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Study of Two Doses of Pembrolizumab (MK-3475) Versus Docetaxel in Previously Treated Participants With Non-Small Cell Lung Cancer (MK-3475-010/KEYNOTE-010)

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ClinicalTrials.gov Identifier: NCT01905657
Recruitment Status : Active, not recruiting
First Posted : July 23, 2013
Results First Posted : January 18, 2017
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Non Small Cell Lung Cancer (NSCLC)
Interventions Biological: Pembrolizumab
Drug: Docetaxel
Enrollment 1061
Recruitment Details Participants who had non-small cell lung cancer (NSCLC) and whose tumors were assessed as being programmed cell death ligand 1 (PD-L1) positive were recruited for this study.
Pre-assignment Details The data cut-off date for this results disclosure was 30 Sep 2015, at which time 159 participants were continuing on study treatment.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description Participants received pembrolizumab 2 mg/kg intravenously (IV) over 30 minutes every 3 weeks (Q3W) for up to 2 years. Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years. Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
Period Title: Overall Study
Started 345 346 343
Treated 339 343 309
Completed 0 0 15
Not Completed 345 346 328
Reason Not Completed
Not Treated             0             1             0
Adverse Event             33             32             47
Death             21             21             21
Other             3             7             1
Physician Decision             82             74             113
Progressive Disease             124             126             89
Protocol Violation             2             1             1
Withdrawal by Subject             5             10             45
Continuing in Study             74             74             11
Excluded from Efficacy Analysis             1             0             0
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2 Total
Hide Arm/Group Description Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years. Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years. Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W. Total of all reporting groups
Overall Number of Baseline Participants 344 346 343 1033
Hide Baseline Analysis Population Description
The Intent-To-Treat population consisted of all participants who were randomized. Participants were included in the treatment group to which they were randomized. Data from one participant in the Pembrolizumab 2 mg/kg group were excluded from efficacy analyses due to Good Clinical Practice (GCP) non-compliance.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 344 participants 346 participants 343 participants 1033 participants
62.1  (9.6) 62.3  (9.7) 61.6  (9.8) 62.0  (9.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 344 participants 346 participants 343 participants 1033 participants
Female
132
  38.4%
133
  38.4%
134
  39.1%
399
  38.6%
Male
212
  61.6%
213
  61.6%
209
  60.9%
634
  61.4%
PD-L1 Tumor Expression Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 344 participants 346 participants 343 participants 1033 participants
Weakly PD-L1 Positive 205 195 191 591
Strongly PD-L1 Positive 139 151 152 442
[1]
Measure Description: PD-L1 expression was evaluated by immunohistochemistry (IHC) assay with a newly obtained tumor tissue with biopsy. If PD-L1 expression was observed in >1%, but ≤49% of tumor cells, a participant was categorized as weakly PD-L1 positive. If PD-L1 expression was observed in ≥50% of tumor cells, a participant was categorized as strongly PD-L1 positive.
1.Primary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from randomization to death due to any cause. OS was analyzed using the Kaplan-Meier method and is reported in months.
Time Frame Through database cutoff date of 30 Sep 2015 (Approximately 23 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-To-Treat population consisted of all participants who were randomized and were included in the efficacy analysis. Participants were included in the treatment group to which they were randomized.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description:
Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
Overall Number of Participants Analyzed 344 346 343
Median (95% Confidence Interval)
Unit of Measure: Months
Strongly PD-L1 Positive (n=139,151,152)
14.9 [1] 
(10.4 to NA)
17.3 [1] 
(11.8 to NA)
8.2
(6.4 to 10.7)
All PD-L1 Positive (n=344, 346, 343)
10.4
(9.4 to 11.9)
12.7
(10.0 to 17.3)
8.5
(7.5 to 9.8)
[1]
Upper limit OS not reached.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with strongly PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00024
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.54
Confidence Interval (2-Sided) 95%
0.38 to 0.77
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=Docetaxel 75 mg/m^2
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with strongly PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00002
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
0.36 to 0.70
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Docetaxel 75 mg/m^2
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00076
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.58 to 0.88
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=Docetaxel 75 mg/m^2
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.00001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.61
Confidence Interval (2-Sided) 95%
0.49 to 0.75
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Docetaxel 75 mg/m^2
2.Primary Outcome
Title Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Hide Description PFS was defined as the time from the first day of study treatment to the first documented disease progression per RECIST 1.1 based on blinded independent central radiologists’ review or death due to any cause, whichever occurred first. Using RECIST 1.1, progressive disease was defined as either a 20% relative increase in the sum of diameters of target lesions, taking as reference the smallest sum on study OR an absolute increase of >5 mm in the sum of lesions, OR the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and is reported in months.
