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    Clinical Trial Results:
    A Single Blind, Randomized, Placebo Controlled, Repeat Dose, Dose Escalating Study Investigating Safety, Tolerability pharmacokinetics, Pharmacodynamics and the Beta-Cell Preserving Effect of Otelixizumab in New-Onset, Autoimmune Type 1 Diabetes Mellitus Patients

    Summary
    EudraCT number
    		 2013-003296-34
    Trial protocol
    		 BE  
    Global end of trial date
    27 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Apr 2019
    First version publication date
    11 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    116505
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.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
    08 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of a single course of otelixizumab treatment on the acute and long term safety and tolerability of otelixizumab in NOT1DM patients.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2014
    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
    Belgium: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    5
    Adults (18-64 years)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was a multi-centered, single-blind, randomized (rand), placebo-controlled 6 Day repeat dose study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy and immunological profile of intravenously administered Otelixizumab (OTX) in New Onset Type 1 Diabetes Mellitus participants (par.).

    Pre-assignment
    Screening details
    		 A total of 30 par. were enrolled at different centers in Belgium, which was conducted from 12-Mar-2014 to 27-Sep-2018.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received 0.9% weight/volume Sodium Chloride solution for injection daily for 6 Days
    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
    Participants were administered 0.9% weight/volume sodium chloride by intravenous infusion

    Arm title
    		 Otelixizumab 9 mg
    Arm description
    		 Participants received 1.5 mg of OTX (intravenous solution for infusion) daily for 6 Days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Otelixizumab 9 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Otelixizumab will be provided as concentrated solution for infusion (5 mg/mL). The study medication will be diluted to 0.1 mg/mL in 0.9% sodium chloride and administered by intravenous infusion using a syringe pump

    Arm title
    		 Otelixizumab 18 mg
    Arm description
    		 Participants received 3 mg of OTX (intravenous solution for infusion) daily for 6 Days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Otelixizumab 18 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Otelixizumab will be provided as concentrated solution for infusion (5 mg/mL). The study medication will be diluted to 0.1 mg/mL in 0.9% sodium chloride and administered by intravenous infusion using a syringe pump

    Arm title
    		 Otelixizumab 27 mg
    Arm description
    		 Participants received 4.5 mg of OTX (intravenous solution for infusion) daily for 6 Days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Otelixizumab 27 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Otelixizumab will be provided as concentrated solution for infusion (5 mg/mL). The study medication will be diluted to 0.1 mg/mL in 0.9% sodium chloride and administered by intravenous infusion using a syringe pump

    Number of subjects in period 1 [1]
    		Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Started
    5
    9
    8
    7
    Completed
    4
    8
    7
    7
    Not completed
    1
    1
    1
    0
         Consent withdrawn by subject
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Overall number of participants were 30 of which only 29 were randomized

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 0.9% weight/volume Sodium Chloride solution for injection daily for 6 Days

    Reporting group title
    Otelixizumab 9 mg
    Reporting group description
    		 Participants received 1.5 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Reporting group title
    Otelixizumab 18 mg
    Reporting group description
    		 Participants received 3 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Reporting group title
    Otelixizumab 27 mg
    Reporting group description
    		 Participants received 4.5 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Reporting group values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg Total
    Number of subjects
    		 5 9 8 7 29
    Age categorical
    Safety Population comprised of participants who received at least one dose of study treatment. 1 participant withdrew after being randomized, prior to receiving any treatment.
    Units: Subjects
        All Participants
    		 5 9 8 7 29
    Age Continuous
    Safety Population comprised of participants who received at least one dose of study treatment. 1 participant withdrew after being randomized, prior to receiving any treatment.
    Units: Years
        arithmetic mean (standard deviation)
    		 24.8 ± 4.44 22.4 ± 2.13 20.5 ± 4.31 22.1 ± 3.98 -
    Sex: Female, Male
    Safety Population comprised of participants who received at least one dose of study treatment. 1 participant withdrew after being randomized, prior to receiving any treatment.
    Units: Subjects
        Female
    		 2 3 3 2 10
        Male
    		 3 6 5 5 19
    Race/Ethnicity, Customized
    Safety Population comprised of participants who received at least one dose of study treatment. 1 participant withdrew after being randomized, prior to receiving any treatment.
    Units: Subjects
        White
    		 5 9 8 7 29

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 0.9% weight/volume Sodium Chloride solution for injection daily for 6 Days

    Reporting group title
    Otelixizumab 9 mg
    Reporting group description
    		 Participants received 1.5 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Reporting group title
    Otelixizumab 18 mg
    Reporting group description
    		 Participants received 3 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Reporting group title
    Otelixizumab 27 mg
    Reporting group description
    		 Participants received 4.5 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Primary: Number of participants with adverse events (AEs) related to cytokine release syndrome (CRS)

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    End point title
    		 Number of participants with adverse events (AEs) related to cytokine release syndrome (CRS) [1]
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. On treatment AEs have been reported. Safety Population comprised of all participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to Day 14
    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: There are no statistical analysis to report.
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [2]
    9 [3]
    8 [4]
    7 [5]
    Units: Participants
    5
    9
    8
    7
    Notes
    [2] - Safety population
    [3] - Safety population
    [4] - Safety population
    [5] - Safety population
    No statistical analyses for this end point

    Primary: Epstein-Barr virus (EBV) viral load detection

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    End point title
    		 Epstein-Barr virus (EBV) viral load detection [6]
    End point description
    Blood samples were collected for analysis of EBV viral load and detection was done by polymerase chain reaction (PCR). Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    Week 3, Week 6, Week 8, Week 12, Week 24 and Week 96
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical analysis to report.
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [7]
    9 [8]
    8 [9]
    7 [10]
    Units: Copies per million cells
    geometric mean (geometric coefficient of variation)
        Week 3, n=5, 8, 8, 7
    12.0 ± 32806.06
    438.5 ± 193067.66
    4266.1 ± 306867.44
    64870.6 ± 723.66
        Week 6, n=4, 9, 8, 7
    28.1 ± 178623.77
    20.5 ± 77662.74
    398.2 ± 131086.12
    974.2 ± 19777.11
        Week 8, n=5, 9, 7, 5
    3.5 ± 4755.63
    8.9 ± 22969.48
    17.0 ± 55312.01
    24.3 ± 3060948.75
        Week 12, n=4, 9, 8, 6
    4.7 ± 12491.55
    15.8 ± 21359.16
    5.5 ± 15292.04
    33.2 ± 227953.09
        Week 24, n=4, 9, 7, 7
    1.0 ± 0.00
    39.3 ± 52129.25
    15.9 ± 39905.91
    2.9 ± 4732.52
        Week 96, n=4, 9, 7, 7
    1.0 ± 0.00
    2.3 ± 2166.53
    3.3 ± 13653.67
    5.9 ± 9925.87
    Notes
    [7] - Safety population
    [8] - Safety population
    [9] - Safety population
    [10] - Safety population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal laboratory results

