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    Clinical Trial Results:
    A Phase 1b/2 Trial of AMG 386 in Combination With Pemetrexed and Carboplatin as First Line Treatment of Metastatic Non-squamous Non-small Cell Lung Cancer

    Summary
    EudraCT number
    		 2011-001111-31
    Trial protocol
    		 BE   ES   GR  
    Global end of trial date
    18 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Nov 2016
    First version publication date
    20 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20101128
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01666977
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    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
    Final
    Date of interim/final analysis
    18 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the incidence of adverse events and clinical laboratory abnormalities defined as dose-limiting toxicity (DLT) in subjects with metastatic non-small cell lung cancer (NSCLC) treated with trebananib in combination with pemetrexed and carboplatin.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and US Food and Drug Administration (FDA) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Aug 2012
    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
    Canada: 5
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    37
    EEA total number of subjects
    3
    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)
    19
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 18 centers in Australia, Canada, Spain, and the United States of America. The first participant enrolled on 23 August 2012 and the last participant enrolled on 25 October 2013.

    Pre-assignment
    Screening details
    		 Subjects were enrolled in 2 parts: In part 1, subjects were enrolled sequentially in 2 dose escalating treatment groups (trebananib 15 mg/mL or trebananib 30 mg//mL). After safety reviews, subjects were randomized in part 2 to receive placebo, trebananib 15 mg/mL or trebananib 30 mg//mL. Data are summarized together for both part 1 and part 2.

    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
    Blinding implementation details
    Part 1 was open label, 8 participants were enrolled. Part 2 was a double-blind and placebo-controlled study. Subjects were randomized in a 1:1:1 ratio to receive placebo, trebananib 15 mg/kg, or trebananib 30 mg/kg. A total of 29 participants were randomized in part 2

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo intravenously (IV) weekly (QW), pemetrexed 500 mg/m² IV every 3 weeks (Q3W), carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with placebo IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion once every week

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion every 3 weeks using the glomerular filtration rate (GFR) and Calvert formula to an AUC/time curve of 6 mg/mL*min

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Alimta®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion at 500 mg/m² every 3 weeks

    Arm title
    		 Trebananib 15 mg/kg
    Arm description
    		 Participants received rebananib 15 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with trebananib 15 mg/kg IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion once every week

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Alimta®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion at 500 mg/m² every 3 weeks

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion every 3 weeks using the glomerular filtration rate (GFR) and Calvert formula to an AUC/time curve of 6 mg/mL*min

    Arm title
    		 Trebananib 30 mg/kg
    Arm description
    		 Participants received rebananib 30 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with trebananib 30 mg/kg IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion once every week

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Alimta®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion at 500 mg/m² every 3 weeks

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion every 3 weeks using the glomerular filtration rate (GFR) and Calvert formula to an AUC/time curve of 6 mg/mL*min

    Number of subjects in period 1
    		Placebo Trebananib 15 mg/kg Trebananib 30 mg/kg
    Started
    10
    15
    12
    Completed
    3
    3
    2
    Not completed
    7
    12
    10
         Consent withdrawn by subject
    2
    3
    1
         Death
    1
    3
    4
         Other
    4
    6
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo intravenously (IV) weekly (QW), pemetrexed 500 mg/m² IV every 3 weeks (Q3W), carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with placebo IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Trebananib 15 mg/kg
    Reporting group description
    		 Participants received rebananib 15 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with trebananib 15 mg/kg IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Trebananib 30 mg/kg
    Reporting group description
    		 Participants received rebananib 30 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with trebananib 30 mg/kg IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group values
    		 Placebo Trebananib 15 mg/kg Trebananib 30 mg/kg Total
    Number of subjects
    		 10 15 12 37
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 4 8 7 19
        From 65-84 years
    		 6 7 5 18
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.5 ± 7.6 62.1 ± 10.9 65.2 ± 9.8 -
    Gender Categorical
    Units: Subjects
        Female
    		 3 5 4 12
        Male
    		 7 10 8 25
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 2 0 0 2
        Black or African American
    		 0 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        White
    		 7 13 11 31
        Other
    		 1 0 1 2
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 1 0 1 2
        Not Hispanic/Latino
    		 9 15 11 35