Time Frame Through database cutoff date of 30 Sep 2015 (Approximately 23 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all participants who were randomized and included in the efficacy analysis. Participants were included in the treatment group to which they were randomized.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description:
Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
Overall Number of Participants Analyzed 344 346 343
Median (95% Confidence Interval)
Unit of Measure: Months
Strongly PD-L1 Positive (n=139, 151, 152)
5.2
(4.0 to 6.5)
5.2
(4.1 to 8.1)
4.1
(3.6 to 4.3)
All PD-L1 Positive (n=344, 346, 343)
3.9
(3.1 to 4.1)
4.0
(2.6 to 4.3)
4.0
(3.1 to 4.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with strongly PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00009
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio, log
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.43 to 0.77
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=Docetaxel 75 mg/m^2
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with strongly PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00007
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio, log
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.45 to 0.78
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Docetaxel 75 mg/m^2
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.06758
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.73 to 1.04
Estimation Comments Numerator=Pembrolizumab 2 mg/kg Denominator=Docetaxel 75 mg/m^2
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00462
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.66 to 0.94
Estimation Comments Numerator=Pembrolizumab 10 mg/kg Denominator=Docetaxel 75 mg/m^2
3.Primary Outcome
Title Percentage of Participants Experiencing Adverse Events (AEs)
Hide Description An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. After discontinuation of study drug, each participant was monitored for a minimum of 30 days after last dose of study drug (serious AEs were monitored for up to 90 days after last dose of study drug).
Time Frame AEs: Up to 30 days after last dose of study drug (Up to approximately 24 months). Serious AEs: Up to 90 days after last dose of study drug (Up to approximately 27 months).
Hide Outcome Measure Data
Hide Analysis Population Description
The All Participants As Treated (APAT) population consisted of all participants who received at least one dose of study drug. Participants were included in the treatment group based on the study treatment they received.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description:
Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
Overall Number of Participants Analyzed 339 343 309
Measure Type: Number
Unit of Measure: Percentage of Participants
97.6 96.2 96.1
4.Primary Outcome
Title Percentage of Participants Discontinuing Study Drug Due to AEs
Hide Description An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE.
Time Frame Up to approximately 23 months
Hide Outcome Measure Data
Hide Analysis Population Description
The APAT population consisted of all participants who received at least one dose of study drug. Participants were included in the treatment group based on the study treatment they received.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description:
Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
Overall Number of Participants Analyzed 339 343 309
Measure Type: Number
Unit of Measure: Percentage of Participants
8.3 7.6 13.6
5.Secondary Outcome
Title Overall Response Rate (ORR) by RECIST 1.1
Hide Description ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR; disappearance of all target lesions) or Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) based on blinded independent central radiologists' review using RECIST 1.1.
Time Frame Through database cutoff date of 30 Sep 2015 (Approximately 23 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all participants who were randomized and included in the efficacy analysis. Participants were included in the treatment group to which they were randomized.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description:
Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
Overall Number of Participants Analyzed 344 346 343
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
Strongly PD-L1 Positive (n=139, 151, 152)
30.2
(22.7 to 38.6)
29.1
(22.0 to 37.1)
7.9
(4.1 to 13.4)
All PD-L1 Positive (n=344, 346, 343)
18.0
(14.1 to 22.5)
18.5
(14.5 to 23.0)
9.3
(6.5 to 12.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
Comments In participants with strongly PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.66608
Comments [Not Specified]
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value -2.3
Confidence Interval (2-Sided) 95%
-12.7 to 8.2
Estimation Comments This is an adjusted risk difference estimated by stratified Miettinen & Nurminen method.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with strongly PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.00001
Comments [Not Specified]
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 22.2
Confidence Interval (2-Sided) 95%
14.0 to 30.7
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 2 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00045
Comments [Not Specified]
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 8.7
Confidence Interval (2-Sided) 95%
3.6 to 13.9
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Pembrolizumab 10 mg/kg, Docetaxel 75 mg/m^2
Comments In participants with PD-L1 positive tumors
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00024
Comments [Not Specified]
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 9.1
Confidence Interval (2-Sided) 95%
4.1 to 14.3
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Duration of Response (DOR) by RECIST 1.1
Hide Description DOR is measured from the time measurement criteria were first met for CR/PR (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented (taking as reference for progressive disease the smallest measurements recorded on study). DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. DOR was analyzed using the Kaplan-Meier method and is reported in weeks.