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    End point title
    		 Number of participants with abnormal laboratory results [11]
    End point description
    Blood samples were collected to analyze the laboratory parameters which included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, calcium, chloride, creatinine, direct bilirubin, glucose, potassium, protein, sodium, urate, urea nitrogen, basophil, eosinophil, mean corpuscular haemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), erythrocytes, haematocrit, haemoglobin, leukocytes, lymphocytes, monocytes, neutrophils, platelets and reticulocytes. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Primary
    End point timeframe
    Up to Month 24
    Notes
    [11] - 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: There are no statistical analysis to report.
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [12]
    9 [13]
    8 [14]
    7 [15]
    Units: Participants
        ALT, Low, n= 5, 9, 8, 7
    0
    0
    0
    1
        ALT, High, n= 5, 9, 8, 7
    2
    5
    6
    4
        Albumin, Low, n= 5, 9, 8, 7
    4
    5
    2
    3
        Albumin, High, n= 5, 9, 8, 7
    1
    4
    1
    0
        ALP, Low, n= 5, 9, 8, 7
    3
    0
    1
    1
        ALP, High, n= 5, 9, 8, 7
    0
    1
    0
    1
        AST, Low, n= 5, 9, 8, 7
    1
    0
    1
    0
        AST, High, n= 5, 9, 8, 7
    1
    4
    5
    5
        Bilirubin, Low, n= 5, 9, 8, 7
    2
    2
    2
    1
        Bilirubin, High, n= 5, 9, 8, 7
    0
    1
    2
    2
        Calcium, Low, n= 5, 9, 8, 7
    1
    5
    5
    1
        Calcium, High, n= 5, 9, 8, 7
    0
    1
    1
    0
        Chloride, Low, n= 5, 9, 8, 7
    0
    2
    0
    1
        Chloride, High, n= 5, 9, 8, 7
    3
    5
    5
    3
        Creatinine, Low, n= 5, 9, 8, 7
    1
    0
    2
    1
        Creatinine, High, n= 5, 9, 8, 7
    0
    3
    0
    0
        Direct Bilirubin, Low, n= 1, 5, 4, 5
    0
    0
    0
    0
        Direct Bilirubin, High, n= 1, 5, 4, 5
    0
    0
    0
    1
        Glucose, Low, n= 5, 9, 8, 7
    4
    0
    0
    2
        Glucose, High, n= 5, 9, 8, 7
    2
    2
    1
    3
        Potassium, Low, n= 5, 9, 8, 7
    0
    3
    3
    2
        Potassium, High, n= 5, 9, 8, 7
    0
    0
    1
    0
        Protein, Low, n= 5, 9, 8, 7
    2
    3
    7
    3
        Protein, High, n= 5, 9, 8, 7
    0
    0
    0
    0
        Sodium, Low, n= 5, 9, 8, 7
    1
    0
    1
    2
        Sodium, High, n= 5, 9, 8, 7
    0
    3
    1
    0
        Urate, Low, n= 5, 9, 8, 7
    1
    6
    1
    6
        Urate, High, n= 5, 9, 8, 7
    0
    0
    0
    1
        Urea Nitrogen, Low, n= 5, 9, 8, 7
    2
    5
    3
    2
        Urea Nitrogen, High, n= 5, 9, 8, 7
    1
    2
    2
    1
        Basophils, Low, n= 5, 9, 8, 7
    0
    1
    0
    0
        Basophils, High, n= 5, 9, 8, 7
    0
    0
    1
    0
        Eosinophils, Low, n= 5, 9, 8, 7
    0
    1
    0
    0
        Eosinophils, High, n= 5, 9, 8, 7
    3
    2
    2
    1
        MCHC, Low, n= 5, 9, 8, 7
    2
    1
    2
    2
        MCHC, High, n= 5, 9, 8, 7
    1
    5
    4
    4
        MCH, Low, n= 5, 9, 8, 7
    0
    2
    4
    3
        MCH, High, n= 5, 9, 8, 7
    0
    0
    1
    0
        MCV, Low, n= 5, 9, 8, 7
    0
    3
    3
    2
        MCV, High, n= 5, 9, 8, 7
    0
    0
    0
    0
        Erythrocytes, Low, n= 5, 9, 8, 7
    4
    6
    6
    4
        Erythrocytes, High, n= 5, 9, 8, 7
    0
    2
    1
    0
        Hematocrit, Low, n= 5, 9, 8, 7
    4
    5
    7
    2
        Hematocrit, High, n= 5, 9, 8, 7
    1
    0
    0
    0
        Hemoglobin, Low, n= 5, 9, 8, 7
    5
    6
    5
    4
        Hemoglobin, High, n= 5, 9, 8, 7
    0
    2
    0
    0
        Leukocytes, Low, n= 5, 9, 8, 7
    0
    5
    2
    2
        Leukocytes, High, n= 5, 9, 8, 7
    3
    1
    1
    1
        Lymphocytes, Low, n= 5, 9, 8, 7
    0
    9
    7
    7
        Lymphocytes, High, n= 5, 9, 8, 7
    1
    1
    2
    3
        Monocytes, Low, n= 5, 9, 8, 7
    0
    1
    0
    2
        Monocytes, High, n= 5, 9, 8, 7
    0
    0
    0
    1
        Neutrophils, Low, n= 5, 9, 8, 7
    0
    2
    2
    2
        Neutrophils, High, n= 5, 9, 8, 7
    2
    1
    2
    2
        Platelets, Low, n= 5, 9, 8, 7
    0
    2
    3
    2
        Platelets, High, n= 5, 9, 8, 7
    0
    0
    2
    0
        Reticulocytes, Low, n= 1, 3, 4, 4
    0
    1
    0
    0
        Reticulocytes, High, n= 1, 3, 4, 4
    0
    2
    1
    1
    Notes
    [12] - Safety population
    [13] - Safety population
    [14] - Safety population
    [15] - Safety population
    No statistical analyses for this end point

    Primary: Number of participants with increase in QT Interval Corrected for heart rate (QTc)

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    End point title
    		 Number of participants with increase in QT Interval Corrected for heart rate (QTc) [16]
    End point description
    12-lead electrocardiograms (ECGs) were obtained in semi-supine position after 5 minutes rest for the participants at indicated time points to measure QTc.
    End point type
    Primary
    End point timeframe
    Up to Month 24
    Notes
    [16] - 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: There are no statistical analysis to report.
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [17]
    9 [18]
    8 [19]
    7 [20]
    Units: Participants
        QTc Interval (Bazett's), Increase >60 millisec
    0
    0
    0
    0
        QTc Interval (Fridericia), Increase >60 millisec
    0
    0
    0
    0
    Notes
    [17] - Safety population
    [18] - Safety population
    [19] - Safety population
    [20] - Safety population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal vital sign results

