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    Clinical Trial Results:
    Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM in Patients with Septic Shock. A Randomised, Double-blind, Two-stage, Placebo Controlled Study.

    Summary
    EudraCT number
    		 2016-005032-14
    Trial protocol
    		 BE   NL   ES  
    Global end of trial date
    13 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2022
    First version publication date
    20 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MOT-C-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03158948
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    INOTREM SA
    Sponsor organisation address
    54 rue de Ponthieu, Paris, France, 75008
    Public contact
    Executive VP Research and Medical Sciences, INOTREM S.A., +33 (0)6 30 62 86 51, jjg@inotrem.com
    Scientific contact
    Executive VP Research and Medical Sciences, INOTREM S.A., +33 (0)6 30 62 86 51, jjg@inotrem.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
    20 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of MOTREM in patients with septic shock
    Protection of trial subjects
    The study was performed in accordance with the Declaration of Helsinki and International Council on Harmonization Good Clinical Practice, and approved by the South Central – Berkshire B Research Ethics Committee, UK. The written informed consent for patient was obtained from relative or independent clinicians before the enrolment when the patient was unable to consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jul 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Belgium: 28
    Country: Number of subjects enrolled
    France: 13
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    23
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled from 03 July 2017 (first patient first visit) to 11 June 2018 (last patient last visit) in 11 centers in 4 countries (Belgium, France, Spain, The Netherlands). 50 patients were included and randomized. 49 (98.0%) patients received the IMP and one patient died before IMP administration.

    Pre-assignment
    Screening details
    		 The duration of this study for each patient was a maximum of 13 weeks (including screening, up to 5 days of treatment and follow-up assessments 28 and 90 days after randomization). The purpose of the screening phase was to confirm patient eligibility for enrolment in the study based on the inclusion and exclusion criteria and to obtain written ICF.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study was conducted in a double-blind fashion, whereby patients and clinical study site staff were blinded to study drug assignment. The pharmacy staff or any other dedicated person preparing the investigational products was not blinded to study drug assignment and was responsible for the blinding of the study drug. During the study, the randomization codes were kept in the site's clinical trials pharmacy, accessible to the pharmacy personnel or any other dedicated person only.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Commercial saline solution (i.e. NaCl 0.9%)

    Arm title
    		 0.3 mg/kg/h
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nangibotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5.0 mg/kg i.v. (loading dose) for 15 minutes followed by a maintenance dose of 0.3 mg/kg/h for up to 5 days

    Arm title
    		 1.0 mg/kg/h
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nangibotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5.0 mg/kg i.v. (loading dose) for 15 minutes followed by a maintenance dose of 1.0 mg/kg/h for up to 5 days

    Arm title
    		 3.0 mg/kg/h
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nangibotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5.0 mg/kg i.v. (loading dose) for 15 minutes followed by a maintenance dose of 3.0 mg/kg/h for up to 5 days

    Number of subjects in period 1
    		Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Started
    12
    13
    12
    12
    Completed
    9
    12
    11
    9
    Not completed
    3
    1
    1
    3
         Adverse event, serious fatal
    2
    1
    1
    3
         Investigator decision
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    0.3 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    1.0 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    3.0 mg/kg/h
    Reporting group description
    		 -

    Reporting group values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h Total
    Number of subjects
    		 12 13 12 12 49
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 8 3 7 23
        From 65-84 years
    		 7 5 9 5 26
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 66 (47 to 80) 63 (38 to 80) 65 (40 to 77) 62 (22 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 4 6 5 4 19
        Male
    		 8 7 7 8 30

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    0.3 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    1.0 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    3.0 mg/kg/h
    Reporting group description
    		 -

    Primary: Adverse Events

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    End point title
    		 Adverse Events [1]
    End point description
    End point type
    Primary
    End point timeframe
    Adverse events experienced until D28 (End of study visit)
    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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: Number of subjects experiencing AEs
    10
    13
    12
    11
    Attachments
    		 Summary of adverse event by patient
    Summary of TEAEs
    No statistical analyses for this end point