Time Frame Through database cutoff date of 30 Sep 2015 (Approximately 23 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all participants who were randomized. Participants were included in the treatment group to which they were randomized.
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description:
Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years.
Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
Overall Number of Participants Analyzed 344 346 343
Median (Full Range)
Unit of Measure: Weeks
Strongly PD-L1 Positive (n=139, 151, 152)
NA [1] 
(3 to NA)
NA [1] 
(9 to NA)
35
(9 to 38)
All PD-L1 Positive (n=344, 346, 343)
NA [1] 
(3 to NA)
NA [1] 
(9 to NA)
27 [2] 
(6 to NA)
[1]
Median DOR: Not reached. DOR upper limit: No progressive disease by the time of last disease assessment.
[2]
DOR upper limit: No progressive disease by the time of last disease assessment.
Time Frame AEs: Up to 30 days after last dose of study drug (Up to approximately 24 months). Serious AEs: Up to 90 days after last dose of study drug (Up to approximately 27 months).
Adverse Event Reporting Description The APAT population consisted of all participants who received at least one dose of study drug. Participants were included in the treatment group based on the study treatment they received.
 
Arm/Group Title Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Hide Arm/Group Description Participants received pembrolizumab 2 mg/kg IV over 30 minutes Q3W for up to 2 years. Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years. Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years. Participants who experienced disease progression, may have been eligible to crossover to receive pembrolizumab 2 mg/kg Q3W.
All-Cause Mortality
Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   115/339 (33.92%)      131/343 (38.19%)      107/309 (34.63%)    
Blood and lymphatic system disorders       
Anaemia  1  2/339 (0.59%)  2 4/343 (1.17%)  4 1/309 (0.32%)  1
Bone marrow failure  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Eosinophilia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Febrile neutropenia  1  1/339 (0.29%)  1 1/343 (0.29%)  1 11/309 (3.56%)  11
Leukocytosis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Leukopenia  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Lymph node pain  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Microcytic anaemia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Neutropenia  1  0/339 (0.00%)  0 0/343 (0.00%)  0 5/309 (1.62%)  5
Normochromic normocytic anaemia  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Cardiac disorders       
Acute coronary syndrome  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Acute myocardial infarction  1  1/339 (0.29%)  1 0/343 (0.00%)  0 1/309 (0.32%)  1
Arrhythmia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Arteriosclerosis coronary artery  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Atrial fibrillation  1  2/339 (0.59%)  3 1/343 (0.29%)  1 2/309 (0.65%)  2
Atrial flutter  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Atrial thrombosis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Atrioventricular block complete  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Bradycardia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Cardiac arrest  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Cardiac failure  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Cardiac failure acute  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Cardiac tamponade  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Cardio-respiratory arrest  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Cardiomyopathy  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Cardiopulmonary failure  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Coronary artery disease  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Myocardial infarction  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Palpitations  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Pericardial effusion  1  4/339 (1.18%)  4 2/343 (0.58%)  2 1/309 (0.32%)  1
Pericarditis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 1/309 (0.32%)  2
Tachycardia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Ventricular fibrillation  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Congenital, familial and genetic disorders       
Pyloric stenosis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Tracheo-oesophageal fistula  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Endocrine disorders       
Adrenal insufficiency  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Hyperthyroidism  1  0/339 (0.00%)  0 2/343 (0.58%)  2 0/309 (0.00%)  0
Hypopituitarism  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Hypothyroidism  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain  1  1/339 (0.29%)  2 1/343 (0.29%)  1 1/309 (0.32%)  1