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    End point title
    		 Number of participants with abnormal vital sign results [21]
    End point description
    Vital signs were measured in semi-supine position after 5 minutes rest for the participants at indicated time points. Vital signs included systolic, diastolic blood pressure, pulse rate and respiratory rate
    End point type
    Primary
    End point timeframe
    Up to Month 24
    Notes
    [21] - 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: There are no statistical analysis to report.
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [22]
    9 [23]
    8 [24]
    7 [25]
    Units: Participants
    number (not applicable)
        Systolic Blood Pressure, Low
    1
    1
    2
    1
        Systolic Blood Pressure, High
    1
    0
    1
    1
        Diastolic Blood Pressure, Low
    2
    5
    4
    1
        Diastolic Blood Pressure, High
    0
    0
    1
    0
        Pulse Rate, Low
    0
    0
    0
    1
        Pulse Rate, High
    1
    2
    3
    2
        Respiratory Rate, Low
    0
    1
    0
    0
        Respiratory Rate, High
    0
    0
    0
    0
    Notes
    [22] - Safety population
    [23] - Safety population
    [24] - Safety population
    [25] - Safety population
    No statistical analyses for this end point

    Secondary: Free serum Otelixizumab concentrations by treatment

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    End point title
    		 Free serum Otelixizumab concentrations by treatment [26]
    End point description
    Blood samples were collected at designated timepoints. Free serum Otelixizumab concentrations were calculated by linear and semi-logarithmic individual serum concentration-time profiles. Fully treated population comprised of all randomized participants who received the full 6 days of treatment based on actual exposure data. 99999 indicates that data could not be calculated as >30% of samples were below the limit of quantification. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1,2,3,4,5,6 and 14; 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 16 hours post-dose on Day 1, and 1 hour post-dose on Day 6.
    Notes
    [26] - 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: There are no statistical analysis to report.
    End point values
    		 Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    8 [27]
    8 [28]
    6 [29]
    Units: Nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1, Pre-dose, n=8, 8, 6
    0.000 ± 99999
    0.000 ± 99999
    0.000 ± 99999
        Day 1, 30 minutes, n=8, 8, 6
    0.000 ± 99999
    0.444 ± 99999
    7.387 ± 4.8946
        Day 1, 1 hour, n=8, 8, 6
    0.513 ± 99999
    2.963 ± 99999
    12.542 ± 7.9086
        Day 1, 2 hours, n=8, 8, 6
    2.995 ± 99999
    7.606 ± 6.1836
    23.598 ± 14.4526
        Day 1, 4 hours, n=7, 8, 6
    6.600 ± 5.2773
    15.929 ± 9.8903
    41.457 ± 26.3827
        Day 1, 6 hours, n=8, 8, 6
    11.870 ± 5.0544
    24.899 ± 14.5630
    100.148 ± 79.4845
        Day 1, 8 hours, n=8, 7, 6
    70.088 ± 153.2593
    37.657 ± 19.8741
    146.298 ± 95.4089
        Day 1, 9 hours, n=7, 8, 6
    18.494 ± 6.0716
    102.865 ± 111.2186
    402.173 ± 246.4271
        Day 1, 16 hours, n=7, 8, 6
    0.000 ± 99999
    30.758 ± 23.3494
    212.487 ± 144.0899
        Day 2, Pre-Dose, n=8, 8, 6
    0.000 ± 99999
    7.329 ± 99999
    112.020 ± 124.1743
        Day 3, Pre-Dose, n=8, 8, 6
    0.000 ± 99999
    36.051 ± 35.6464
    420.228 ± 344.7569
        Day 4, Pre-Dose, n=8, 8, 6
    0.523 ± 99999
    114.993 ± 152.7864
    829.148 ± 473.9342
        Day 5, Pre-Dose, n=8, 8, 6
    9.550 ± 16.2697
    213.305 ± 257.3174
    1088.808 ± 542.8032
        Day 6, Pre-Dose, n=8, 8, 6
    4.416 ± 3.2896
    174.448 ± 258.4873
    1386.008 ± 623.1118
        Day 6, 1 hour, n=8, 8, 6
    413.488 ± 262.5248
    2048.336 ± 1889.7194
    2868.735 ± 771.5457
        Day 14, n=7, 8, 5
    0.523 ± 99999
    0.899 ± 99999
    12.474 ± 8.7977
    Notes
    [27] - Fully Treated population
    [28] - Fully Treated population
    [29] - Fully Treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in C-Peptide weighted mean (area under curve from 0 to 120 minutes [AUC0-120 minutes]) from mixed meal tolerance test

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    End point title
    		 Change from Baseline in C-Peptide weighted mean (area under curve from 0 to 120 minutes [AUC0-120 minutes]) from mixed meal tolerance test
    End point description
    Blood samples were collected at indicated time points to assess levels of C-peptide. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Mixed meal-stimulated C-peptide AUC was calculated from area under C-peptide/time curve from time 0 to 120 minutes, using trapezoidal rule. ITT treated population comprised of all randomized participants who received at least one dose of study treatment. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Month 3, Month 6, Month 12, Month 18 and Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [30]
    9 [31]
    8 [32]
    7 [33]
    Units: Nanomoles minute per liter
    arithmetic mean (standard deviation)
        Month 3, n=5, 8, 8, 7
    0.175 ± 0.0797
    0.255 ± 0.2852
    0.118 ± 0.2462
    0.153 ± 0.1312
        Month 6, n=5, 8, 8, 7
    0.118 ± 0.0895
    0.147 ± 0.3215
    -0.185 ± 0.2148
    0.076 ± 0.2788
        Month 12, n=5, 8, 8, 7
    -0.103 ± 0.0552
    0.023 ± 0.3145
    -0.215 ± 0.2597
    -0.016 ± 0.3689
        Month 18, n=5, 8, 7, 7
    -0.278 ± 0.1142
    0.015 ± 0.3903
    -0.295 ± 0.3105
    -0.201 ± 0.3132
        Month 24, n=4, 7, 7, 7
    -0.296 ± 0.0962
    -0.042 ± 0.2905
    -0.349 ± 0.3917
    -0.165 ± 0.3729
    Notes
    [30] - Intent-To-Treat treated population
    [31] - Intent-To-Treat treated population
    [32] - Intent-To-Treat treated population
    [33] - Intent-To-Treat treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in glucose weighted mean (area under curve from 0 to 120 minutes, AUC0-120 minutes) from mixed meal tolerance test