    Primary: Systolic Blood Pressure

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    End point title
    		 Systolic Blood Pressure [2]
    End point description
    Mean SBP at each visit is summarized by treatment group. No obvious difference between treatment groups was shown.
    End point type
    Primary
    End point timeframe
    Vital signs were assessed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p- values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12 [3]
    13 [4]
    12 [5]
    12 [6]
    Units: mmHg
    arithmetic mean (standard deviation)
        D0
    118.8 ± 22.2
    109.8 ± 14.5
    119.2 ± 11.4
    116.3 ± 22.3
        D1
    108.8 ± 19.1
    121.8 ± 18.0
    112.1 ± 9.1
    114.3 ± 16.7
        D2
    107.0 ± 4.2
    118.8 ± 21.6
    120.2 ± 9.4
    116.6 ± 17.0
        D3
    94.0 ± 9.9
    126.5 ± 3.5
    110.0 ± 13.3
    112.5 ± 8.7
        D4
    108.0 ± 5.7
    133.0 ± 0
    110.3 ± 12.9
    107.0 ± 10.1
        D5/EOI
    110.4 ± 19.5
    120.3 ± 23.1
    120.2 ± 19.9
    107.9 ± 15.4
        D28/EOS
    132.3 ± 24.3
    116.6 ± 14.8
    117.0 ± 21.2
    109.0 ± 8.9
    Notes
    [3] - D0: N=10 D1: N=8 D2: N=2 D3: N=2 D4: N=2 D5/EOI: N=10 D29/EOS: N=9
    [4] - D0: N=13 D1: N=9 D2: N=4 D3: N=2 D4: N=1 D5/EOI: N=13 D29/EOS: N=11
    [5] - D0: N=12 D1: N=10 D2: N=5 D3: N=4 D4: N=3 D5/EOI: N=12 D29/EOS: N=11
    [6] - D0: N=12 D1: N=11 D2: N=7 D3: N=4 D4: N=4 D5/EOI: N=12 D29/EOS: N=9
    No statistical analyses for this end point

    Primary: Diastolic Blood Pressure

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    End point title
    		 Diastolic Blood Pressure [7]
    End point description
    Mean DBP at each visit is summarized by treatment group. No obvious difference between treatment groups was shown.
    End point type
    Primary
    End point timeframe
    Vital signs were assessed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).
    Notes
    [7] - 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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12 [8]
    13 [9]
    12 [10]
    12 [11]
    Units: mmHg
    arithmetic mean (standard deviation)
        D0
    56.1 ± 11.3
    56.9 ± 11.0
    61.1 ± 9.1
    56.3 ± 7.5
        D1
    59.4 ± 10.3
    56.4 ± 13.7
    67.7 ± 22.9
    59.2 ± 11.0
        D2
    61.0 ± 7.1
    65.8 ± 6.4
    65.4 ± 6.3
    66.6 ± 14.7
        D3
    58.5 ± 12.0
    60.5 ± 0.7
    53.3 ± 9.8
    60.0 ± 10.4
        D4
    61.5 ± 9.2
    64.0 ± 0
    54.3 ± 2.1
    56.3 ± 7.6
        D5/EOI
    55.7 ± 6.5
    60.4 ± 15.0
    59.3 ± 12.5
    54.4 ± 13.8
        D28/EOS
    67.3 ± 14.0
    66.9 ± 14.4
    60.9 ± 13.8
    68.2 ± 7.2
    Notes
    [8] - D0: N=10 D1: N=8 D2: N=2 D3: N=2 D4: N=2 D5/EOI: N=10 D29/EOS: N=9
    [9] - D0: N=13 D1: N=9 D2: N=4 D3: N=2 D4: N=1 D5/EOI: N=13 D29/EOS: N=11
    [10] - D0: N=12 D1: N=10 D2: N=5 D3: N=4 D4: N=3 D5/EOI: N=12 D29/EOS: N=11
    [11] - D0: N=12 D1: N=11 D2: N=7 D3: N=4 D4: N=4 D5/EOI: N=12 D29/EOS: N=9
    No statistical analyses for this end point