Abdominal pain lower  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Ascites  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Colitis  1  3/339 (0.88%)  3 0/343 (0.00%)  0 0/309 (0.00%)  0
Colitis ischaemic  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Constipation  1  1/339 (0.29%)  1 1/343 (0.29%)  1 2/309 (0.65%)  2
Diarrhoea  1  0/339 (0.00%)  0 0/343 (0.00%)  0 2/309 (0.65%)  2
Dysphagia  1  0/339 (0.00%)  0 3/343 (0.87%)  4 1/309 (0.32%)  1
Faecaloma  1  2/339 (0.59%)  2 0/343 (0.00%)  0 0/309 (0.00%)  0
Gastric haemorrhage  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Gastritis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Gastrooesophageal reflux disease  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Ileus  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Inguinal hernia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Intra-abdominal haemorrhage  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Large intestinal obstruction  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Nausea  1  2/339 (0.59%)  2 0/343 (0.00%)  0 0/309 (0.00%)  0
Oesophageal obstruction  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Oesophageal stenosis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 2/309 (0.65%)  2
Pancreatitis  1  2/339 (0.59%)  2 0/343 (0.00%)  0 0/309 (0.00%)  0
Upper gastrointestinal haemorrhage  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Vomiting  1  1/339 (0.29%)  1 0/343 (0.00%)  0 1/309 (0.32%)  1
General disorders       
Asthenia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Chest pain  1  2/339 (0.59%)  2 1/343 (0.29%)  1 0/309 (0.00%)  0
Death  1  3/339 (0.88%)  3 3/343 (0.87%)  3 1/309 (0.32%)  1
Device dislocation  1  0/339 (0.00%)  0 1/343 (0.29%)  2 0/309 (0.00%)  0
Fatigue  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
General physical health deterioration  1  3/339 (0.88%)  3 1/343 (0.29%)  1 1/309 (0.32%)  1
Malaise  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Mucosal inflammation  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Multi-organ failure  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Oedema  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Oedema peripheral  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Pain  1  2/339 (0.59%)  2 1/343 (0.29%)  1 1/309 (0.32%)  1
Pyrexia  1  2/339 (0.59%)  2 3/343 (0.87%)  3 4/309 (1.29%)  4
Hepatobiliary disorders       
Autoimmune hepatitis  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Hepatic failure  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Hepatocellular injury  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Jaundice cholestatic  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Immune system disorders       
Drug hypersensitivity  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Infections and infestations       
Bronchitis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 3/309 (0.97%)  3
Cellulitis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Clostridium difficile infection  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Device related infection  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Device related sepsis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Diverticulitis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Endocarditis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
External ear cellulitis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Gastroenteritis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 1/309 (0.32%)  1
Gastrointestinal infection  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Herpes zoster  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Infectious colitis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Infectious pleural effusion  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Influenza  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Laryngitis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Lower respiratory tract infection  1  0/339 (0.00%)  0 1/343 (0.29%)  1 2/309 (0.65%)  2
Lung infection  1  2/339 (0.59%)  2 0/343 (0.00%)  0 3/309 (0.97%)  3
Mucosal infection  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Nasopharyngitis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Osteomyelitis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Phlebitis infective  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Pleural infection  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Pneumocystis jirovecii pneumonia  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Pneumonia  1  15/339 (4.42%)  16 21/343 (6.12%)  22 16/309 (5.18%)  18
Pneumonia bacterial  1  1/339 (0.29%)  1 1/343 (0.29%)  1 1/309 (0.32%)  1
Pneumonia haemophilus  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Pneumonia pneumococcal  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Pyelonephritis acute  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Pyopneumothorax  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Respiratory tract infection  1  3/339 (0.88%)  3 3/343 (0.87%)  3 3/309 (0.97%)  3