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    End point title
    		 Change from Baseline in glucose weighted mean (area under curve from 0 to 120 minutes, AUC0-120 minutes) from mixed meal tolerance test
    End point description
    Blood samples were collected at indicated time points to assess levels of glucose. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Mixed meal-stimulated glucose was calculated from area under the glucose /time curve from time 0 to 120 minutes, using trapezoidal rule. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Month 3, Month 6, Month 12, Month 18 and Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [34]
    9 [35]
    8 [36]
    7 [37]
    Units: Millmoles minute per liter
    arithmetic mean (standard deviation)
        Month 3, n=5, 8, 8, 7
    1.382 ± 1.5801
    -0.550 ± 1.7140
    0.999 ± 3.3953
    0.641 ± 3.0009
        Month 6, n=5, 8, 8, 7
    1.423 ± 2.9999
    -1.041 ± 1.5506
    0.643 ± 4.1751
    0.749 ± 2.7698
        Month 12, n=5, 8, 8, 7
    2.314 ± 2.2718
    0.067 ± 2.0492
    1.875 ± 2.7440
    1.842 ± 3.2408
        Month 18, n=5, 8, 7, 7
    3.142 ± 3.2172
    1.159 ± 2.4073
    2.676 ± 3.0803
    3.942 ± 1.9745
        Month 24, n=4, 7, 7, 7
    4.029 ± 1.2365
    -1.807 ± 2.1615
    2.557 ± 3.9428
    3.435 ± 2.3714
    Notes
    [34] - ITT treated population
    [35] - ITT treated population
    [36] - ITT treated population
    [37] - ITT treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in C-Peptide weighted mean (area under curve from 60 to 140 minutes, [AUC 60-140 minutes]) from hyperglycemic clamp test

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    End point title
    		 Change from Baseline in C-Peptide weighted mean (area under curve from 60 to 140 minutes, [AUC 60-140 minutes]) from hyperglycemic clamp test
    End point description
    Blood samples were collected at indicated time points to assess levels of C-peptide during hyperglycemic (H) phase. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from specified time point value. C-peptide AUC was calculated from area under C-peptide/time curve from time H60 to H140 minutes. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Month 6, Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [38]
    9 [39]
    8 [40]
    7 [41]
    Units: Nanomoles minute per liter
    arithmetic mean (standard deviation)
        Month 6, n=5, 8, 8, 7
    -0.037 ± 0.2107
    0.105 ± 0.2520
    -0.201 ± 0.2643
    0.006 ± 0.3011
        Month 24, n=4, 5, 7, 7
    -0.423 ± 0.1630
    -0.273 ± 0.1552
    -0.373 ± 0.2308
    -0.344 ± 0.3397
    Notes
    [38] - ITT treated population
    [39] - ITT treated population
    [40] - ITT treated population
    [41] - ITT treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in glucose weighted mean (area under curve from 60 to 140 minutes, AUC60-140 minutes) from hyperglycemic clamp Test

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    End point title
    		 Change from Baseline in glucose weighted mean (area under curve from 60 to 140 minutes, AUC60-140 minutes) from hyperglycemic clamp Test
    End point description
    Blood samples were collected at indicated time points to assess levels of glucose during hyperglycemic (H) phase. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Glucose AUC was calculated from area under the C-peptide/time curve from time H60 to H140 minutes. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Month 6 and Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [42]
    9 [43]
    8 [44]
    7 [45]
    Units: Millmoles minute per liter
    arithmetic mean (standard deviation)
        Month 6, n=5, 8, 8, 7
    0.645 ± 1.0094
    0.415 ± 1.3255
    0.723 ± 1.5955
    1.074 ± 0.6264
        Month 24, n=4, 5, 7, 7
    1.346 ± 1.1063
    -0.501 ± 3.2542
    0.094 ± 2.2642
    1.095 ± 1.3972
    Notes
    [42] - ITT treated population
    [43] - ITT treated population
    [44] - ITT treated population
    [45] - ITT treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in insulin sensitivity (IS) Index from hyperglycemic clamp test

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    End point title
    		 Change from Baseline in insulin sensitivity (IS) Index from hyperglycemic clamp test
    End point description
    Insulin sensitivity index is defined as the ratio of glucose metabolized and average insulin concentration multiplied by 100 by hyperglycemic clamp test. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Month 6, Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [46]
    9 [47]
    8 [48]
    7 [49]
    Units: (100*mmol*l)/(pmol*kg*min)
    arithmetic mean (standard deviation)
        Month 6, n=5, 8, 7, 6
    -0.0003 ± 0.00130
    -0.0000 ± 0.00030
    -0.0002 ± 0.00197
    -0.0002 ± 0.00066
        Month 24, n=4, 4, 6, 6
    0.0037 ± 0.00591
    -0.0006 ± 0.00344
    -0.0013 ± 0.01299
    0.0023 ± 0.00351
    Notes
    [46] - ITT treated population
    [47] - ITT treated population
    [48] - ITT treated population
    [49] - ITT treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in mean daily insulin use

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    End point title
    		 Change from Baseline in mean daily insulin use
    End point description
    Participants were asked to record their daily insulin usage thoroughly and accurately in a diary from 7 days prior to study visit. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Week 2, Week 3, Week 6, Week 8, Week 12, Week 24, Week 36, Week 48, Week 72 and Week 96
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [50]
    9 [51]
    8 [52]
    7 [53]
    Units: International unit
    arithmetic mean (standard deviation)
        Week 2, n=5, 8, 7, 6
    -0.0901 ± 0.05997
    -0.0265 ± 0.07580
    0.0941 ± 0.12919
    -0.0741 ± 0.08855
        Week 3, n=5, 8, 8, 7
    -0.1504 ± 0.06424
    -0.0424 ± 0.08708
    0.0706 ± 0.14989
    -0.0440 ± 0.08753
        Week 6, n=5, 4, 8, 7
    -0.1727 ± 0.05431
    -0.1009 ± 0.12893
    -0.0332 ± 0.19098
    -0.1090 ± 0.11777
        Week 8, n=4, 7, 5, 6
    -0.1566 ± 0.07033
    -0.1514 ± 0.15364
    -0.0666 ± 0.21066
    -0.1492 ± 0.14713
        Week 12, n=4, 8, 8, 7
    -0.1850 ± 0.08007
    -0.1629 ± 0.14706
    -0.1115 ± 0.16950
    -0.1850 ± 0.20173
        Week 24, n=5, 8, 5, 7
    -0.1449 ± 0.09069
    -0.1168 ± 0.20181
    0.0298 ± 0.13942
    -0.1678 ± 0.17308
        Week 36, n=4, 8, 7, 7
    -0.0776 ± 0.13492
    -0.0673 ± 0.26527
    0.0701 ± 0.20840
    -0.1114 ± 0.21943
        Week 48, n=5, 8, 8, 7
    -0.1221 ± 0.16778
    -0.0936 ± 0.24246
    0.0970 ± 0.15473
    -0.1155 ± 0.25461
        Week 72, n=5, 8, 7, 5
    -0.1000 ± 0.23378
    0.0172 ± 0.43320
    0.1088 ± 0.07406
    0.0807 ± 0.27375
        Week 96, n=4, 6, 7, 7
    -0.0390 ± 0.34885
    -0.0811 ± 0.34104
    0.1131 ± 0.16596
    0.1117 ± 0.19080
    Notes
    [50] - ITT treated population
    [51] - ITT treated population
    [52] - ITT treated population
    [53] - ITT treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in hemoglobin A1c