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo intravenously (IV) weekly (QW), pemetrexed 500 mg/m² IV every 3 weeks (Q3W), carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with placebo IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Trebananib 15 mg/kg
    Reporting group description
    		 Participants received rebananib 15 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with trebananib 15 mg/kg IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Trebananib 30 mg/kg
    Reporting group description
    		 Participants received rebananib 30 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles. After completion of up to 6 cycles participants continued on maintenance therapy with trebananib 30 mg/kg IV QW and pemetrexed, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Primary: Number of Participants with Dose-limiting Toxicities

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    End point title
    		 Number of Participants with Dose-limiting Toxicities [1]
    End point description
    A dose-limiting toxicity (DLT) was defined as any related, grade ≥ 3 hematologic or non-hematologic toxicity (according to Common Terminology Criteria for Adverse Events [CTCAE] version 3) with the exception of some modifications defined in the protocol. The DLT analysis set includes part 1 subjects who had received ≥ 2 infusions of trebananib and 1 dose of both pemetrexed and carboplatin and followed for the first 21 days of treatment.
    End point type
    Primary
    End point timeframe
    21 days
    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: Statistical analyses were not performed.
    End point values
    		 Placebo Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    0 [2]
    3
    4
    Units: participants
    0
    0
    Notes
    [2] - Only part 1 subjects were included in DLT analysis
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events
    End point description
    All adverse events (AEs) were graded for severity based on the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Trebananib-related adverse events are those events for which the investigator considered there to be a reasonable possibility that the event may have been caused by trebananib.
    End point type
    Secondary
    End point timeframe
    From study day 1 through 30 days after the last dose of any study drug; median time on study was 32 weeks.
    End point values
    		 Placebo Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    10
    15
    12
    Units: participants
        Any adverse event (AE)
    10
    15
    12
        Grade ≥ 3 adverse event
    9
    10
    9
        Grade ≥ 4 adverse event
    3
    3
    1
        Serious adverse events (SAE)
    5
    7
    7
        Fatal adverse events
    1
    0
    1
        AE leading to discontinuation of trebananib
    1
    5
    4
        AE leading to discontinuation of all study drugs
    1
    2
    2
        Trebananib-related adverse events
    5
    14
    9
        Trebananib-related grade ≥ 3 adverse events
    1
    5
    5
        Trebananib-related grade ≥ 4 adverse events
    1
    0
    0
        Trebananib-related serious adverse events
    1
    4
    3
        Trebananib-related fatal adverse events
    0
    0
    0
        Related AE leading to trebananib discontinuation
    1
    5
    3
        Related AE leading to discontinuation of all drugs
    1
    2
    1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an Objective Response

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    End point title
    		 Percentage of Participants with an Objective Response
    End point description
    Participants underwent radiological assessment for tumor response including computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis, and head/brain. Response was assessed by the investigator according to the response evaluation criteria in solid tumors (RECIST) guideline (version 1.1) with modifications. Objective response is defined as a complete response or partial response. This analysis was performed in subjects in the safety analysis set with ≥ 1 unidimensionally measurable lesion per RECIST 1.1 with modifications.
    End point type
    Secondary
    End point timeframe
    Radiological assessments were performed every 12 weeks until the end of treatment
    End point values
    		 Placebo Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    10
    15
    11
    Units: percentage of participants
        number (confidence interval 80%)
    20 (5.5 to 45)
    53.3 (34.2 to 71.8)
    27.3 (10.5 to 51.1)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS is defined as the time from the date of the first dosing of any study drug to the earlier of the dates of first disease progression per RECIST 1.1 with modifications or death from any cause. Subjects not meeting the criteria for disease progression by the analysis cutoff date were censored at their last evaluable radiographic assessment. Events of radiographic progression that occurred after initiation of subsequent anticancer therapy were not considered PFS events and were censored at the last evaluable radiographic tumor assessment before initiation of subsequent anticancer therapy. Deaths occurring after initiation of subsequent anticancer therapy were considered PFS events. PFS was analyzed using Kaplan-Meier methods. "99999" indicates data that could not be estimated.
    End point type
    Secondary
    End point timeframe
    From the first dose of any study drug until the end of study drug treatment
    End point values
    		 Placebo Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    10
    15
    12
    Units: months
        median (confidence interval 80%)
    6.9 (1.7 to 99999)
    7.2 (5.4 to 8.1)
    5.4 (3.3 to 6)
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Trebananib With and Without Pemetrexed and Carboplatin

