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    Clinical Trial Results:
    A Phase 1 Study Of Ramucirumab, a Human Monoclonal Antibody Against the Vascular Endothelial Growth Factor-2 (VEGFR-2) Receptor in Children With Refractory Solid Tumors, Including CNS Tumors

    Summary
    EudraCT number
    		 2021-000364-30
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    16 Jul 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Aug 2021
    First version publication date
    30 Jun 2021
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Aligning EudraCT results because of a CT.gov updated would be correction.

    Trial information

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    Trial identification
    Sponsor protocol code
    I4T-MC-JVDA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02564198
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 15542
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the safety of the study drug known as ramucirumab in children with recurrent or refractory solid tumors including central nervous system (CNS) tumors.
    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
    11 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    29
    EEA total number of subjects
    0
    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)
    1
    Children (2-11 years)
    10
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 No Text Available

    Pre-assignment
    Screening details
    		 Completers included participants who had progressive disease, death due to any cause or alive and on study at conclusion, but off treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 8 mg/kg Ramucirumab (Part A)
    Arm description
    		 Participants received 8 milligram per kilogram [mg/kg] Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    IMC-1121B, Cyramza, LY3009806
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion.

    Arm title
    		 12 mg/kg Ramucirumab (Part A)
    Arm description
    		 Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    IMC-1121B, Cyramza, LY3009806
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 12 mg/kg Ramucirumab administered as an intravenous infusion.

    Arm title
    		 12 mg/kg Ramucirumab (Part B)
    Arm description
    		 Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    IMC-1121B, Cyramza, LY3009806
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 12 mg/kg Ramucirumab administered as an intravenous infusion.

    Number of subjects in period 1
    		8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Started
    8
    15
    6
    Received at least 1 dose of study drug
    8
    15
    6
    Completed
    6
    10
    6
    Not completed
    2
    5
    0
         Consent withdrawn by subject
    2
    4
    -
         Adverse event, non-fatal
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    8 mg/kg Ramucirumab (Part A)
    Reporting group description
    		 Participants received 8 milligram per kilogram [mg/kg] Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.

    Reporting group title
    12 mg/kg Ramucirumab (Part A)
    Reporting group description
    		 Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.

    Reporting group title
    12 mg/kg Ramucirumab (Part B)
    Reporting group description
    		 Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.

    Reporting group values
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B) Total
    Number of subjects
    		 8 15 6 29
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.8 ± 3.33 11.9 ± 5.59 9.7 ± 5.9 -
    Gender categorical
    Units: Subjects
        Female
    		 4 6 2 12
        Male
    		 4 9 4 17
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 2 2 6
        Not Hispanic or Latino
    		 6 12 4 22
        Unknown or Not Reported
    		 0 1 0 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 2 1 3
        White
    		 7 12 4 23
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 1 1 1 3
    Region of Enrollment
    Units: Subjects
        United States
    		 8 15 6 29

    End points

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    End points reporting groups
    Reporting group title
    8 mg/kg Ramucirumab (Part A)
    Reporting group description
    		 Participants received 8 milligram per kilogram [mg/kg] Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.

    Reporting group title
    12 mg/kg Ramucirumab (Part A)
    Reporting group description
    		 Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.

    Reporting group title
    12 mg/kg Ramucirumab (Part B)
    Reporting group description
    		 Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.

    Subject analysis set title
    8 mg/kg Ramucirumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.

    Subject analysis set title
    12 mg/kg Ramucirumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.

    Primary: Part A: Number of participants with Dose Limiting Toxicities (DLTs): Maximum Tolerated Dose of Ramucirumab

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    End point title
    		 Part A: Number of participants with Dose Limiting Toxicities (DLTs): Maximum Tolerated Dose of Ramucirumab [1] [2]
    End point description
    A DLT is defined as an AE that is likely related to the study medication or combination, and fulfills any one of the following criteria, graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0: 1. Any death not clearly due to the underlying disease or extraneous causes 2. Neutropenic fever 2. Any Grade ≥3 non-hematologic toxicity 3. Grade ≥4 neutropenia or thrombocytopenia >7 days 4. Grade ≥3 thrombocytopenia with bleeding 5. Grade ≥3 nausea/vomiting or diarrhea>72 hours with adequate antiemetic and other supportive care 6. Grade ≥3 fatigue ≥1 week 7. Grade ≥3 electrolyte abnormality that lasts>72 hours, unless the Participant has clinical symptoms, in which case all Grade 3+electrolyte abnormality regardless of duration should count as a DLT. Analysis Population Description (APD): All randomized participants from Part A, who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to Study Completion (Up to 42 Months)
    Notes
    [1] - 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: No inferential statistics were planned for this endpoint.
    [2] - 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 this outcome is to identify recommended dose for Part B.
    End point values
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A)
    Number of subjects analysed
    8
    15
    Units: Participants
        number (not applicable)
    1
    1
    No statistical analyses for this end point