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    End point title
    		 Change from Baseline in hemoglobin A1c
    End point description
    Hemoglobin A1C levels were measured at indicated time points. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Month 6, Month 12 and Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [54]
    9 [55]
    8 [56]
    7 [57]
    Units: Percentage of HbA1c
    arithmetic mean (standard deviation)
        Month 6, n=5, 8, 8, 7
    -3.26 ± 1.119
    -2.29 ± 1.883
    -0.68 ± 2.437
    -2.04 ± 2.141
        Month 12, n=5, 9, 8, 7
    -3.26 ± 1.665
    -2.10 ± 2.125
    -1.15 ± 1.384
    -1.60 ± 2.985
        Month 24, n=4, 9, 7, 7
    -2.53 ± 2.445
    -2.23 ± 1.736
    -0.33 ± 2.075
    -1.41 ± 2.174
    Notes
    [54] - ITT treated population
    [55] - ITT treated population
    [56] - ITT treated population
    [57] - ITT treated population
    No statistical analyses for this end point

    Secondary: Absolute body weight

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    End point title
    		 Absolute body weight
    End point description
    Body weight was measured at indicated time points. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day-1, Month 12, Month 18 and Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [58]
    9 [59]
    8 [60]
    7 [61]
    Units: Kilogram
    arithmetic mean (standard deviation)
        Day -1, n=5, 9, 8, 7
    65.22 ± 10.608
    72.84 ± 16.118
    64.19 ± 9.545
    65.27 ± 8.714
        Month 12, n=5, 9, 8, 7
    70.24 ± 12.691
    75.86 ± 15.503
    64.58 ± 9.851
    67.96 ± 8.373
        Month 18, n=5, 9, 7, 7
    70.44 ± 13.209
    75.22 ± 16.504
    63.56 ± 8.658
    68.97 ± 10.167
        Month 24, n=4, 9, 7, 7
    66.98 ± 11.226
    75.82 ± 17.507
    63.71 ± 8.037
    69.79 ± 8.689
    Notes
    [58] - ITT treated population
    [59] - ITT treated population
    [60] - ITT treated population
    [61] - ITT treated population
    No statistical analyses for this end point

    Secondary: Time-normalized number of hypoglycemic and hyperglycemic events

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    End point title
    		 Time-normalized number of hypoglycemic and hyperglycemic events
    End point description
    As per American Diabetes Association (ADA), hypoglycemia is defined as blood glucose level <= 70 milligram/deciliter (mg/dl) and hyperglycemia is defined as blood glucose level > 250 mg/dL. Hypoglycaemic and hyperglycaemic events will be recorded in a diary whenever they occur, along with the start and stop dates. Mean number of events is defined as the average number of events reported per subject. Normalization is expressed by dividing number of events by length of reporting period in month (1 month = 30 days). Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Up to Month 24
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    4 [62]
    9 [63]
    7 [64]
    7 [65]
    Units: Number of events
    arithmetic mean (standard deviation)
        Hypoglycemia
    14.13 ± 3.533
    21.45 ± 2.383
    7.74 ± 1.105
    24.55 ± 3.508
        Hyperglycemia
    2.79 ± 0.698
    11.03 ± 1.225
    14.13 ± 2.019
    8.48 ± 1.211
    Notes
    [62] - ITT treated population
    [63] - ITT treated population
    [64] - ITT treated population
    [65] - ITT treated population
    No statistical analyses for this end point

    Secondary: Relative change from Baseline in percentage (%) in CD4+ cells

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    End point title
    		 Relative change from Baseline in percentage (%) in CD4+ cells
    End point description
    Whole blood samples were collected and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Relative change from Baseline (percentage) was calculated as change from Baseline relative to Baseline in percentage. 99999 indicates that standard deviation could not be calculated for a single participant. 99999 indicates that data was not collected. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [66]
    9 [67]
    8 [68]
    7 [69]
    Units: Percentage
    arithmetic mean (standard deviation)
        Day 1, 30 minutes, n=5, 7, 8, 6
    -2.2331 ± 8.06090
    15.7568 ± 9.45733
    22.3101 ± 11.38275
    37.9286 ± 7.06740
        Day 1, 1 hour, n=5, 7, 8, 6
    -0.9229 ± 3.79426
    24.8673 ± 8.97161
    33.2356 ± 10.06318
    40.8432 ± 17.12371
        Day 1, 2 hours, n=5, 7, 8, 6
    4.6329 ± 10.59418
    32.0976 ± 13.50078
    42.2579 ± 11.17916
    54.2045 ± 9.65956
        Day 1, 4 hours, n=5, 7, 8, 6
    -1.8509 ± 9.27472
    31.4853 ± 18.78336
    49.3861 ± 14.33838
    49.1721 ± 30.22147
        Day 1, 6 hours, n=5, 7, 8, 6
    3.3922 ± 6.75373
    58.4446 ± 9.17750
    70.8026 ± 8.26487
    67.9378 ± 25.45192
        Day 1, 8 hours, n=5, 7, 7, 6
    6.9714 ± 8.64363
    58.4772 ± 9.97693
    76.5366 ± 12.00112
    69.8593 ± 23.77517
        Day 1, 9 hours, n=1, 6, 0, 0
    18.8383 ± 99999
    58.2218 ± 11.84589
    999999 ± 999999
    999999 ± 999999
        Day 1, 12 hours, n=4, 0, 7, 6
    1.1168 ± 9.94441
    999999 ± 999999
    72.0336 ± 10.97106
    72.4138 ± 28.39518
        Day 1, 16 hours, n=4, 6, 8, 6
    -1.9654 ± 4.50998
    47.1603 ± 7.15517
    79.1078 ± 8.03676
    75.8997 ± 24.65609
        Day 2, n=5, 7, 8, 6
    5.8586 ± 11.64080
    38.9846 ± 10.09414
    67.5197 ± 8.13498
    71.3820 ± 20.92599
        Day 3, n=5, 7, 8, 6
    8.4017 ± 21.57257
    47.8814 ± 8.46678
    77.5903 ± 8.78800
    88.1872 ± 3.79283
        Day 4, n=5, 7, 8, 6
    -2.2685 ± 9.15020
    48.5169 ± 11.02802
    82.0325 ± 10.26798
    91.6139 ± 1.52341
        Day 5, n=5, 7, 8, 6
    9.4816 ± 10.25461
    64.5703 ± 8.16040
    88.1950 ± 6.33948
    94.2542 ± 1.59484
        Day 6, n=5, 7, 8, 6
    4.6145 ± 5.61446
    70.6624 ± 7.58163
    89.9853 ± 4.21710
    95.1333 ± 1.79263
        Day 6, 1 hour, n=5, 7, 8, 6
    8.0058 ± 7.53027
    93.5215 ± 2.42406
    91.9917 ± 2.78804
    95.3978 ± 1.70448
        Day 14, n=5, 6, 8, 4
    16.0448 ± 15.71866
    18.3627 ± 15.59835
    17.6415 ± 27.54591
    38.7962 ± 17.92367
    Notes
    [66] - Fully treated population
    [67] - Fully treated population
    [68] - Fully treated population
    [69] - Fully treated population
    No statistical analyses for this end point

