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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2014-004824-22
    Trial protocol
    		 ES   DE   FR   GR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    02 Feb 2020
    First version publication date
    02 Feb 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    I4T-MC-JVCY
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02411448
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 15540
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    23 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jan 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 May 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 21 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    Taiwan: 56
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Hong Kong: 15
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Japan: 218
    Worldwide total number of subjects
    463
    EEA total number of subjects
    102
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    220
    From 65 to 84 years
    241
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 No Text Available

    Pre-assignment
    Screening details
    		 This study consists of 3 parts: - Part A: open-label. - Part B: randomized, double-blind and placebo-controlled. - Part C: Open-label. Part C data will be reported after study completion.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Ramucirumab + Erlotinib
    Arm description
    		 Part A: 10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV) in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    LY3009806
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV).

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg erlotinib daily orally.

    Arm title
    		 Part B: Ramucirumab+ Erlotinib
    Arm description
    		 Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    LY3009806
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV).

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg erlotinib daily orally.

    Arm title
    		 Part B: Placebo+ Erlotinib
    Arm description
    		 Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo administered every 2 weeks.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg erlotinib daily orally.

    Number of subjects in period 1
    		Part A: Ramucirumab + Erlotinib Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Started
    14
    224
    225
    Received at least one dose of study drug
    14
    221
    225
    Completed
    10
    141
    173
    Not completed
    4
    83
    52
         Consent withdrawn by subject
    1
    14
    9
         Not Specified
    -
    2
    -
         Alive on study treatment
    3
    64
    43
         Did not receive study treatment
    -
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Ramucirumab + Erlotinib
    Reporting group description
    		 Part A: 10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV) in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B: Ramucirumab+ Erlotinib
    Reporting group description
    		 Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B: Placebo+ Erlotinib
    Reporting group description
    		 Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group values
    		 Part A: Ramucirumab + Erlotinib Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib Total
    Number of subjects
    		 14 224 225 463
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.6 ( 13.2 ) 63.7 ( 10.2 ) 62.9 ( 10.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 141 142 294
        Male
    		 3 83 83 169
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 13 10 23
        Not Hispanic or Latino
    		 1 150 160 311
        Unknown or Not Reported
    		 13 61 55 129
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 1 1
        Asian
    		 7 172 174 353
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 1 1
        White
    		 7 52 48 107
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 1 1
    Region of Enrollment
    Units: Subjects
        Romania
    		 0 2 0 2
        Hong Kong
    		 0 9 6 15
        United States
    		 0 7 2 9
        Japan
    		 7 106 105 218
        United Kingdom
    		 0 4 3 7
        Spain
    		 7 23 19 49
        Canada
    		 0 0 2 2
        South Korea
    		 0 25 29 54
        Turkey
    		 0 3 4 7
        Taiwan
    		 0 26 30 56
        Italy
    		 0 8 12 20
        France
    		 0 4 7 11
        Germany
    		 0 7 6 13
    Geographic Region
    * Geographic region “Other” includes Canada, France, Germany, Italy, Romania, Spain, Turkey, US, UK.
    Units: Subjects
        East Asia
    		 7 166 170 343
        Other*
    		 7 58 55 120

    End points

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    End points reporting groups
    Reporting group title
    Part A: Ramucirumab + Erlotinib
    Reporting group description
    		 Part A: 10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV) in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B: Ramucirumab+ Erlotinib
    Reporting group description
    		 Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B: Placebo+ Erlotinib
    Reporting group description
    		 Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Subject analysis set title
    Part B: Ramucirumab + Erlotinib
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Subject analysis set title
    Part B: Placebo + Erlotinib
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Primary: Part B: Progression Free Survival (PFS)

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    End point title
    		 Part B: Progression Free Survival (PFS) [1]
    End point description
    PFS is defined as the time from the date of randomization to the date of radiographically documented progressive disease (PD) based on investigator assessment, or the date of death due to any cause, whichever is first assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. Analysis Population Description (APD): Part B: All randomized participants grouped according to their assigned treatment at randomization. Censored participants were: Part B: Ramucirumab+ Erlotinib= 102 and Part B: Placebo+ Erlotinib= 67. Per protocol, Part A did not evaluate efficacy.
    End point type
    Primary
    End point timeframe
    Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    224
    225
    Units: Months
        median (confidence interval 95%)
    19.4 (15.4 to 21.6)
    12.4 (11.0 to 13.5)
    Statistical analysis title
    		 Part B: Progression Free Survival (PFS)
    Comparison groups
    Part B: Ramucirumab+ Erlotinib v Part B: Placebo+ Erlotinib
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.591
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.461
         upper limit
    		 0.76