Respiratory tract infection viral  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Sepsis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Septic shock  1  0/339 (0.00%)  0 0/343 (0.00%)  0 2/309 (0.65%)  2
Staphylococcal infection  1  1/339 (0.29%)  1 0/343 (0.00%)  0 1/309 (0.32%)  1
Upper respiratory tract infection  1  0/339 (0.00%)  0 0/343 (0.00%)  0 3/309 (0.97%)  3
Urinary tract infection  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Urosepsis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 1/309 (0.32%)  1
Wound sepsis  1  0/339 (0.00%)  0 1/343 (0.29%)  2 0/309 (0.00%)  0
Injury, poisoning and procedural complications       
Accidental overdose  1  0/339 (0.00%)  0 1/343 (0.29%)  3 0/309 (0.00%)  0
Contusion  1  0/339 (0.00%)  0 1/343 (0.29%)  1 1/309 (0.32%)  1
Fall  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Femur fracture  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Hip fracture  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Humerus fracture  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Incisional hernia, obstructive  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Pneumonitis chemical  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Post procedural urine leak  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Radiation pneumonitis  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Seroma  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Spinal compression fracture  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Thoracic vertebral fracture  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Traumatic intracranial haemorrhage  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Upper limb fracture  1  2/339 (0.59%)  2 0/343 (0.00%)  0 0/309 (0.00%)  0
Investigations       
Alanine aminotransferase increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Aspartate aminotransferase increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Aspiration bronchial  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Blood alkaline phosphatase increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Blood bilirubin increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Blood creatine phosphokinase increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Blood creatinine increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
C-reactive protein increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Gamma-glutamyltransferase increased  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Neutrophil count decreased  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Metabolism and nutrition disorders       
Decreased appetite  1  1/339 (0.29%)  1 0/343 (0.00%)  0 3/309 (0.97%)  3
Dehydration  1  1/339 (0.29%)  1 2/343 (0.58%)  2 4/309 (1.29%)  4
Diabetes mellitus  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Diabetic ketoacidosis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Hypercalcaemia  1  1/339 (0.29%)  1 5/343 (1.46%)  7 0/309 (0.00%)  0
Hypertriglyceridaemia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Hypoalbuminaemia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Hypokalaemia  1  0/339 (0.00%)  0 1/343 (0.29%)  2 0/309 (0.00%)  0
Hypomagnesaemia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Hyponatraemia  1  1/339 (0.29%)  1 2/343 (0.58%)  2 1/309 (0.32%)  1
Hypophosphataemia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Type 1 diabetes mellitus  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Arthralgia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 1/309 (0.32%)  1
Arthritis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Back pain  1  2/339 (0.59%)  2 2/343 (0.58%)  2 1/309 (0.32%)  1
Bone pain  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Flank pain  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Muscle fatigue  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Muscle haemorrhage  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Muscle necrosis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Musculoskeletal chest pain  1  1/339 (0.29%)  2 0/343 (0.00%)  0 0/309 (0.00%)  0
Musculoskeletal pain  1  2/339 (0.59%)  2 0/343 (0.00%)  0 0/309 (0.00%)  0
Myopathy  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Neck pain  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Osteoporosis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Osteoporotic fracture  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Pain in extremity  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Spinal column stenosis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Spinal osteoarthritis  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Synovitis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Basal cell carcinoma  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Cancer pain  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Gastric cancer  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Lung neoplasm malignant  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Malignant neoplasm progression  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Malignant pleural effusion  1  1/339 (0.29%)  2 0/343 (0.00%)  0 0/309 (0.00%)  0