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Trebananib With and Without Pemetrexed and Carboplatin [3]
    End point description
    The Cmax of trebananib following weekly IV infusions was assessed at cycle 3 day 1 (administered with pemetrexed and carboplatin) and at cycle 2 day 15 (trebananib alone).
    End point type
    Secondary
    End point timeframe
    Cycle 2, day 15 and cycle 3, day 1
    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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4
    Units: µg/mL
    arithmetic mean (standard deviation)
        Trebananib Monotherapy (Cycle 2 Day 15)
    289 ± 53.7
    603 ± 127
        With Carboplatin + Pemetrexed (Cycle 3 Day1)
    301 ± 40.6
    670 ± 123
    No statistical analyses for this end point

    Secondary: Time to Maximum Serum Concentration (Tmax) of Trebananib Administered With and Without Pemetrexed and Carboplatin

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    End point title
    		 Time to Maximum Serum Concentration (Tmax) of Trebananib Administered With and Without Pemetrexed and Carboplatin [4]
    End point description
    Tmax of trebananib following weekly IV infusions was assessed at cycle 3 day 1 (administered with pemetrexed and carboplatin) and at cycle 2 day 15 (trebananib alone).
    End point type
    Secondary
    End point timeframe
    Cycle 2 day 15 and cycle 3 day 1
    Notes
    [4] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4
    Units: hours
    median (full range (min-max))
        Trebananib Monotherapy (Cycle 2 Day 15)
    0.583 (0.5 to 0.75)
    0.625 (0.583 to 0.95)
        With Carboplatin + Pemetrexed (Cycle 3 Day1)
    0.667 (0.667 to 0.833)
    0.625 (0.55 to 0.85)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve from Start of Infusion to 168 Hours Post-dose (AUC0-168) of Trebananib

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    End point title
    		 Area Under the Concentration-time Curve from Start of Infusion to 168 Hours Post-dose (AUC0-168) of Trebananib [5]
    End point description
    The AUC0-168 of trebananib following weekly IV infusions was assessed at cycle 3 day 1 (administered with pemetrexed and carboplatin) and at cycle 2 day 15 (trebananib alone).
    End point type
    Secondary
    End point timeframe
    Cycle 2 day 15 and cycle 3 day 1
    Notes
    [5] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4
    Units: hr*µg/mL
    arithmetic mean (standard deviation)
        Trebananib Monotherapy (Cycle 2 Day 15)
    12300 ± 1110
    21800 ± 11400
        With Carboplatin + Pemetrexed (Cycle 3 Day1)
    10900 ± 3060
    21800 ± 11100
    No statistical analyses for this end point

    Secondary: Minimum Observed Concentration (Cmin) of Trebananib Administered With and Without Pemetrexed and Carboplatin

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    End point title
    		 Minimum Observed Concentration (Cmin) of Trebananib Administered With and Without Pemetrexed and Carboplatin [6]
    End point description
    The minimum observed concentration (trough concentration) of trebananib following weekly IV infusions was assessed at cycle 3 day 1 (administered with pemetrexed and carboplatin) and at cycle 2 day 15 (trebananib alone).
    End point type
    Secondary
    End point timeframe
    Cycle 2 day 15 and cycle 3 day 1
    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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4
    Units: µg/mL
    arithmetic mean (standard deviation)
        Trebananib Monotherapy (Cycle 2 Day 15)
    24.7 ± 2.15
    58.1 ± 45.7
        With Carboplatin + Pemetrexed (Cycle 3 Day1)
    28.7 ± 19.4
    65.4 ± 85.1
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Pemetrexed Administered With and Without Trebananib

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Pemetrexed Administered With and Without Trebananib [7]
    End point description
    The Cmax of pemetrexed was assessed when administered without trebananib (cycle 1, day 1) and with trebananib (cycle 3 day 1).
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4 [8]
    Units: µg/mL
    arithmetic mean (standard deviation)
        Pemetrexed Without Trebananib (Cycle 1 Day 1)
    137 ± 7.02
    114 ± 9.54
        Pemetrexed With Trebananib (Cycle 3 Day 1)
    104 ± 10.9
    92 ± 21.6
    Notes
    [8] - N=3 for cycle 1 day 1
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma Concentration (Tmax) of Pemetrexed Administered With and Without Trebananib

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax) of Pemetrexed Administered With and Without Trebananib [9]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4 [10]
    Units: hours
    median (full range (min-max))
        Pemetrexed Without Trebananib (Cycle 1 Day 1)
    0.2 (0.167 to 0.217)
    0.25 (0.233 to 0.25)
        Pemetrexed With Trebananib (Cycle 3 Day 1)
    0.25 (0.25 to 0.333)
    0.308 (0.183 to 0.45)
    Notes
    [10] - N=3 for cycle 1 day 1
    No statistical analyses for this end point