    Primary: Number of Participants with Treatment-Emergent Adverse Events

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    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events [2]
    End point description
    A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section. Analysis Population Description: All randomized participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 through End of Study (Up To 3 Years)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, there were no statistical analysis planned for this outcome measure.
    End point values
    		 Part A: Ramucirumab + Erlotinib Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    14
    221
    225
    Units: participants
    14
    221
    225
    No statistical analyses for this end point

    Secondary: Part B: Overall Survival (OS)

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    End point title
    		 Part B: Overall Survival (OS) [3]
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who was not known to have died as of the data-inclusion cutoff date for a particular analysis, OS was censored for that analysis at the date of last contact prior to the data-inclusion cutoff date (contacts considered in the determination of last contact date include adverse event (AE) date, lesion assessment date, visit date, and last known alive date). Analysis Population Description: Part B: All randomized participants grouped according to their assigned treatment at randomization. Censored participants were: Part B: Ramucirumab+ Erlotinib= 187 and Part B: Placebo+ Erlotinib= 183. Per protocol, Part A did not evaluate efficacy.
    End point type
    Secondary
    End point timeframe
    Randomization to Date of Death from Any Cause (Up To 37 Months) 9999=NA. Interim OS data were immature due to high censoring.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    224 [4]
    225 [5]
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [4] - 9999=NA. Interim OS data were immature due to high censoring.
    [5] - 9999=NA. Interim OS data were immature due to high censoring; and the median OS was not reached.
    Statistical analysis title
    		 Part B: Overall Survival (OS)
    Comparison groups
    Part B: Ramucirumab+ Erlotinib v Part B: Placebo+ Erlotinib
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4209
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.832
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.532
         upper limit
    		 1.303

    Secondary: Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])

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    End point title
    		 Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) [6]
    End point description
    ORR was defined as the percentage of randomized participants achieving a best overall response of partial response (PR) or complete response (CR) assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.
    End point type
    Secondary
    End point timeframe
    Randomization to Disease Progression (Up To 37 Months) Analysis Population Description: Part B: All randomized participants grouped according to their assigned treatment at randomization. Per protocol, Part A did not evaluate efficacy.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    224
    225
    Units: percentage of participants
        number (confidence interval 95%)
    76.3 (70.8 to 81.9)
    74.7 (69.0 to 80.3)
    Statistical analysis title
    		 Part B: Percentage of Participants With ORR
    Comparison groups
    Part B: Ramucirumab+ Erlotinib v Part B: Placebo+ Erlotinib
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7413
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])

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    End point title
    		 Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR]) [7]
    End point description
    DCR was defined as the percentage of randomized participants achieving a best overall response of CR,PR, or stable disease(SD) assessed via Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1. CR was defined as the disappearance of all lesions,pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions.PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease(PD) was at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of 1 or more new lesions is also considered progression.
    End point type
    Secondary
    End point timeframe
    Randomization to Disease Progression (Up To 37 Months) Analysis Population Description: Part B: All randomized participants grouped according to their assigned treatment at randomization. Per protocol, Part A did not evaluate efficacy.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    224
    225
    Units: percentage of participants
        number (confidence interval 95%)
    95.1 (92.3 to 97.9)
    95.6 (92.9 to 98.2)
    Statistical analysis title
    		 Part B: Percentage of Participants With DCR
    Comparison groups
    Part B: Ramucirumab+ Erlotinib v Part B: Placebo+ Erlotinib
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Part B: Duration of Response (DoR)