Metastases to central nervous system  1  0/339 (0.00%)  0 1/343 (0.29%)  1 2/309 (0.65%)  2
Metastatic pain  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Tumour associated fever  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Tumour pain  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Nervous system disorders       
Brain oedema  1  1/339 (0.29%)  1 0/343 (0.00%)  0 1/309 (0.32%)  1
Cerebral ischaemia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Cerebrovascular accident  1  1/339 (0.29%)  1 1/343 (0.29%)  1 1/309 (0.32%)  1
Cognitive disorder  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Dizziness  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Haemorrhage intracranial  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Hemiparesis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Ischaemic stroke  1  1/339 (0.29%)  1 2/343 (0.58%)  2 0/309 (0.00%)  0
Myelitis transverse  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Neurological decompensation  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Peripheral sensory neuropathy  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Seizure  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Spinal cord compression  1  0/339 (0.00%)  0 2/343 (0.58%)  2 0/309 (0.00%)  0
Syncope  1  0/339 (0.00%)  0 2/343 (0.58%)  2 1/309 (0.32%)  1
Toxic leukoencephalopathy  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Transient ischaemic attack  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Psychiatric disorders       
Anxiety  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Completed suicide  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Confusional state  1  3/339 (0.88%)  4 0/343 (0.00%)  0 1/309 (0.32%)  1
Delirium  1  0/339 (0.00%)  0 1/343 (0.29%)  1 1/309 (0.32%)  1
Disorientation  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Mental status changes  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury  1  2/339 (0.59%)  2 2/343 (0.58%)  2 1/309 (0.32%)  1
Bladder hypertrophy  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Haematuria  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Renal failure  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Tubulointerstitial nephritis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Urinary bladder polyp  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Urinary retention  1  1/339 (0.29%)  1 0/343 (0.00%)  0 1/309 (0.32%)  1
Reproductive system and breast disorders       
Erectile dysfunction  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Chronic obstructive pulmonary disease  1  6/339 (1.77%)  6 1/343 (0.29%)  2 1/309 (0.32%)  1
Dyspnoea  1  6/339 (1.77%)  6 2/343 (0.58%)  2 6/309 (1.94%)  7
Haemoptysis  1  3/339 (0.88%)  3 1/343 (0.29%)  1 0/309 (0.00%)  0
Hypoxia  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Interstitial lung disease  1  0/339 (0.00%)  0 1/343 (0.29%)  1 1/309 (0.32%)  1
Painful respiration  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Pleural effusion  1  4/339 (1.18%)  5 4/343 (1.17%)  5 3/309 (0.97%)  3
Pleurisy  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Pleuritic pain  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Pneumonia aspiration  1  1/339 (0.29%)  1 2/343 (0.58%)  2 1/309 (0.32%)  1
Pneumonitis  1  8/339 (2.36%)  9 9/343 (2.62%)  9 2/309 (0.65%)  2
Pneumothorax  1  0/339 (0.00%)  0 0/343 (0.00%)  0 3/309 (0.97%)  3
Pulmonary embolism  1  8/339 (2.36%)  8 7/343 (2.04%)  7 5/309 (1.62%)  5
Pulmonary haemorrhage  1  0/339 (0.00%)  0 2/343 (0.58%)  2 2/309 (0.65%)  2
Pulmonary hypertension  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Pulmonary oedema  1  0/339 (0.00%)  0 2/343 (0.58%)  2 0/309 (0.00%)  0
Pulmonary vascular disorder  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Respiratory distress  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Respiratory failure  1  2/339 (0.59%)  2 1/343 (0.29%)  1 2/309 (0.65%)  2
Skin and subcutaneous tissue disorders       
Drug eruption  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Rash maculo-papular  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Vascular disorders       
Deep vein thrombosis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 2/309 (0.65%)  2
Embolism  1  1/339 (0.29%)  1 1/343 (0.29%)  1 0/309 (0.00%)  0
Femoral artery occlusion  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Hypertension  1  0/339 (0.00%)  0 0/343 (0.00%)  0 1/309 (0.32%)  1