    Secondary: Area under the Concentration-time Curve from Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Pemetrexed

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    End point title
    		 Area under the Concentration-time Curve from Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Pemetrexed [11]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4 [12]
    Units: hr*µg/mL
    arithmetic mean (standard deviation)
        Pemetrexed Without Trebananib (Cycle 1 Day 1)
    198 ± 84.1
    140 ± 12.7
        Pemetrexed With Trebananib (Cycle 3 Day 1)
    221 ± 87.8
    227 ± 223
    Notes
    [12] - N=3 for cycle 1 day 1
    No statistical analyses for this end point

    Secondary: Minimum Observed Concentration (Cmin) of Pemetrexed Administered With and Without Trebananib

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    End point title
    		 Minimum Observed Concentration (Cmin) of Pemetrexed Administered With and Without Trebananib [13]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    3
    4 [14]
    Units: µg/mL
    arithmetic mean (standard deviation)
        Pemetrexed Without Trebananib (Cycle 1 Day 1)
    2.37 ± 2.45
    3.33 ± 0.702
        Pemetrexed With Trebananib (Cycle 3 Day 1)
    1.09 ± 1.51
    3.86 ± 2.16
    Notes
    [14] - N=3 for cycle 1 day 1
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Total Platinum After Administration of Carboplatin With and Without Trebananib

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Total Platinum After Administration of Carboplatin With and Without Trebananib [15]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [16]
    4
    Units: µg/mL
    arithmetic mean (standard deviation)
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    23.1 ± 7.1
    20.1 ± 2.91
        Carboplatin With Trebananib (Cycle 3 Day 1)
    22.4 ± 5.76
    11.4 ± 1.55
    Notes
    [16] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma Concentration (Tmax) of Total Platinum After Administration of Carboplatin With and Without Trebananib

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax) of Total Platinum After Administration of Carboplatin With and Without Trebananib [17]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    Notes
    [17] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [18]
    4
    Units: hours
    median (full range (min-max))
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    0.392 (0.25 to 0.833)
    0.442 (0.333 to 0.833)
        Carboplatin With Trebananib (Cycle 3 Day 1)
    0.5 (0.5 to 0.583)
    0.517 (0.5 to 22.6)
    Notes
    [18] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Secondary: AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Total Platinum

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    End point title
    		 AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Total Platinum [19]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    Notes
    [19] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [20]
    4
    Units: µg/mL
    arithmetic mean (standard deviation)
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    65.9 ± 45.8
    60.3 ± 19.2
        Carboplatin With Trebananib (Cycle 3 Day 1)
    93.9 ± 8.48
    66.2 ± 33.2
    Notes
    [20] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Cmin) of Total Platinum After Administration of Carboplatin With and Without Trebananib

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    End point title
    		 Minimum Observed Plasma Concentration (Cmin) of Total Platinum After Administration of Carboplatin With and Without Trebananib [21]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    Notes
    [21] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [22]
    4
    Units: hr*µg/mL
    arithmetic mean (standard deviation)
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    2.17 ± 0.505
    2.09 ± 0.64
        Carboplatin With Trebananib (Cycle 3 Day 1)
    1.13 ± 0.108
    1.18 ± 0.251
    Notes
    [22] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Unbound Platinum After Administration of Carboplatin With and Without Trebananib

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Unbound Platinum After Administration of Carboplatin With and Without Trebananib [23]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    Notes
    [23] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [24]
    4
    Units: µg/mL
    arithmetic mean (standard deviation)
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    24.5 ± 8.44
    20.1 ± 3.28
        Carboplatin With Trebananib (Cycle 3 Day 1)
    23.6 ± 7.49
    12.4 ± 11.1
    Notes
    [24] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma Concentration (Tmax) of Unbound Platinum After Administration of Carboplatin With and Without Trebananib

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax) of Unbound Platinum After Administration of Carboplatin With and Without Trebananib [25]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    Notes
    [25] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [26]
    4 [27]
    Units: hours
    median (full range (min-max))
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    0.392 (0.25 to 0.833)
    0.442 (0.333 to 0.833)
        Carboplatin With Trebananib (Cycle 3 Day 1)
    0.5 (0.5 to 0.583)
    0.5 (0.5 to 0.533)
    Notes
    [26] - N=3 for cycle 3 day 1
    [27] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Secondary: AUC from Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Unbound Platinum