    Primary: Mean Arterial Pressure

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    End point title
    		 Mean Arterial Pressure [12]
    End point description
    MAP at each visit is summarized by treatment group. No obvious difference between treatment groups was shown.
    End point type
    Primary
    End point timeframe
    Vital signs were assessed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).
    Notes
    [12] - 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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12 [13]
    13 [14]
    12 [15]
    12 [16]
    Units: mmHg
    arithmetic mean (standard deviation)
        D0
    75.4 ± 13.8
    74.7 ± 10.8
    80.6 ± 9.2
    77.9 ± 14.0
        D1
    76.1 ± 13.8
    79.0 ± 13.8
    73.8 ± 9.5
    77.1 ± 10.9
        D2
    76.0 ± 9.9
    86.8 ± 12.6
    76.8 ± 14.3
    80.6 ± 11.2
        D3
    71.0 ± 12.7
    84.5 ± 0.7
    70.5 ± 12.2
    79.0 ± 7.3
        D4
    76.5 ± 10.6
    92.0 ± 0
    71.3 ± 2.5
    75.8 ± 4.3
        D5/EOI
    74.2 ± 7.4
    80.7 ± 18.3
    80.2 ± 14.0
    70.7 ± 15.6
        D28/EOS
    86.1 ± 12.7
    84.3 ± 15.0
    80.0 ± 15.8
    80.3 ± 8.3
    Notes
    [13] - D0: N=10 D1: N=8 D2: N=2 D3: N=2 D4: N=2 D5/EOI: N=10 D29/EOS: N=8
    [14] - D0: N=13 D1: N=9 D2: N=4 D3: N=2 D4: N=1 D5/EOI: N=13 D29/EOS: N=10
    [15] - D0: N=12 D1: N=10 D2: N=5 D3: N=4 D4: N=3 D5/EOI: N=12 D29/EOS: N=11
    [16] - D0: N=12 D1: N=11 D2: N=7 D3: N=4 D4: N=4 D5/EOI: N=12 D29/EOS: N=9
    No statistical analyses for this end point

    Primary: Heart Rate

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    End point title
    		 Heart Rate [17]
    End point description
    Mean DBP at each visit is summarized by treatment group. No obvious difference between treatment groups was shown.
    End point type
    Primary
    End point timeframe
    Vital signs were assessed each day from D0 (before IMP initiation) to D5 (EOI).
    Notes
    [17] - 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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12 [18]
    13 [19]
    12 [20]
    12 [21]
    Units: bpm
    arithmetic mean (standard deviation)
        D0
    90.2 ± 26.8
    97.2 ± 17.7
    101.8 ± 24.2
    106.4 ± 22.7
        D1
    94.4 ± 30.9
    90.2 ± 18.1
    94.1 ± 19.4
    103.3 ± 18.7
        D2
    74.0 ± 19.8
    88.8 ± 11.2
    108.0 ± 15.7
    94.4 ± 35.1
        D3
    95.0 ± 35.4
    60.5 ± 3.5
    96.8 ± 26.8
    85.3 ± 17.0
        D4
    75.0 ± 7.1
    61.0 ± 0
    125.7 ± 28.3
    82.8 ± 14.2
        D5/EOI
    90.9 ± 20.6
    90.6 ± 19.5
    89.5 ± 15.7
    92.7 ± 14.9
    Notes
    [18] - D0: N=10 D1: N=8 D2: N=2 D3: N=2 D4: N=2 D5/EOI: N=10
    [19] - D0: N=13 D1: N=9 D2: N=4 D3: N=2 D4: N=1 D5/EOI: N=13
    [20] - D0: N=12 D1: N=10 D2: N=5 D3: N=4 D4: N=3 D5/EOI: N=12
    [21] - D0: N=12 D1: N=11 D2: N=7 D3: N=4 D4: N=4 D5/EOI: N=12
    No statistical analyses for this end point