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    End point title
    		 Part B: Duration of Response (DoR) [8]
    End point description
    DoR was defined as the date of first documented CR or PR (responder) to the date of objective progression or the date of death due to any cause, whichever was earlier. If a responder was not known to have died or have objective progression, then the patient was censored at the date of last evaluable tumor assessment.CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.
    End point type
    Secondary
    End point timeframe
    Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up To 37 Months) APD: Part B: All randomized participants grouped according to their assigned treatment at randomization that had a response (CR or PR).
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, there were no statistical analysis planned for this outcome measure.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    171
    168
    Units: months
        median (confidence interval 95%)
    18.0 (13.9 to 19.8)
    11.1 (9.7 to 12.3)
    Statistical analysis title
    		 Part B: Duration of Response (DoR)
    Comparison groups
    Part B: Ramucirumab+ Erlotinib v Part B: Placebo+ Erlotinib
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0003
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.619
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.477
         upper limit
    		 0.805

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

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    End point title
    		 Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [9]
    End point description
    Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Analysis Population Description: Part B participants who received at least one dose of Ramucirumab+ Erlotinib who had evaluable PK data. Per protocol, Part A did not evaluate PK. Geometric coefficient of variation is in percentage.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib
    Number of subjects analysed
    185
    Units: microgram per milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 2
    39.6 ( 32 )
        Cycle 4
    68.5 ( 37 )
        Cycle 7
    85.7 ( 32 )
        Cycle 14
    99.4 ( 31 )
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants with Anti-Ramucirumab Antibodies

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    End point title
    		 Part B: Number of Participants with Anti-Ramucirumab Antibodies [10]
    End point description
    Part B: Number of Participants With Anti-Ramucirumab Antibodies. Analysis Population Description: All participants who received at least one dose of study drug. Per protocol, Part A did not evaluate Anti-Ramucirumab Antibodies.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Predose through Follow-up (Up To 37 Months)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    221
    210
    Units: participants
    14
    18
    No statistical analyses for this end point

    Secondary: Part B: Best Change from Baseline on the Lung Cancer Symptom Scale (LCSS)

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    End point title
    		 Part B: Best Change from Baseline on the Lung Cancer Symptom Scale (LCSS) [11]
    End point description
    The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-millimeter (mm) lines. A higher score for any item represented a higher level of symptoms/problems. The LCSS total score was defined as the mean of all 9 items. Average symptom burden index (ASBI) was calculated as the mean of the six symptom-specific questions from the LCSS. Potential scores range from 0 (for best outcome) to 100 (for worst outcome).
    End point type
    Secondary
    End point timeframe
    Baseline, End of Study (Up To 37 Months) Analysis Population Description: Part B:All randomized participants who completed the LCSS at baseline and at least once post-baseline. Per protocol, Part A did not evaluate efficacy.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    213
    217 [12]
    Units: millimeter
    least squares mean (standard error)
        Appetite
    -17.07 ( 0.92 )
    -18.16 ( 0.91 )
        Fatigue
    -19.35 ( 0.91 )
    -19.45 ( 0.90 )
        Shortness of Breath
    -14.46 ( 0.57 )
    -15.93 ( 0.57 )
        Blood in Sputum
    -1.58 ( 0.25 )
    -1.94 ( 0.25 )
        Pain
    -13.57 ( 0.59 )
    -14.69 ( 0.59 )
        Average Symptom Burden Index
    -12.17 ( 0.57 )
    -13.05 ( 0.57 )
        Total LCSS
    -12.00 ( 0.62 )
    -12.71 ( 0.61 )
        Cough
    -21.22 ( 0.58 )
    -22.09 ( 0.57 )
        Interference with Activity Level
    -14.43 ( 0.83 )
    -15.60 ( 0.82 )
        Symptom distress
    -15.91 ( 0.67 )
    -16.15 ( 0.67 )
        Global Quality of Life
    -16.21 ( 0.95 )
    -18.12 ( 0.94 )
    Notes
    [12] - The N for Blood in Sputum, pain, Average Symptom Burden Index and Total LCSS is 216.
    No statistical analyses for this end point

    Secondary: Part B: Change from Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

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    End point title
    		 Part B: Change from Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [13]
    End point description
    The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the patient. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death. Analysis Population Description: Part B: All randomized participants who completed the EQ-5D-5L at baseline and at least once post-baseline. Per protocol, Part A did not evaluate efficacy.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 10
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    170
    170
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.02 ( 0.15 )
    0.02 ( 0.15 )
    No statistical analyses for this end point

    Secondary: Part B: Change from Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