    Secondary: Relative change from Baseline in percentage (%) in CD8+ cells

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    End point title
    		 Relative change from Baseline in percentage (%) in CD8+ cells
    End point description
    Whole blood samples were collected and analyzed by flow cytometry. Day1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Relative change from baseline (%) was calculated as change from Baseline relative to Baseline in %. 99999 indicates that standard deviation could not be calculated for a single participant.999999 indicates that data was not collected. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [70]
    9 [71]
    8 [72]
    7 [73]
    Units: Percentage
    arithmetic mean (standard deviation)
        Day 1, 30 minutes, n=5, 7, 8, 6
    1.4489 ± 5.86548
    13.6045 ± 6.84553
    18.4972 ± 10.57226
    35.6721 ± 7.81791
        Day 1, 1 hour, n=5, 7, 8, 6
    3.9227 ± 3.52082
    23.2571 ± 8.77440
    29.9262 ± 9.11960
    37.1052 ± 15.47566
        Day 1, 2 hours, n=5, 7, 8, 6
    5.7591 ± 7.62243
    29.7916 ± 10.08248
    36.7030 ± 11.18167
    48.2854 ± 10.33624
        Day 1, 4 hours, n=5, 7, 8, 6
    2.4574 ± 5.34591
    27.9312 ± 15.06025
    40.2754 ± 12.70208
    41.5574 ± 26.91586
        Day 1, 6 hours, n=5, 7, 8, 6
    5.2570 ± 5.13603
    50.6248 ± 8.12251
    63.2777 ± 9.16749
    61.0355 ± 22.44049
        Day 1, 8 hours, n=5, 7, 7, 6
    3.0516 ± 5.05296
    50.0586 ± 13.15793
    64.0559 ± 8.96743
    64.6389 ± 23.37406
        Day 1, 9 hours, n=1, 6, 0, 0
    12.0124 ± 99999
    47.3877 ± 10.18779
    999999 ± 999999
    999999 ± 999999
        Day 1, 12 hours, n=4, 0, 7, 6
    4.6297 ± 1.55778
    999999 ± 999999
    63.0325 ± 11.60295
    68.2523 ± 25.41788
        Day 1, 16 hours, n=4, 6, 8, 6
    2.4031 ± 9.29601
    36.5804 ± 11.00323
    73.7619 ± 9.27676
    73.7870 ± 23.65616
        Day 2, n=5, 7, 8, 6
    11.5153 ± 12.44266
    32.3389 ± 17.53306
    63.2076 ± 11.90764
    68.8582 ± 23.13445
        Day 3, n=5, 7, 8, 6
    9.6580 ± 17.96579
    38.6763 ± 10.50068
    73.4518 ± 13.11370
    86.3391 ± 4.07679
        Day 4, n=5, 7, 8, 6
    1.4965 ± 9.56563
    39.4735 ± 13.72429
    78.2797 ± 13.97813
    89.7661 ± 2.38427
        Day 5, n=5, 7, 8, 6
    13.1690 ± 10.31403
    55.7138 ± 7.92647
    84.6850 ± 10.08105
    92.6561 ± 1.66146
        Day 6, n=5, 7, 8, 6
    9.5352 ± 4.64977
    62.6915 ± 6.12617
    87.5358 ± 6.72558
    93.6820 ± 1.51640
        Day 6, 1 hour, n=5, 7, 8, 6
    9.6315 ± 7.30255
    90.8426 ± 2.43623
    91.3298 ± 3.00883
    93.9939 ± 1.50147
        Day 14, n=5, 6, 8, 4
    21.2448 ± 18.40147
    19.6382 ± 18.17904
    20.1594 ± 27.60057
    33.4359 ± 23.03254
    Notes
    [70] - Fully treated population
    [71] - Fully treated population
    [72] - Fully treated population
    [73] - Fully treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in free CD3 on CD8+ cells

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    End point title
    		 Change from Baseline in free CD3 on CD8+ cells
    End point description
    Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. 99999 indicates that standard deviation could not be calculated for a single participant. 999999 indicates that data was not collected. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [74]
    9 [75]
    8 [76]
    7 [77]
    Units: Copies per cell
    arithmetic mean (standard deviation)
        Day 1, 30 minutes, n=5, 7, 8, 6
    -1570.2 ± 7996.97
    -17344.6 ± 8219.24
    -33177.1 ± 26046.74
    -46590.5 ± 14242.51
        Day 1, 1 hour, n=5, 7, 8, 6
    -5367.8 ± 4454.93
    -30170.0 ± 11702.96
    -52164.3 ± 25780.68
    -45971.2 ± 17371.50
        Day 1, 2 hours, n=5, 7, 8, 6
    -7599.6 ± 9683.28
    -38063.3 ± 12268.28
    -64195.5 ± 30475.25
    -63303.5 ± 19743.02
        Day 1, 4 hours, n=5, 7, 8, 6
    -2668.2 ± 7081.48
    -37523.3 ± 21827.29
    -70708.9 ± 35060.26
    -50216.3 ± 33433.24
        Day 1, 6 hours, n=5, 7, 8, 6
    -7434.0 ± 6566.98
    -65821.7 ± 14778.18
    -109702.0 ± 36004.22
    -75299.7 ± 24515.25
        Day 1, 8 hours, n=5, 7, 7, 6
    -5118.8 ± 9260.84
    -64346.1 ± 16499.07
    -113884.9 ± 36548.70
    -79778.2 ± 25001.56
        Day 1, 9 hours, n=1, 6, 0, 0
    -14630.0 ± 99999
    -62113.7 ± 17114.28
    999999 ± 999999
    999999 ± 999999
        Day 1, 12 hours, n=4, 0, 7, 6
    -7671.0 ± 3453.02
    999999 ± 999999
    -111484.0 ± 37822.49
    -84085.8 ± 27533.48
        Day 1, 16 hours, n=4, 6, 8, 6
    -2398.0 ± 12735.14
    -48607.8 ± 17774.03
    -126378.6 ± 34284.38
    -91537.5 ± 23378.53
        Day 2, n=5, 7, 8, 6
    -16282.6 ± 18931.53
    -42379.1 ± 25223.07
    -108857.0 ± 36292.51
    -85611.5 ± 24571.30
        Day 3, n=5, 7, 8, 6
    -12613.4 ± 23082.56
    -50757.1 ± 16662.32
    -126037.9 ± 39171.31
    -112220.0 ± 20740.64
        Day 4, n=5, 7, 8, 6
    -2479.6 ± 14120.73
    -52064.6 ± 22177.41
    -133794.1 ± 38684.37
    -116816.5 ± 22469.30
        Day 5, n=5, 7, 8, 6
    -19504.4 ± 14161.40
    -72058.3 ± 13158.75
    -144613.4 ± 35791.57
    -120512.7 ± 22578.38
        Day 6, n=5, 7, 8, 6
    -13905.4 ± 6365.89
    -81326.7 ± 14410.25
    -149202.1 ± 32099.88
    -121836.0 ± 22706.98
        Day 6, 1 hour, n=5, 7, 8, 6
    -14414.4 ± 10131.25
    -118000.6 ± 18946.75
    -155565.6 ± 29776.06
    -122237.2 ± 22786.52
        Day 14, n=5, 6, 8, 4
    -30658.2 ± 25814.70
    -25656.7 ± 23202.59
    -34478.6 ± 46509.48
    -49846.8 ± 42800.88
    Notes
    [74] - Fully treated population
    [75] - Fully treated population
    [76] - Fully treated population
    [77] - Fully treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in free CD3 on CD4+ cells