    Primary: Temperature

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    End point title
    		 Temperature [22]
    End point description
    Mean DBP at each visit is summarized by treatment group. No obvious difference between treatment groups was shown.
    End point type
    Primary
    End point timeframe
    Vital signs were assessed each day from D0 (before IMP initiation) to D5 (EOI).
    Notes
    [22] - 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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12 [23]
    13 [24]
    12 [25]
    12 [26]
    Units: °C
    arithmetic mean (standard deviation)
        D0
    37.1 ± 1.5
    36.9 ± 1.1
    37.0 ± 0.6
    37.1 ± 1.4
        D1
    37.1 ± 1.8
    36.3 ± 1.5
    36.9 ± 0.7
    37.1 ± 1.0
        D2
    36.1 ± 0.8
    36.3 ± 0.6
    36.7 ± 0.6
    37.0 ± 1.5
        D3
    36.6 ± 0.8
    36.3 ± 0.9
    36.8 ± 0.7
    37.3 ± 1.1
        D4
    36.1 ± 0.1
    36.1 ± 0
    37.0 ± 0.4
    36.7 ± 0.5
        D5/EOI
    36.7 ± 0.6
    36.7 ± 0.9
    36.8 ± 1.1
    36.6 ± 1.2
    Notes
    [23] - D0: N=10 D1: N=8 D2: N=2 D3: N=2 D4: N=2 D5/EOI: N=10
    [24] - D0: N=13 D1: N=9 D2: N=4 D3: N=2 D4: N=1 D5/EOI: N=13
    [25] - D0: N=12 D1: N=10 D2: N=5 D3: N=4 D4: N=3 D5/EOI: N=12
    [26] - D0: N=12 D1: N=11 D2: N=7 D3: N=4 D4: N=4 D5/EOI: N=11
    No statistical analyses for this end point

    Primary: Electrocardiogram

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    End point title
    		 Electrocardiogram [27]
    End point description
    There was no obvious dose effect in the frequency of abnormal CS ECG in nangibotide groups, and no obvious difference with the placebo group. Based, on Listing of ECG abnormalities: - 13 patients had abnormal CS ECG (emergent or not): 3 patients in the nangibotide group 0.3 mg/kg/h, 2 patients in the nangibotide group 1.0 mg/kg/h, 4 patients in the nangibotide group 3.0 mg/kg/h and 2 patients in the placebo group. - 4 patients had emergent (i.e. not reported at baseline) abnormal clinically significant ECG during the study: 1 patient in the nangibotide group 0.3 mg/kg/h, 1 patient in the nangibotide group 1.0 mg/kg/h, 2 patients in the nangibotide group 3.0 mg/kg/h and none in the placebo group.
    End point type
    Primary
    End point timeframe
    Electrocardiogram was performed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).
    Notes
    [27] - 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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: Number of subjects
        abnormal CS ECG
    2
    3
    2
    4
        emergent abnormal clinically significant ECG
    1
    1
    2
    0
    Attachments
    		 Electrocardiogram
    No statistical analyses for this end point

    Primary: Anti-Drug Antibodies (ADA Dimer)

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    End point title
    		 Anti-Drug Antibodies (ADA Dimer) [28]
    End point description
    Anti-Drug Antibodies test were negative at D0 and D28 in all patients.
    End point type
    Primary
    End point timeframe
    Anti-Drug Antibodies test were done at D0, D10 and D28 in all patients.
    Notes
    [28] - 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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12 [29]
    13 [30]
    12 [31]
    12 [32]
    Units: ADA DIMER
        Missing
    3
    4
    2
    3
        Negative
    9
    9
    10
    9
    Notes
    [29] - Results for D28 represented
    [30] - Results for D28 represented
    [31] - Results for D28 represented
    [32] - Results for D28 represented
    No statistical analyses for this end point

    Primary: Anti-Drug Antibodies (ADA Monomer)