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    End point title
    		 Part B: Change from Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [14]
    End point description
    The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 28 Analysis Population Description: Part B: All randomized participants who completed the EQ-5D-5L at baseline and at least once post-baseline. Per protocol, Part A did not evaluate efficacy.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    108
    81
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.02 ( 0.18 )
    0.01 ( 0.1 )
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

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    End point title
    		 Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [15]
    End point description
    The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 40 Analysis Population Description: Part B: All randomized participants who completed the EQ-5D-5L at baseline and at least once post-baseline. Per protocol, Part A did not evaluate efficacy.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Part A did not evaluate efficacy.
    End point values
    		 Part B: Ramucirumab+ Erlotinib Part B: Placebo+ Erlotinib
    Number of subjects analysed
    57
    44
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.01 ( 0.15 )
    -0.01 ( 0.14 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up To 3 Years
    Adverse event reporting additional description
    All participants who received at least one dose of study drug. Part C data will be reported after study completion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Part A: Ramucirumab+Erlotinib
    Reporting group description
    		 Part A: 10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV) in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B: Ramucirumab+Erlotinib
    Reporting group description
    		 Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B: Placebo+Erlotinib
    Reporting group description
    		 Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

    Serious adverse events
    		 Part A: Ramucirumab+Erlotinib Part B: Ramucirumab+Erlotinib Part B: Placebo+Erlotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    65 / 221 (29.41%)
    47 / 225 (20.89%)
         number of deaths (all causes)
    0
    6
    1
         number of deaths resulting from adverse events
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    adenocarcinoma of colon
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    basal cell carcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cancer pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lymphoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    mesenteric neoplasm
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ovarian neoplasm
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [1]
    0 / 11 (0.00%)
    1 / 139 (0.72%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pericarditis malignant
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    embolism
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypertension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    hepatectomy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    malaise
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    mucous membrane disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 221 (1.36%)
    4 / 225 (1.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    endometriosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [2]
    0 / 11 (0.00%)
    0 / 139 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dysphonia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dyspnoea exertional
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    haemoptysis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    haemothorax
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    pleural effusion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pleurisy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumomediastinum
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    4 / 221 (1.81%)
    3 / 225 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    adjustment disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    blood creatinine increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    concussion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    fall
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    humerus fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    infusion related reaction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    radius fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    rib fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ulna fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    cardiac failure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cardiac failure congestive
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pericardial effusion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    wolff-parkinson-white syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    depressed level of consciousness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hydrocephalus
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    neuralgia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    somnolence
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    cataract
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    macular fibrosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    retinal detachment
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal distension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    abdominal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    colitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    colitis ischaemic
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 221 (1.36%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    duodenal ulcer
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dyspepsia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    haemorrhoids
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    irritable bowel syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lower gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    melaena
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    small intestinal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    drug-induced liver injury