    Primary: Population Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

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    End point title
    		 Population Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [3]
    End point description
    Population Pharmacokinetics (PK): Minimum observed plasma concentration of Ramucirumab. APD: All randomized participants who received at least one dose of study drug and had evaluable PK data. Per protocol, 12 mg/kg Ramucirumab PK data were reported per dose level combining Part A and B participants.
    End point type
    Primary
    End point timeframe
    Predose, Cycle 1 Day 1 (end of infusion (EOI), 1 hour after EOI) and Cycle 1 Day 43 (1 hour after EOI)
    Notes
    [3] - 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: No inferential statistics were planned for this endpoint.
    End point values
    		 8 mg/kg Ramucirumab 12 mg/kg Ramucirumab
    Number of subjects analysed
    8 [4]
    19 [5]
    Units: microgram per milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    30.0 ± 32
    48.3 ± 41
        Cycle 1 Day 43
    53.6 ± 31
    80.2 ± 44
    Notes
    [4] - Cycle 1 Day 1: 8 participants Cycle 1 Day 43: 4 participants
    [5] - Cycle 1 Day 1: 19 participants Cycle 1 Day 43: 16 participants
    No statistical analyses for this end point

    Primary: Number of Participants with Anti-Ramucirumab Antibodies

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    End point title
    		 Number of Participants with Anti-Ramucirumab Antibodies [6]
    End point description
    Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline. APD: All randomized participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Predose Cycle 1 Day 1 through Follow-Up (Up to 42 Months)
    Notes
    [6] - 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: No inferential statistics were planned for this endpoint.
    End point values
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Number of subjects analysed
    8
    15
    6
    Units: participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR)

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    End point title
    		 Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR)
    End point description
    ORR is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants per cohort with at least 1 measurable lesion, multiplied by 100. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. APD: All randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Date of Objective Disease Progression (Up to 42 Months)
    End point values
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Number of subjects analysed
    8
    15
    6
    Units: Percentage of participants
        number (confidence interval 95%)
    0 (0.0 to 41.0)
    0 (0.0 to 23.2)
    0 (0.0 to 45.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD): Disease Control Rate (DCR)

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    End point title
    		 Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD): Disease Control Rate (DCR)
    End point description
    Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. APD: All randomized participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Date of Objective Disease Progression (Up to 42 Months)
    End point values
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Number of subjects analysed
    8
    15
    6
    Units: Percentage of participants
        number (confidence interval 95%)
    62.5 (29.0 to 96.3)
    40.0 (17.7 to 71.1)
    33.3 (4.3 to 77.7)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date. APD: Zero participants analyzed. Duration of response was not evaluable, as there were no participants with CR or PR.
    End point type
    Secondary
    End point timeframe
    Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up to 42 Months)
    End point values
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [7] - Duration of response was not evaluable, as there were no participants with CR or PR.
    [8] - Duration of response was not evaluable, as there were no participants with CR or PR.
    [9] - Duration of response was not evaluable, as there were no participants with CR or PR.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival is defined as the time from date of randomization to the date of death (due to any cause). For participants whose last known status is alive at the data cutoff date for the analysis, time will be censored as the last contact date prior to the data cutoff date. APD: All randomized participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Date of Death from Any Cause (Up to 42 Months)
    End point values
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Number of subjects analysed
    8 [10]
    15 [11]
    6 [12]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [10] - 99999= There were not enough events/deaths to compute a median or 95% confidence interval.
    [11] - 99999= There were not enough events/deaths to compute a median or 95% confidence interval.
    [12] - 99999= There were not enough events/deaths to compute a median or 95% confidence interval.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline, up to 4 years 8 months
    Adverse event reporting additional description
    I4T-MC-JVDA
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    8 mg/kg Ramucirumab (Part A)
    Reporting group description
    		 -

    Reporting group title
    12 mg/kg Ramucirumab (Part A)
    Reporting group description
    		 -

    Reporting group title
    12 mg/kg Ramucirumab (Part B)
    Reporting group description
    		 -