Hypotension  1  0/339 (0.00%)  0 1/343 (0.29%)  1 2/309 (0.65%)  2
Peripheral ischaemia  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Superior vena cava occlusion  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Superior vena cava syndrome  1  2/339 (0.59%)  2 0/343 (0.00%)  0 1/309 (0.32%)  1
Thrombosis  1  0/339 (0.00%)  0 1/343 (0.29%)  1 0/309 (0.00%)  0
Vena cava thrombosis  1  1/339 (0.29%)  1 0/343 (0.00%)  0 0/309 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 75 mg/m^2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   297/339 (87.61%)      293/343 (85.42%)      276/309 (89.32%)    
Blood and lymphatic system disorders       
Anaemia  1  34/339 (10.03%)  47 27/343 (7.87%)  32 59/309 (19.09%)  68
Neutropenia  1  1/339 (0.29%)  1 2/343 (0.58%)  3 47/309 (15.21%)  101
Endocrine disorders       
Hyperthyroidism  1  12/339 (3.54%)  12 18/343 (5.25%)  18 3/309 (0.97%)  3
Hypothyroidism  1  27/339 (7.96%)  28 27/343 (7.87%)  31 1/309 (0.32%)  1
Eye disorders       
Lacrimation increased  1  2/339 (0.59%)  2 2/343 (0.58%)  2 17/309 (5.50%)  17
Gastrointestinal disorders       
Abdominal pain  1  18/339 (5.31%)  22 18/343 (5.25%)  20 13/309 (4.21%)  17
Constipation  1  54/339 (15.93%)  59 49/343 (14.29%)  54 37/309 (11.97%)  44
Diarrhoea  1  53/339 (15.63%)  73 42/343 (12.24%)  48 79/309 (25.57%)  106
Nausea  1  73/339 (21.53%)  84 65/343 (18.95%)  75 57/309 (18.45%)  70
Stomatitis  1  19/339 (5.60%)  20 11/343 (3.21%)  12 46/309 (14.89%)  69
Vomiting  1  44/339 (12.98%)  52 43/343 (12.54%)  52 31/309 (10.03%)  36
General disorders       
Asthenia  1  38/339 (11.21%)  47 37/343 (10.79%)  48 47/309 (15.21%)  66
Chest pain  1  24/339 (7.08%)  24 28/343 (8.16%)  35 20/309 (6.47%)  21
Fatigue  1  91/339 (26.84%)  107 79/343 (23.03%)  92 99/309 (32.04%)  120
Oedema peripheral  1  29/339 (8.55%)  33 23/343 (6.71%)  24 33/309 (10.68%)  36
Pyrexia  1  40/339 (11.80%)  52 34/343 (9.91%)  52 41/309 (13.27%)  54
Infections and infestations       
Nasopharyngitis  1  12/339 (3.54%)  16 17/343 (4.96%)  20 16/309 (5.18%)  16
Investigations       
Alanine aminotransferase increased  1  23/339 (6.78%)  27 16/343 (4.66%)  16 4/309 (1.29%)  4
Blood creatinine increased  1  17/339 (5.01%)  22 15/343 (4.37%)  18 4/309 (1.29%)  4
Neutrophil count decreased  1  2/339 (0.59%)  3 3/343 (0.87%)  4 25/309 (8.09%)  44
Weight decreased  1  27/339 (7.96%)  30 31/343 (9.04%)  32 9/309 (2.91%)  10
White blood cell count decreased  1  0/339 (0.00%)  0 3/343 (0.87%)  4 16/309 (5.18%)  28
Metabolism and nutrition disorders       
Decreased appetite  1  95/339 (28.02%)  110 72/343 (20.99%)  82 70/309 (22.65%)  82
Musculoskeletal and connective tissue disorders       
Arthralgia  1  40/339 (11.80%)  50 35/343 (10.20%)  40 27/309 (8.74%)  32
Back pain  1  35/339 (10.32%)  36 36/343 (10.50%)  39 23/309 (7.44%)  25
Musculoskeletal pain  1  32/339 (9.44%)  36 31/343 (9.04%)  34 10/309 (3.24%)  16
Myalgia  1  20/339 (5.90%)  25 15/343 (4.37%)  17 34/309 (11.00%)  48
Pain in extremity  1  19/339 (5.60%)  20 22/343 (6.41%)  22 13/309 (4.21%)  16
Nervous system disorders       
Dizziness  1  26/339 (7.67%)  32 21/343 (6.12%)  23 12/309 (3.88%)  15
Dysgeusia  1  7/339 (2.06%)  7 7/343 (2.04%)  7 18/309 (5.83%)  24
Headache  1  36/339 (10.62%)  38 28/343 (8.16%)  33 19/309 (6.15%)  22
Neuropathy peripheral  1  6/339 (1.77%)  6 8/343 (2.33%)  8 36/309 (11.65%)  38
Paraesthesia  1  7/339 (2.06%)  9 8/343 (2.33%)  9 20/309 (6.47%)  22
Peripheral sensory neuropathy  1  4/339 (1.18%)  6 6/343 (1.75%)  6 17/309 (5.50%)  17
Psychiatric disorders       
Insomnia  1  21/339 (6.19%)  22 21/343 (6.12%)  21 20/309 (6.47%)  22
Respiratory, thoracic and mediastinal disorders       
Cough  1  72/339 (21.24%)  83 58/343 (16.91%)  72 42/309 (13.59%)  46
Dyspnoea  1  79/339 (23.30%)  87 71/343 (20.70%)  85 58/309 (18.77%)  64
Haemoptysis  1  23/339 (6.78%)  32 22/343 (6.41%)  28 20/309 (6.47%)  29
Productive cough  1  18/339 (5.31%)  27 25/343 (7.29%)  27 8/309 (2.59%)  10
Skin and subcutaneous tissue disorders       
Alopecia  1  5/339 (1.47%)  5 4/343 (1.17%)  4 105/309 (33.98%)  107
Dry skin  1  10/339 (2.95%)  10 18/343 (5.25%)  21 8/309 (2.59%)  8
Pruritus  1  32/339 (9.44%)  37 41/343 (11.95%)  58 10/309 (3.24%)  10
Rash  1  41/339 (12.09%)  48 53/343 (15.45%)  64 22/309 (7.12%)  22
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this study 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.
Results Point of Contact
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01905657     History of Changes
Other Study ID Numbers: 3475-010
2012-004391-19 ( EudraCT Number )
132355 ( Registry Identifier: Japic-CTI )
MK-3475-010 ( Other Identifier: Merck Protocol Number )
First Submitted: July 18, 2013
First Posted: July 23, 2013
Results First Submitted: September 15, 2016
Results First Posted: January 18, 2017
Last Update Posted: February 15, 2019