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hepatic function abnormal
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 221 (1.36%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hepatic steatosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hepatitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    liver disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    dermatitis acneiform
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dermatitis exfoliative generalised
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    eczema asteatotic
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    skin exfoliation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    proteinuria
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    neck pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    abdominal infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    appendicitis perforated
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    4 / 221 (1.81%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diverticulitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    empyema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    encephalitis influenzal
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis bacterial
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    herpes zoster
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    infectious pleural effusion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lung infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    meningitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    7 / 221 (3.17%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    pneumonia bacterial
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    rash pustular
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    septic shock
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    skin infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tonsillitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 221 (1.36%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hyperglycaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Ramucirumab+Erlotinib Part B: Ramucirumab+Erlotinib Part B: Placebo+Erlotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    220 / 221 (99.55%)
    225 / 225 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    cancer pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    4 / 225 (1.78%)
         occurrences all number
    1
    1
    5
    pyogenic granuloma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    4 / 221 (1.81%)
    0 / 225 (0.00%)
         occurrences all number
    2
    6
    0
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    7 / 14 (50.00%)
    100 / 221 (45.25%)
    27 / 225 (12.00%)
         occurrences all number
    27
    246
    72
    thrombosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    varicose ulceration
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    Surgical and medical procedures
    dental care
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    dental operation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    inguinal hernia repair
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    tooth extraction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    3 / 225 (1.33%)
         occurrences all number
    1
    3
    3
    vaginal pessary insertion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [3]
    1 / 11 (9.09%)
    0 / 139 (0.00%)
    0 / 142 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    17 / 221 (7.69%)
    14 / 225 (6.22%)
         occurrences all number
    11
    34
    29
    chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    5 / 221 (2.26%)
    3 / 225 (1.33%)
         occurrences all number
    2
    5
    3
    cyst
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences all number
    1
    0
    1
    fatigue
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    25 / 221 (11.31%)
    27 / 225 (12.00%)
         occurrences all number
    10
    55
    51
    influenza like illness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    5 / 221 (2.26%)
    13 / 225 (5.78%)
         occurrences all number
    0
    8
    17
    malaise
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    34 / 221 (15.38%)
    19 / 225 (8.44%)
         occurrences all number
    0
    69
    35
    mucosal inflammation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    14 / 221 (6.33%)
    6 / 225 (2.67%)
         occurrences all number
    3
    28
    6
    non-cardiac chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    10 / 221 (4.52%)
    5 / 225 (2.22%)
         occurrences all number
    1
    13
    5
    oedema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    3 / 221 (1.36%)
    2 / 225 (0.89%)
         occurrences all number
    2
    4
    2
    oedema peripheral
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    50 / 221 (22.62%)
    10 / 225 (4.44%)
         occurrences all number
    6
    78
    11
    pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    6 / 221 (2.71%)
    9 / 225 (4.00%)
         occurrences all number
    1
    6
    10
    pyrexia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    45 / 221 (20.36%)
    24 / 225 (10.67%)
         occurrences all number
    4
    57
    34
    xerosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    7 / 221 (3.17%)
    4 / 225 (1.78%)
         occurrences all number
    1
    9
    5
    Immune system disorders
    allergy to arthropod sting
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    hypersensitivity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    2 / 225 (0.89%)
         occurrences all number
    1
    1
    2
    Reproductive system and breast disorders
    genital rash
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences all number
    2
    2
    0
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    48 / 221 (21.72%)
    35 / 225 (15.56%)
         occurrences all number
    10
    62
    49
    dysphonia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    14 / 221 (6.33%)
    2 / 225 (0.89%)
         occurrences all number
    2
    17
    2
    dyspnoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    18 / 221 (8.14%)
    9 / 225 (4.00%)
         occurrences all number
    3
    25
    9
