%)  1
Infusion site thrombosis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Injection site haemorrhage † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Injection site rash † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Injection site reaction † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Localised oedema † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 3/102 (2.94%)  3 0/48 (0.00%)  0
Malaise † 1  3/104 (2.88%)  3 0/52 (0.00%)  0 1/102 (0.98%)  1 1/48 (2.08%)  1
Mucosal inflammation † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 3/102 (2.94%)  3 2/48 (4.17%)  2
Non-cardiac chest pain † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 3/102 (2.94%)  3 1/48 (2.08%)  2
Oedema † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 4/102 (3.92%)  4 0/48 (0.00%)  0
Oedema peripheral † 1  33/104 (31.73%)  46 7/52 (13.46%)  10 18/102 (17.65%)  22 6/48 (12.50%)  9
Pain † 1  5/104 (4.81%)  5 2/52 (3.85%)  2 1/102 (0.98%)  1 3/48 (6.25%)  3
Peripheral swelling † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 1/102 (0.98%)  2 1/48 (2.08%)  1
Pyrexia † 1  25/104 (24.04%)  46 6/52 (11.54%)  12 26/102 (25.49%)  52 9/48 (18.75%)  11
Secretion discharge † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Hepatobiliary disorders         
Bile duct obstruction † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 1/102 (0.98%)  1 1/48 (2.08%)  1
Bile duct stenosis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Biliary colic † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Cholangitis † 1  3/104 (2.88%)  6 1/52 (1.92%)  1 3/102 (2.94%)  3 4/48 (8.33%)  4
Hepatic failure † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Hepatic infarction † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Hepatic pain † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 2/102 (1.96%)  3 0/48 (0.00%)  0
Hepatocellular injury † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Hepatomegaly † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Hyperbilirubinaemia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  1 2/48 (4.17%)  2
Hypertransaminasaemia † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Jaundice † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 1/102 (0.98%)  1 2/48 (4.17%)  2
Jaundice cholestatic † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Portal vein stenosis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Portal vein thrombosis † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 3/102 (2.94%)  3 0/48 (0.00%)  0
Immune system disorders         
Allergy to arthropod sting † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Contrast media allergy † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Drug hypersensitivity † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 3/102 (2.94%)  3 0/48 (0.00%)  0
Hypersensitivity † 1  3/104 (2.88%)  4 1/52 (1.92%)  1 2/102 (1.96%)  2 0/48 (0.00%)  0
Seasonal allergy † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 0/102 (0.00%)  0 1/48 (2.08%)  1
Infections and infestations         
Abdominal infection † 1  1/104 (0.96%)  1 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Acute sinusitis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Bacteraemia † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Biliary sepsis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Biliary tract infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 1/102 (0.98%)  2 0/48 (0.00%)  0
Bronchitis † 1  0/104 (0.00%)  0 2/52 (3.85%)  3 0/102 (0.00%)  0 0/48 (0.00%)  0
Candida infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Cellulitis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Cholecystitis infective † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 1/48 (2.08%)  1
Clostridium difficile colitis † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 1/48 (2.08%)  1
Cystitis † 1  2/104 (1.92%)  2 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Device related infection † 1  4/104 (3.85%)  4 0/52 (0.00%)  0 2/102 (1.96%)  2 0/48 (0.00%)  0
Diverticulitis † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Ear infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Enterococcal infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Escherichia infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Fungaemia † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Fungal infection † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 0/102 (0.00%)  0 1/48 (2.08%)  1
Gastroenteritis viral † 1  0/104 (0.00%)  0 0/52 (0.00%)  0 1/102 (0.98%)  1 0/48 (0.00%)  0
Gingivitis † 1  4/104 (3.85%)  4 1/52 (1.92%)  2 3/102 (2.94%)  3 1/48 (2.08%)  1
Helicobacter infection † 1  1/104 (0.96%)  1 0/52 (0.00%)  0 0/102 (0.00%)  0 0/48 (0.00%)  0
Hepatic infection † 1  0/104 (0.00%)  0 1/52 (1.92%)  1 1/102 (0.98%)  1 0/48 (0.00%)  0
Herpes zoster † 1  0/104 (0.00%)  0 2/52 (3.85%)  2 0/102 (0.00%)  0 0/48 (0.00%)  0
Hordeolum † 1  1/104 (0.96%)  1