    Serious adverse events
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    7 / 15 (46.67%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    tumour pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    fracture
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    paraesthesia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    peripheral motor neuropathy
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    seizure
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         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
    pyrexia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Respiratory, thoracic and mediastinal disorders
    dyspnoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (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
    hypoxia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (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
    pulmonary haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Renal and urinary disorders
    urinary tract obstruction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Musculoskeletal and connective tissue disorders
    bone pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    kidney infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 8 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part A) 12 mg/kg Ramucirumab (Part B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    15 / 15 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    tumour haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    tumour pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    flushing
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    hypertension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    6 / 15 (40.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    13
    3
    hypotension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    8
    2
    General disorders and administration site conditions
    chills
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    face oedema
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    facial pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    fatigue
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    8 / 15 (53.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    9
    1
    impaired healing
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    localised oedema
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    malaise
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    pyrexia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    6 / 15 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    6
    1
    swelling
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    aphonia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    aspiration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    atelectasis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    cough
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    7 / 15 (46.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    10
    3
    dyspnoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    2
    epistaxis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    nasal congestion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    5
    1
    oropharyngeal pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 15 (26.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    1
    productive cough
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    rhinitis allergic
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    rhinorrhoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    2
    upper respiratory tract congestion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    wheezing
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    2
    confusional state
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    depression
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    insomnia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    personality change
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Investigations
    activated partial thromboplastin time prolonged
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    6 / 15 (40.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    7
    3
    anion gap increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    12 / 15 (80.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    14
    2
    bacterial test positive
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 15 (26.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    5
    0
    blood bicarbonate decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    blood bilirubin increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    blood cholesterol increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    blood creatinine increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    2
    c-reactive protein increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    ejection fraction decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    haemoglobin increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    3 / 6 (50.00%)
         occurrences all number
    2
    6
    5
    international normalised ratio decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    international normalised ratio increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    lipase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    lymphocyte count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    4 / 8 (50.00%)
    2 / 15 (13.33%)
    4 / 6 (66.67%)
         occurrences all number
    7
    2
    5
    neutrophil count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 15 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    2
    6
    2
    platelet count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 15 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    4
    3
    prothrombin time shortened
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    weight decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    weight increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    2
    white blood cell count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    6 / 15 (40.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    7
    2
    Injury, poisoning and procedural complications
    arthropod bite
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    contusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    gastrostomy tube site complication
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    infusion related reaction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    post procedural discharge
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    skin laceration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    vascular access complication
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    sinus bradycardia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    sinus tachycardia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 15 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    2
    7
    3
    Nervous system disorders
    ataxia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    disturbance in attention
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    dizziness
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    headache
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    7 / 15 (46.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    8
    0
    hemiparesis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    hypersomnia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    hypoaesthesia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    memory impairment
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    sinus headache
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    somnolence
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    9 / 15 (60.00%)
    2 / 6 (33.33%)
         occurrences all number
    4
    9
    3
    eosinophilia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    ear pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    hypoacusis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    eye pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    photophobia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    vision blurred
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    2
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    2
    6
    2
    abdominal pain upper
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    constipation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    3
    diarrhoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    2
    dysphagia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    mouth ulceration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    nausea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    4 / 8 (50.00%)
    7 / 15 (46.67%)
    1 / 6 (16.67%)
         occurrences all number
    5
    7
    1
    oral disorder
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    periodontal disease
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    stomatitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    tongue geographic
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    vomiting
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 8 (37.50%)
    7 / 15 (46.67%)
    2 / 6 (33.33%)
         occurrences all number
    4
    7
    3
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    dermatitis acneiform
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    dry skin
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    eczema asteatotic
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    erythema multiforme
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    onychomadesis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    pain of skin
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    petechiae
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    pruritus
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    1
    rash maculo-papular
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    3
    1
    skin ulcer
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Renal and urinary disorders
    chromaturia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    haematuria
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 15 (26.67%)
    1 / 6 (16.67%)
         occurrences all number
    2
    4
    1
    pollakiuria
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    proteinuria
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    6 / 15 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    8
    1
    urinary hesitation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    urinary tract pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    hyperthyroidism
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    flank pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    muscular weakness
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    musculoskeletal pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    myalgia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    neck pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    osteoporosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    pain in extremity
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    3
    5
    0
    Infections and infestations
    coxsackie viral infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    mucosal infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    skin infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    soft tissue infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    urinary tract infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    7 / 15 (46.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    9
    2
    dehydration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    hypercalcaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    hyperglycaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    8
    2
    hyperkalaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    3
    4
    1
    hypermagnesaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 15 (26.67%)
    3 / 6 (50.00%)
         occurrences all number
    0
    4
    4
    hypernatraemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    hyperphosphataemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 15 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    2
    hypoalbuminaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 15 (26.67%)
    1 / 6 (16.67%)
         occurrences all number
    2
    6
    1
    hypocalcaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    7 / 15 (46.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    7
    3
    hypochloraemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    hypoglycaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 15 (26.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    hypokalaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    1
    hyponatraemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    7 / 15 (46.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    12
    1
    hypophosphataemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 15 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    1
    5
    3
    vitamin d deficiency
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0

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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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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