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    End point title
    		 AUC from Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Unbound Platinum [28]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    Notes
    [28] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [29]
    4
    Units: hr*µg/mL
    arithmetic mean (standard deviation)
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    51.2 ± 16.6
    46.9 ± 4.51
        Carboplatin With Trebananib (Cycle 3 Day 1)
    50.2 ± 12.6
    24 ± 16.2
    Notes
    [29] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Cmin) of Unbound Platinum After Administration of Carboplatin With and Without Trebananib

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    End point title
    		 Minimum Observed Plasma Concentration (Cmin) of Unbound Platinum After Administration of Carboplatin With and Without Trebananib [30]
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 and cycle 3 day 1
    Notes
    [30] - 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: Pharmacokinetic analyses were only performed on participants enrolled in part 1 of the study.
    End point values
    		 Trebananib 15 mg/kg Trebananib 30 mg/kg
    Number of subjects analysed
    4 [31]
    4 [32]
    Units: µg/mL
    arithmetic mean (standard deviation)
        Carboplatin Without Trebananib (Cycle 1 Day 1)
    2.42 ± 1.28
    2.01 ± 0.835
        Carboplatin With Trebananib (Cycle 3 Day 1)
    3.19 ± 0.358
    2.93 ± 0.944
    Notes
    [31] - N=3 for cycle 3 day 1
    [32] - N=3 for cycle 3 day 1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until 30 days after last dose; median time on study was 32 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Induction Phase: Placebo
    Reporting group description
    		 Participants received placebo IV QW, pemetrexed 500 mg/m² IV Q3W, carboplatin IV Q3W, for up to 6 cycles in the induction phase.

    Reporting group title
    Induction Phase: Trebananib 15 mg/kg
    Reporting group description
    		 Participants received rebananib 15 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles in the induction phase.

    Reporting group title
    Induction Phase: Trebananib 30 mg/kg
    Reporting group description
    		 Participants received rebananib 30 mg/kg IV QW, pemetrexed 500 mg/m² IV Q3W, and carboplatin IV Q3W, for up to 6 cycles in the induction phase.