    epistaxis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    74 / 221 (33.48%)
    27 / 225 (12.00%)
         occurrences all number
    5
    102
    33
    haemoptysis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    11 / 221 (4.98%)
    2 / 225 (0.89%)
         occurrences all number
    4
    19
    2
    interstitial lung disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    2 / 225 (0.89%)
         occurrences all number
    1
    1
    2
    nasal disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences all number
    1
    1
    0
    nasal inflammation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    4 / 221 (1.81%)
    4 / 225 (1.78%)
         occurrences all number
    4
    5
    5
    oropharyngeal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    19 / 221 (8.60%)
    13 / 225 (5.78%)
         occurrences all number
    1
    25
    14
    orthopnoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences all number
    1
    1
    0
    productive cough
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    15 / 221 (6.79%)
    11 / 225 (4.89%)
         occurrences all number
    0
    21
    17
    rhinorrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    13 / 221 (5.88%)
    9 / 225 (4.00%)
         occurrences all number
    1
    17
    9
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    7 / 221 (3.17%)
    4 / 225 (1.78%)
         occurrences all number
    1
    16
    5
    confusional state
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences all number
    1
    3
    0
    depressed mood
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences all number
    1
    0
    1
    depression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    4 / 225 (1.78%)
         occurrences all number
    2
    2
    5
    insomnia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    32 / 221 (14.48%)
    29 / 225 (12.89%)
         occurrences all number
    3
    36
    33
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    7 / 14 (50.00%)
    93 / 221 (42.08%)
    70 / 225 (31.11%)
         occurrences all number
    12
    270
    192
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    92 / 221 (41.63%)
    58 / 225 (25.78%)
         occurrences all number
    7
    270
    128
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    23 / 221 (10.41%)
    20 / 225 (8.89%)
         occurrences all number
    2
    39
    46
    blood bilirubin increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    68 / 221 (30.77%)
    70 / 225 (31.11%)
         occurrences all number
    4
    254
    251
    blood creatinine increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 221 (2.26%)
    6 / 225 (2.67%)
         occurrences all number
    1
    13
    8
    blood lactate dehydrogenase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    6 / 221 (2.71%)
    2 / 225 (0.89%)
         occurrences all number
    1
    22
    11
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 221 (1.36%)
    4 / 225 (1.78%)
         occurrences all number
    2
    6
    5
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    12 / 221 (5.43%)
    7 / 225 (3.11%)
         occurrences all number
    2
    35
    11
    neutrophil count decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    25 / 221 (11.31%)
    16 / 225 (7.11%)
         occurrences all number
    1
    83
    39
    platelet count decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    31 / 221 (14.03%)
    6 / 225 (2.67%)
         occurrences all number
    5
    54
    10
    transaminases increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences all number
    1
    5
    1
    weight decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    28 / 221 (12.67%)
    29 / 225 (12.89%)
         occurrences all number
    2
    54
    37
    white blood cell count decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    14 / 221 (6.33%)
    7 / 225 (3.11%)
         occurrences all number
    0
    53
    14
    Injury, poisoning and procedural complications
    fall
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    6 / 225 (2.67%)
         occurrences all number
    1
    2
    6
    infusion related reaction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 221 (1.36%)
    2 / 225 (0.89%)
         occurrences all number
    1
    3
    2
    skin abrasion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences all number
    1
    0
    1
    skin laceration
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    2 / 225 (0.89%)
         occurrences all number
    1
    1
    2
    Cardiac disorders
    sinus bradycardia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences all number
    1
    3
    1
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    20 / 221 (9.05%)
    19 / 225 (8.44%)
         occurrences all number
    1
    27
    24
    dysgeusia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    39 / 221 (17.65%)
    32 / 225 (14.22%)
         occurrences all number
    3
    46
    44
    headache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    7 / 14 (50.00%)
    33 / 221 (14.93%)
    16 / 225 (7.11%)
         occurrences all number
    13
    56
    21
    neuralgia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    2 / 225 (0.89%)
         occurrences all number
    1
    0
    2
    paraesthesia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    5 / 225 (2.22%)
         occurrences all number
    1
    3
    5
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    7 / 221 (3.17%)
    9 / 225 (4.00%)
         occurrences all number
    1
    7
    10
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    21 / 221 (9.50%)
    10 / 225 (4.44%)
         occurrences all number
    2
    49
    15
    neutropenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    3 / 221 (1.36%)
    2 / 225 (0.89%)
         occurrences all number
    4
    9
    11
    thrombocytopenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 221 (2.26%)
    0 / 225 (0.00%)
         occurrences all number
    6
    9
    0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    12 / 221 (5.43%)
    4 / 225 (1.78%)
         occurrences all number
    0
    16
    5
    Eye disorders
    blepharitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    4 / 221 (1.81%)
    9 / 225 (4.00%)
         occurrences all number
    1
    7
    11