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    End point title
    		 Anti-Drug Antibodies (ADA Monomer) [33]
    End point description
    Anti-Drug Antibodies test were negative at D0 and D28 in all patients.
    End point type
    Primary
    End point timeframe
    Anti-Drug Antibodies test were measured at D0, D10 and D28.
    Notes
    [33] - 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: As the primary endpoints in this study are safety endpoints concerning primarily adverse events, statistics for the aforementioned do not contain p-values. For this reason statistical analysis is not provided here.
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12 [34]
    13 [35]
    12 [36]
    12 [37]
    Units: ADA Monomer
        Missing
    3
    5
    2
    3
        Negative
    9
    8
    10
    9
    Notes
    [34] - Values are presented for D28
    [35] - Values are presented for D28
    [36] - Values are presented for D28
    [37] - Values are presented for D28
    No statistical analyses for this end point

    Secondary: PK (Cmax)

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    End point title
    		 PK (Cmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    0 [38]
    13
    12
    12
    Units: ng/mL
        median (full range (min-max))
    ( to )
    71.2 (20.0 to 219)
    234 (71.3 to 514)
    914 (502 to 6095)
    Notes
    [38] - PK not analyzed for placebo
    No statistical analyses for this end point

    Secondary: PK (tmax)

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    End point title
    		 PK (tmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    0 [39]
    13
    12
    12
    Units: hour
        median (full range (min-max))
    ( to )
    22.7 (14.3 to 76.0)
    25.4 (9.25 to 118)
    36.0 (9.00 to 75.8)
    Notes
    [39] - PK not analyzed for placebo
    No statistical analyses for this end point

    Secondary: PK (AUC0-last)

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    End point title
    		 PK (AUC0-last)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    0 [40]
    13
    12
    12
    Units: ng*h/mL
        median (full range (min-max))
    ( to )
    1722 (360 to 5243)
    7579 (668 to 45189)
    47320 (3830 to 393506)
    Notes
    [40] - PK not analyzed for placebo
    No statistical analyses for this end point

    Secondary: PK (Cavg)

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    End point title
    		 PK (Cavg)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    0 [41]
    13
    12
    12
    Units: ng/mL
        median (full range (min-max))
    ( to )
    67.6 (20.0 to 219)
    223 (71.3 to 418)
    729 (93.9 to 3778)
    Notes
    [41] - PK not analyzed for placebo
    No statistical analyses for this end point

    Secondary: PK (CL)

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    End point title
    		 PK (CL)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    0 [42]
    13
    12
    12
    Units: L/h/kg
        median (full range (min-max))
    ( to )
    4.52 (1.36 to 15.3)
    4.50 (2.39 to 14.0)
    4.12 (0.794 to 25.0)
    Notes
    [42] - PK not analyzed for placebo
    No statistical analyses for this end point

    Secondary: PD (Biomarker- Ang-1)

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    End point title
    		 PD (Biomarker- Ang-1)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: ng/mL
        arithmetic mean (standard deviation)
    3.6 ± 6.1
    7.8 ± 16.6
    3.1 ± 3.5
    3.1 ± 2.3
    No statistical analyses for this end point

    Secondary: PD (Biomarker- Ang-2)

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    End point title
    		 PD (Biomarker- Ang-2)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: ng/mL
        arithmetic mean (standard deviation)
    29.7 ± 33.3
    20.4 ± 15.2
    18.6 ± 9.1
    25.3 ± 19.7
    No statistical analyses for this end point

    Secondary: PD (Biomarker- CCL-2 [MCP-1])

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    End point title
    		 PD (Biomarker- CCL-2 [MCP-1])
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    3643 ± 4177
    2839 ± 3023
    5505 ± 10947
    22427 ± 22738
    No statistical analyses for this end point

    Secondary: PD (Biomarker-INF gamma)

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    End point title
    		 PD (Biomarker-INF gamma)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    3
    0 [43]
    5
    6
    Units: pg/ml
        arithmetic mean (standard deviation)
    1.6 ± 0
    ±
    35.8 ± 26.0
    15.9 ± 17.6
    Notes
    [43] - INF gamma not analyzed for this group
    No statistical analyses for this end point

    Secondary: PD (Biomarker IL-10)

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    End point title
    		 PD (Biomarker IL-10)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: pg/mL
        arithmetic mean (standard deviation)
    261 ± 364
    123 ± 81
    2102 ± 4436
    1650 ± 4565
    No statistical analyses for this end point

    Secondary: PD (Biomarker IL-6)