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    End point title
    		 Change from Baseline in free CD3 on CD4+ cells
    End point description
    Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. 99999 indicates that standard deviation could not be calculated for a single participant. 999999 indicates that data was not collected. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [78]
    9 [79]
    8 [80]
    7 [81]
    Units: Copies per cell
    arithmetic mean (standard deviation)
        Day 1, 30 minutes, n=5, 7, 8, 6
    5529.0 ± 13037.93
    -26310.0 ± 15691.77
    -46612.6 ± 31524.47
    -61053.8 ± 16266.15
        Day 1, 1 hour, n=5, 7, 8, 6
    2819.2 ± 8108.55
    -41955.9 ± 16287.89
    -68726.5 ± 33738.60
    -63524.8 ± 26817.94
        Day 1, 2 hours, n=5, 7, 8, 6
    -5833.0 ± 17972.31
    -54111.1 ± 23197.46
    -86880.5 ± 37961.85
    -87013.2 ± 20852.00
        Day 1, 4 hours, n=5, 7, 8, 6
    2651.6 ± 14138.56
    -54076.3 ± 34638.82
    -101829.5 ± 45896.19
    -73042.7 ± 45129.43
        Day 1, 6 hours, n=5, 7, 8, 6
    -5072.0 ± 11737.82
    -97871.0 ± 18824.51
    -143635.8 ± 41952.00
    -104097.7 ± 36063.45
        Day 1, 8 hours, n=5, 7, 7, 6
    -10668.4 ± 11325.47
    -97642.4 ± 17931.01
    -156878.1 ± 38450.32
    -107788.0 ± 34304.89
        Day 1, 9 hours, n=1, 6, 0, 0
    -31435.0 ± 99999
    -98963.5 ± 25253.18
    999999 ± 999999
    999999 ± 999999
        Day 1, 12 hours, n=4, 0, 7, 6
    -4958.5 ± 15637.79
    999999 ± 999999
    -150231.0 ± 46611.02
    -111627.8 ± 43965.70
        Day 1, 16 hours, n=4, 6, 8, 6
    4546.3 ± 7628.46
    -79792.2 ± 16063.80
    -159376.9 ± 40492.21
    -117485.2 ± 35848.96
        Day 2, n=5, 7, 8, 6
    -9071.4 ± 22730.36
    -64674.3 ± 14881.25
    -136989.0 ± 40208.17
    -111246.8 ± 30955.42
        Day 3, n=5, 7, 8, 6
    -9750.2 ± 28173.66
    -80703.6 ± 19670.68
    -156782.3 ± 42746.51
    -141892.0 ± 28600.19
        Day 4, n=5, 7, 8, 6
    4442.8 ± 16258.54
    -81174.3 ± 21094.09
    -165042.3 ± 42878.04
    -147344.5 ± 28442.20
        Day 5, n=5, 7, 8, 6
    -14696.4 ± 15969.14
    -107817.7 ± 16112.46
    -177310.9 ± 40876.20
    -151768.5 ± 30266.62
        Day 6, n=5, 7, 8, 6
    -7848.0 ± 10416.76
    -118246.4 ± 17896.58
    -180424.5 ± 37325.84
    -153238.7 ± 30828.00
        Day 6, 1 hour, n=5, 7, 8, 6
    -12708.6 ± 8424.98
    -156241.0 ± 14748.58
    -184362.0 ± 36070.44
    -153638.3 ± 30779.71
        Day 14, n=5, 6, 8, 4
    -25564.4 ± 24902.78
    -31243.3 ± 25714.52
    -37536.4 ± 55570.83
    -70890.5 ± 40581.96
    Notes
    [78] - Fully treated population
    [79] - Fully treated population
    [80] - Fully treated population
    [81] - Fully treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in bound CD3 copies on CD4+ cells

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    End point title
    		 Change from Baseline in bound CD3 copies on CD4+ cells
    End point description
    Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. 99999 indicates that standard deviation could not be calculated for a single participant.999999 indicates that data was not collected. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [82]
    9 [83]
    8 [84]
    7 [85]
    Units: Copies per cell
    arithmetic mean (standard deviation)
        Day 1, 30 minutes, n=5, 7, 8, 6
    -54.0 ± 103.13
    29059.1 ± 15150.15
    27538.5 ± 12441.29
    28035.7 ± 14672.79
        Day 1, 1 hour, n=5, 7, 8, 6
    -10.2 ± 82.62
    39472.3 ± 16401.81
    43911.8 ± 14701.05
    38406.5 ± 19297.11
        Day 1, 2 hours, n=5, 7, 8, 6
    27.6 ± 133.59
    54116.3 ± 14159.80
    56840.6 ± 15756.66
    47028.2 ± 24507.94
        Day 1, 4 hours, n=5, 7, 8, 6
    -50.4 ± 113.62
    62635.7 ± 24380.73
    54693.1 ± 16678.89
    42730.2 ± 24609.04
        Day 1, 6 hours, n=5, 7, 8, 6
    -77.4 ± 168.73
    86518.1 ± 23953.89
    74664.6 ± 5837.58
    49078.8 ± 27502.89
        Day 1, 8 hours, n=5, 7, 7, 6
    13.6 ± 203.64
    86801.1 ± 24642.24
    60435.0 ± 24147.90
    51092.2 ± 25386.18
        Day 1, 9 hours, n=1, 6, 0, 0
    -36.0 ± 999999
    55085.3 ± 14474.39
    999999 ± 999999
    999999 ± 999999
        Day 1, 12 hours, n=4, 0, 7, 6
    -2.8 ± 188.70
    999999 ± 999999
    57280.0 ± 7920.20
    34176.7 ± 22339.84
        Day 1, 16 hours, n=4, 6, 8, 6
    62.3 ± 278.48
    33286.2 ± 10303.10
    46080.4 ± 7254.50
    28515.0 ± 13537.67
        Day 2, n=5, 7, 8, 6
    -120.8 ± 157.70
    14676.3 ± 4819.20
    27994.6 ± 7683.11
    23777.3 ± 10220.98
        Day 3, n=5, 7, 8, 6
    -56.4 ± 209.56
    15982.6 ± 5415.43
    23383.9 ± 7380.09
    19095.8 ± 4142.74
        Day 4, n=5, 7, 8, 6
    -199.0 ± 221.61
    12522.1 ± 4472.75
    17241.8 ± 3135.36
    14843.3 ± 3645.33
        Day 5, n=5, 7, 8, 6
    -31.4 ± 334.36
    9679.6 ± 3432.37
    5748.1 ± 2499.44
    6979.3 ± 4026.59
        Day 6, n=5, 7, 8, 6
    -103.4 ± 138.02
    4856.7 ± 4683.55
    3671.9 ± 1663.91
    4700.3 ± 2723.61
        Day 6, 1 hour, n=5, 7, 8, 6
    -22.2 ± 385.45
    15972.9 ± 4968.41
    4262.9 ± 2221.09
    4658.3 ± 2789.87
        Day 14, n=5, 6, 8, 4
    -111.2 ± 227.74
    -874.7 ± 2068.49
    688.0 ± 513.77
    1506.3 ± 2330.70
    Notes
    [82] - Fully treated population
    [83] - Fully treated population
    [84] - Fully treated population
    [85] - Fully treated population
    No statistical analyses for this end point