    dry eye
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    22 / 221 (9.95%)
    23 / 225 (10.22%)
         occurrences all number
    1
    27
    24
    eyelid oedema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    ocular discomfort
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences all number
    2
    0
    1
    ocular hyperaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 221 (1.36%)
    2 / 225 (0.89%)
         occurrences all number
    1
    3
    2
    Gastrointestinal disorders
    abdominal discomfort
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    2 / 225 (0.89%)
         occurrences all number
    1
    1
    2
    abdominal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    15 / 221 (6.79%)
    15 / 225 (6.67%)
         occurrences all number
    5
    26
    18
    abdominal pain upper
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    17 / 221 (7.69%)
    19 / 225 (8.44%)
         occurrences all number
    2
    23
    41
    anal fissure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences all number
    1
    5
    1
    anal fistula
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    cheilitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    7 / 221 (3.17%)
    5 / 225 (2.22%)
         occurrences all number
    1
    8
    5
    constipation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    42 / 221 (19.00%)
    31 / 225 (13.78%)
         occurrences all number
    3
    52
    38
    dental caries
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    8 / 221 (3.62%)
    8 / 225 (3.56%)
         occurrences all number
    1
    8
    8
    diarrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    13 / 14 (92.86%)
    154 / 221 (69.68%)
    160 / 225 (71.11%)
         occurrences all number
    57
    410
    388
    dry mouth
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    8 / 221 (3.62%)
    3 / 225 (1.33%)
         occurrences all number
    1
    8
    5
    dyspepsia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    11 / 221 (4.98%)
    12 / 225 (5.33%)
         occurrences all number
    1
    17
    21
    dysphagia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    4 / 221 (1.81%)
    5 / 225 (2.22%)
         occurrences all number
    1
    6
    6
    gastritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    19 / 221 (8.60%)
    9 / 225 (4.00%)
         occurrences all number
    0
    22
    11
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    16 / 221 (7.24%)
    9 / 225 (4.00%)
         occurrences all number
    1
    22
    12
    gingival bleeding
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    19 / 221 (8.60%)
    3 / 225 (1.33%)
         occurrences all number
    2
    23
    3
    haemorrhoids
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    14 / 221 (6.33%)
    9 / 225 (4.00%)
         occurrences all number
    0
    19
    12
    inguinal hernia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    nausea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 14 (28.57%)
    57 / 221 (25.79%)
    44 / 225 (19.56%)
         occurrences all number
    5
    81
    79
    oesophageal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    rectal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences all number
    2
    2
    0
    stomatitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    6 / 14 (42.86%)
    92 / 221 (41.63%)
    82 / 225 (36.44%)
         occurrences all number
    13
    148
    144
    tooth disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    toothache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 221 (2.26%)
    1 / 225 (0.44%)
         occurrences all number
    1
    5
    1
    vomiting
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 14 (28.57%)
    26 / 221 (11.76%)
    25 / 225 (11.11%)
         occurrences all number
    6
    34
    31
    Hepatobiliary disorders
    hepatitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences all number
    1
    6
    0
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    6 / 14 (42.86%)
    75 / 221 (33.94%)
    44 / 225 (19.56%)
         occurrences all number
    7
    84
    47
    dermatitis acneiform
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    9 / 14 (64.29%)
    149 / 221 (67.42%)
    153 / 225 (68.00%)
         occurrences all number
    33
    433
    447
    dermatitis contact
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    4 / 221 (1.81%)
    6 / 225 (2.67%)
         occurrences all number
    1
    5
    10
    dry skin
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    9 / 14 (64.29%)
    83 / 221 (37.56%)
    91 / 225 (40.44%)
         occurrences all number
    19
    127
    181
    ecchymosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    erythema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    12 / 221 (5.43%)
    10 / 225 (4.44%)
         occurrences all number
    2
    83
    24
    hair disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences all number
    1
    2
    1
    hirsutism
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [4]
    1 / 11 (9.09%)
    1 / 139 (0.72%)
    4 / 142 (2.82%)
         occurrences all number
    1
    1
    4
    intertrigo
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences all number
    1
    1
    0
    nail dystrophy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    3 / 225 (1.33%)
         occurrences all number
    1
    0
    3
    nail toxicity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    2 / 225 (0.89%)
         occurrences all number
    1
    0
    2
    pruritus
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    51 / 221 (23.08%)
    66 / 225 (29.33%)
         occurrences all number
    12
    110
    165
    purpura
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    11 / 221 (4.98%)
    5 / 225 (2.22%)
         occurrences all number
    2
    17
    5
    rash
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    39 / 221 (17.65%)
    54 / 225 (24.00%)
         occurrences all number
    29
    103
    148
    rash macular
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    1 / 225 (0.44%)
         occurrences all number
    1
    1
    1
    rash maculo-papular
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 14 (28.57%)
    20 / 221 (9.05%)
    21 / 225 (9.33%)