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    End point title
    		 PD (Biomarker IL-6)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: pg/mL
        arithmetic mean (standard deviation)
    6549 ± 11639
    3255 ± 6285
    19060 ± 55879
    27774 ± 52882
    No statistical analyses for this end point

    Secondary: PD (Biomarker IL-8)

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    End point title
    		 PD (Biomarker IL-8)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: pg/mL
        arithmetic mean (standard deviation)
    1551 ± 2888
    984 ± 2259
    3490 ± 11177
    10742 ± 27964
    No statistical analyses for this end point

    Secondary: PD (Biomarker TNF alpha)

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    End point title
    		 PD (Biomarker TNF alpha)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: pg/mL
        arithmetic mean (standard deviation)
    397 ± 538
    313 ± 303
    551 ± 674
    614 ± 548
    No statistical analyses for this end point

    Secondary: PD (Biomarker VCAM-1)

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    End point title
    		 PD (Biomarker VCAM-1)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: ng/mL
        arithmetic mean (standard deviation)
    5010 ± 3600
    4616 ± 3538
    5363 ± 3756
    3606 ± 2059
    No statistical analyses for this end point

    Secondary: PD (Biomarker VEGFR-1)

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    End point title
    		 PD (Biomarker VEGFR-1)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.74 ± 0.53
    1.46 ± 2.28
    3.07 ± 6.85
    3.20 ± 5.06
    No statistical analyses for this end point

    Secondary: PD (Biomarker sCD62E)

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    End point title
    		 PD (Biomarker sCD62E)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: ng/mL
        arithmetic mean (standard deviation)
    101.9 ± 86.8
    93.8 ± 96.7
    148.9 ± 145.4
    169.4 ± 212.1
    No statistical analyses for this end point

    Secondary: PD (Biomarker sTREM-1)

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    End point title
    		 PD (Biomarker sTREM-1)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Number of subjects analysed
    12
    13
    12
    12
    Units: pg/mL
        arithmetic mean (standard deviation)
    676 ± 622
    474 ± 221
    519 ± 306
    616 ± 365
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline until D28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    0.3 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    1.0 mg/kg/h
    Reporting group description
    		 -

    Reporting group title
    3.0 mg/kg/h
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 12 (58.33%)
    4 / 13 (30.77%)
    2 / 12 (16.67%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    2
    4
    2
    4
         number of deaths resulting from adverse events
    2
    1
    1
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Mechanical ventilation complication
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haemodynamic instability
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Shock
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple Organ Failure syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Encephalitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 0.3 mg/kg/h 1.0 mg/kg/h 3.0 mg/kg/h
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 12 (83.33%)
    12 / 13 (92.31%)
    12 / 12 (100.00%)
    11 / 12 (91.67%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 13 (38.46%)
    2 / 12 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    1
    5
    2
    3
    Arrhythmia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    2
    Nervous system disorders
    Confusional state
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 13 (23.08%)
    2 / 12 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    3
    3
    2
    3
    Thrombocytopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    4 / 12 (33.33%)
         occurrences all number
    1
    0
    1
    4
    Gastrointestinal disorders
    Intra-Abdominal Fluid Collection
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    2
    1
    2
    2
    Bronchitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Pneumothorax
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    1
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    0
    1
    Infections and infestations
    Oral Fungal Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    2
    Infectious Pleural Effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Septic Shock
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    1
    2
    Hypophosphataemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2017
    • Addition of blood samples for DNA analyses related to the TREM-1 signalling pathway • Changes requested by the ethics committee in the Netherlands and implemented in the country specific amendment 1.1 • Change of the lower age limit to 16 years (applicable only for sites in the Netherlands) • Addition of a paragraph detailing the analysis and storage of blood samples • Blood levels of sTLT-1 will not be analysed • Name change of IMP management provider implemented • Rating of Adverse Events updated for consistency with eCRF • Minor corrections and clarifications
    08 Jan 2018
    • Addition of an interim analysis (section 15.4) • Clarification of concomitant medication recording • Minor corrections and clarifications.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32468087
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