    Reporting group title
    Maintenance Phase: Placebo
    Reporting group description
    		 Participants continued on maintenance therapy with placebo IV QW and pemetrexed 500 mg/m² IV Q3W, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Maintenance Phase: Trebananib 15 mg/kg
    Reporting group description
    		 Participants continued on maintenance therapy with trebananib 15 mg/kg IV QW and pemetrexed 500 mg/m² IV Q3W, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Maintenance Phase: Trebananib 30 mg/kg
    Reporting group description
    		 Participants continued on maintenance therapy with trebananib 30 mg/kg IV QW and pemetrexed 500 mg/m² IV Q3W, until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Serious adverse events
    		 Induction Phase: Placebo Induction Phase: Trebananib 15 mg/kg Induction Phase: Trebananib 30 mg/kg Maintenance Phase: Placebo Maintenance Phase: Trebananib 15 mg/kg Maintenance Phase: Trebananib 30 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 15 (33.33%)
    7 / 12 (58.33%)
    1 / 2 (50.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
         number of deaths (all causes)
    2
    3
    5
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Platelet adhesiveness decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to spine
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Localised oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Induction Phase: Placebo Induction Phase: Trebananib 15 mg/kg Induction Phase: Trebananib 30 mg/kg Maintenance Phase: Placebo Maintenance Phase: Trebananib 15 mg/kg Maintenance Phase: Trebananib 30 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    15 / 15 (100.00%)
    12 / 12 (100.00%)
    2 / 2 (100.00%)
    7 / 7 (100.00%)
    5 / 5 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Diastolic hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Hot flush
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    1
    0
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Peripheral venous disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    Phlebitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    2
    3
    1
    0
    2
    0
    Chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    7 / 10 (70.00%)
    12 / 15 (80.00%)
    9 / 12 (75.00%)
    1 / 2 (50.00%)
    3 / 7 (42.86%)
    1 / 5 (20.00%)
         occurrences all number
    7
    21
    10
    1
    6
    2
    Generalised oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    2 / 10 (20.00%)
    7 / 15 (46.67%)
    5 / 12 (41.67%)
    2 / 2 (100.00%)
    5 / 7 (71.43%)
    3 / 5 (60.00%)
         occurrences all number
    2
    16
    11
    2
    7
    4
    Mucosal inflammation
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    4
    2
    2
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
    1 / 12 (8.33%)
    1 / 2 (50.00%)
    3 / 7 (42.86%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    1
    1
    6
    0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 15 (33.33%)
    3 / 12 (25.00%)
    1 / 2 (50.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    1
    5
    4
    1
    1
    0
    Dyspnoea
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 15 (26.67%)
    4 / 12 (33.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    3
    5
    5
    0
    0
    2
    Dyspnoea exertional
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
         occurrences all number
    2
    2
    2
    0
    1
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sinus disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Delirium
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    2
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 15 (26.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    9
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    4
    0
    0
    0
    Investigation abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Neutrophil count abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    2
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
    3 / 12 (25.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    White blood cell count
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Atrial flutter
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 15 (26.67%)
    4 / 12 (33.33%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    4
    4
    7
    0
    2
    0
    Dizziness postural
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    1
    5
    0
    0
    2
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Migraine
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 10 (40.00%)
    4 / 15 (26.67%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
         occurrences all number
    5
    6
    5
    0
    5
    2
    Neutropenia
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 15 (26.67%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    5
    6
    3
    0
    0
    2
    Platelet disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 15 (33.33%)
    4 / 12 (33.33%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
         occurrences all number
    0
    9
    8
    0
    2
    2
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    2
    0
    0
    0
    Photophobia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    2
    0
    3
    1
    Ascites
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Colitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    4 / 10 (40.00%)
    9 / 15 (60.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
         occurrences all number
    4
    11
    4
    0
    2
    1
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    5 / 15 (33.33%)
    3 / 12 (25.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    7
    8
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 10 (20.00%)
    11 / 15 (73.33%)
    8 / 12 (66.67%)
    1 / 2 (50.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    5
    21
    12
    2
    2
    0
    Retching
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 10 (20.00%)
    7 / 15 (46.67%)
    3 / 12 (25.00%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
         occurrences all number
    3
    14
    5
    0
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Onychomadesis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain of skin
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Purpura
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Rash
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 15 (20.00%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    4
    2
    0
    0
    0
    Skin mass
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nephropathy toxic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
    3 / 12 (25.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    3
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pain in jaw
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye infection bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Hepatitis viral
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    1
    0
    2
    0
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Oral infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    1
    0
    3
    2
    Wound infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    3 / 10 (30.00%)
    5 / 15 (33.33%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    4 / 7 (57.14%)
    0 / 5 (0.00%)
         occurrences all number
    3
    5
    6
    0
    8
    0
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Food intolerance
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Gout
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Hypochloraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
    4 / 12 (33.33%)
    1 / 2 (50.00%)
    1 / 7 (14.29%)
    2 / 5 (40.00%)
         occurrences all number
    0
    4
    11
    2
    3
    2
    Hypomagnesaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 15 (6.67%)
    2 / 12 (16.67%)
    1 / 2 (50.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    7
    2
    2
    5
    2
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    4
    0
    0
    0
    0
    Hypovolaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Increased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2012
    •Amgen documentation was amended regarding the process for determination of expectedness of clinical trial adverse events for the purpose of expedited reporting to regulatory agencies globally. •The change in timeline for serious adverse event reporting from Investigators to sponsors was updated to be within 24 hours. •The Pregnancy and Lactation Reporting section was updated per current Amgen protocol template. In line with this, a new lactation notification worksheet was added. •It was clarified that this study now reports serious adverse events through electronic serious adverse event report form. A sample electronic serious adverse event contingency report form has replaced the old version. •The exclusion criterion on subjects with known epidermal growth factor receptor mutation was clarified. •The Dose-limiting Toxicity analysis set definition was clarified. •Typographic and formatting errors were corrected.
    26 Nov 2013
    •The sponsor decided to close the study to further randomization/enrollment on 15 October 2013 because of the changing therapeutic landscape that limits the future utility of trebananib in this disease setting. •Total number of subjects in part 2 was decreased from 210 to 29. •All subjects randomized to part 2 were unblinded and placebo was discontinued. •Objectives, endpoints, and statistical analysis plan were updated. •Text was added on how to address and report serious adverse events occurring outside the protocol required reporting period. •Changes were made to the sample collection requirements, and other procedures such as electrocardiogram evaluation and imaging schedules. •Changes were made to the list of protocol-required or recommended drugs in the study. •Patient-related outcomes questionnaires were discontinued. •Administrative information was updated and typographical errors were corrected.

    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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