         occurrences all number
    13
    47
    53
    skin fissures
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    9 / 221 (4.07%)
    14 / 225 (6.22%)
         occurrences all number
    2
    13
    19
    skin lesion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    2 / 225 (0.89%)
         occurrences all number
    2
    4
    4
    xeroderma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences all number
    1
    0
    1
    Renal and urinary disorders
    haematuria
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    10 / 221 (4.52%)
    8 / 225 (3.56%)
         occurrences all number
    2
    11
    12
    leukocyturia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    proteinuria
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    75 / 221 (33.94%)
    19 / 225 (8.44%)
         occurrences all number
    18
    278
    35
    Endocrine disorders
    hypothyroidism
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 221 (1.36%)
    0 / 225 (0.00%)
         occurrences all number
    1
    3
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    8 / 221 (3.62%)
    7 / 225 (3.11%)
         occurrences all number
    6
    9
    7
    back pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 14 (28.57%)
    24 / 221 (10.86%)
    17 / 225 (7.56%)
         occurrences all number
    6
    28
    22
    muscle spasms
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    9 / 221 (4.07%)
    8 / 225 (3.56%)
         occurrences all number
    1
    12
    11
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    7 / 221 (3.17%)
    12 / 225 (5.33%)
         occurrences all number
    1
    8
    15
    musculoskeletal discomfort
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences all number
    2
    1
    0
    musculoskeletal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 14 (28.57%)
    12 / 221 (5.43%)
    5 / 225 (2.22%)
         occurrences all number
    5
    14
    5
    myalgia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 221 (2.26%)
    9 / 225 (4.00%)
         occurrences all number
    1
    10
    9
    neck pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 14 (21.43%)
    6 / 221 (2.71%)
    6 / 225 (2.67%)
         occurrences all number
    3
    8
    7
    pain in extremity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    9 / 221 (4.07%)
    12 / 225 (5.33%)
         occurrences all number
    2
    9
    16
    tendonitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 221 (0.45%)
    0 / 225 (0.00%)
         occurrences all number
    1
    1
    0
    Infections and infestations
    angular cheilitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 221 (1.36%)
    6 / 225 (2.67%)
         occurrences all number
    1
    3
    7
    bacteriuria
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    candida infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    conjunctivitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    21 / 221 (9.50%)
    32 / 225 (14.22%)
         occurrences all number
    6
    26
    40
    cystitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    8 / 221 (3.62%)
    9 / 225 (4.00%)
         occurrences all number
    1
    12
    17
    eye infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    0 / 225 (0.00%)
         occurrences all number
    1
    2
    0
    folliculitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    7 / 221 (3.17%)
    11 / 225 (4.89%)
         occurrences all number
    1
    17
    15
    gastroenteritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 221 (2.26%)
    4 / 225 (1.78%)
         occurrences all number
    1
    5
    4
    gingivitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    6 / 221 (2.71%)
    1 / 225 (0.44%)
         occurrences all number
    1
    16
    1
    infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    5 / 14 (35.71%)
    22 / 221 (9.95%)
    18 / 225 (8.00%)
         occurrences all number
    6
    27
    28
    paronychia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    10 / 14 (71.43%)
    118 / 221 (53.39%)
    114 / 225 (50.67%)
         occurrences all number
    24
    277
    238
    parotitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    perichondritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences all number
    1
    0
    1
    pharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    15 / 221 (6.79%)
    6 / 225 (2.67%)
         occurrences all number
    1
    20
    7
    pulpitis dental
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    rash pustular
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    6 / 221 (2.71%)
    14 / 225 (6.22%)
         occurrences all number
    0
    12
    34
    respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    1 / 225 (0.44%)
         occurrences all number
    1
    0
    1
    rhinitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    4 / 221 (1.81%)
    4 / 225 (1.78%)
         occurrences all number
    1
    4
    4
    tinea cruris
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    0 / 225 (0.00%)
         occurrences all number
    1
    0
    0
    tonsillitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 221 (0.90%)
    1 / 225 (0.44%)
         occurrences all number
    1
    3
    1
    upper respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    38 / 221 (17.19%)
    34 / 225 (15.11%)
         occurrences all number
    5
    53
    52
    urinary tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 14 (14.29%)
    17 / 221 (7.69%)
    11 / 225 (4.89%)
         occurrences all number
    3
    23
    21
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 14 (28.57%)
    57 / 221 (25.79%)
    47 / 225 (20.89%)
         occurrences all number
    11
    101
    84
    hypoalbuminaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    14 / 221 (6.33%)
    10 / 225 (4.44%)
         occurrences all number
    1
    27
    17
    hypokalaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 14 (0.00%)
    18 / 221 (8.14%)
    5 / 225 (2.22%)
         occurrences all number
    0
    38
    12
    hypomagnesaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 221 (0.00%)
    2 / 225 (0.89%)
         occurrences all number
    1
    0
    4
    Notes
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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