    Secondary: Change from Baseline in bound CD3 copies on CD8+ cells

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    End point title
    		 Change from Baseline in bound CD3 copies on CD8+ cells
    End point description
    Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. 99999 indicates that standard deviation could not be calculated for a single participant.999999 indicates that data was not collected. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [86]
    9 [87]
    8 [88]
    7 [89]
    Units: Copies per cell
    arithmetic mean (standard deviation)
        Day 1, 30 minutes, n=5, 7, 8, 6
    10.8 ± 168.01
    20952.1 ± 9089.08
    22141.3 ± 9619.64
    23518.7 ± 12011.07
        Day 1, 1 hour, n=5, 7, 8, 6
    85.8 ± 253.77
    28365.3 ± 9711.56
    34147.9 ± 11206.05
    32445.0 ± 16424.62
        Day 1, 2 hours, n=5, 7, 8, 6
    101.2 ± 265.29
    35963.7 ± 6942.11
    42469.1 ± 13977.93
    38510.7 ± 19273.02
        Day 1, 4 hours, n=5, 7, 8, 6
    76.0 ± 209.69
    41046.0 ± 14859.06
    43492.8 ± 15811.41
    43477.2 ± 28963.40
        Day 1, 6 hours, n=5, 7, 8, 6
    -130.8 ± 273.14
    68337.3 ± 22986.71
    77279.4 ± 14115.24
    55195.8 ± 27523.26
        Day 1, 8 hours, n=5, 7, 7, 6
    -60.4 ± 242.85
    68342.4 ± 27742.23
    70935.4 ± 10888.79
    50511.3 ± 25067.72
        Day 1, 9 hours, n=1, 6, 0, 0
    50.0 ± 99999
    46941.7 ± 15418.31
    999999 ± 999999
    999999 ± 999999
        Day 1, 12 hours, n=4, 0, 7, 6
    -9.8 ± 267.43
    999999 ± 999999
    56618.7 ± 8092.43
    40765.8 ± 21505.21
        Day 1, 16 hours, n=4, 6, 8, 6
    30.8 ± 353.27
    35124.7 ± 31051.56
    47713.4 ± 7841.92
    29753.0 ± 15501.29
        Day 2, n=5, 7, 8, 6
    -41.2 ± 263.98
    14020.9 ± 2453.61
    26096.8 ± 5228.98
    22559.8 ± 13107.67
        Day 3, n=5, 7, 8, 6
    -29.0 ± 351.20
    13502.1 ± 6856.86
    19841.5 ± 4986.13
    20615.5 ± 11473.73
        Day 4, n=5, 7, 8, 6
    -90.0 ± 332.42
    11065.7 ± 5053.88
    17923.5 ± 2476.65
    17694.8 ± 8442.57
        Day 5, n=5, 7, 8, 6
    49.0 ± 412.48
    7781.6 ± 2908.32
    7139.3 ± 2922.96
    9209.5 ± 5670.67
        Day 6, n=5, 7, 8, 6
    -59.4 ± 291.67
    4706.7 ± 4049.36
    4795.4 ± 2544.14
    6093.3 ± 3673.79
        Day 6, 1 hour, n=5, 7, 8, 6
    10.0 ± 566.43
    20140.3 ± 6799.16
    6011.8 ± 3638.55
    6167.5 ± 3965.76
        Day 14, n=5, 6, 8, 4
    -84.4 ± 321.06
    -783.3 ± 1407.22
    564.3 ± 374.97
    1082.3 ± 1638.04
    Notes
    [86] - Fully treated population
    [87] - Fully treated population
    [88] - Fully treated population
    [89] - Fully treated population
    No statistical analyses for this end point

    Secondary: Number of participants with anti-drug antibody binding

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    End point title
    		 Number of participants with anti-drug antibody binding
    End point description
    Samples were analyzed for the presence of anti-Otelixizumab antibodies using a validated immunoelectrochemiluminescent (ECL) assay.
    End point type
    Secondary
    End point timeframe
    Day-1, Month 3 and Month 6
    End point values
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Number of subjects analysed
    5 [90]
    9 [91]
    8 [92]
    7 [93]
    Units: Participants
        Day -1, Negative
    3
    9
    8
    6
        Day-1, Positive
    2
    0
    0
    1
        Month 3, Negative
    3
    0
    0
    0
        Month 3, Positive
    2
    9
    8
    7
        Month 3, Newly Positive
    0
    9
    8
    6
        Month 3, Negative who were Positive previously
    0
    0
    0
    0
        Month 6, Negative
    3
    0
    0
    0
        Month 6, Positive
    2
    8
    8
    7
        Month 6, Newly Positive
    0
    0
    0
    0
        Month 6, Negative who were Positive previously
    0
    0
    0
    0
    Notes
    [90] - Safety population
    [91] - Safety population
    [92] - Safety population
    [93] - Safety population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On treatment serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment up to 36 months.
    Adverse event reporting additional description
    Safety population was used. Safety population comprised of all participants who received at least one dose of a study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 0.9% weight/volume Sodium Chloride solution for injection daily for 6 Days

    Reporting group title
    Otelixizumab 9 mg
    Reporting group description
    		 Participants received 1.5 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Reporting group title
    Otelixizumab 18 mg
    Reporting group description
    		 Participants received 3 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Reporting group title
    Otelixizumab 27 mg
    Reporting group description
    		 Participants received 4.5 mg of OTX (intravenous solution for infusion) daily for 6 Days

    Serious adverse events
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (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
    Fibula fracture
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (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
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (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
    Metabolic disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (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: 0%
    Non-serious adverse events
    		 Placebo Otelixizumab 9 mg Otelixizumab 18 mg Otelixizumab 27 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    9 / 9 (100.00%)
    8 / 8 (100.00%)
    7 / 7 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Surgical and medical procedures
    Nail operation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wisdom teeth removal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 9 (33.33%)
    6 / 8 (75.00%)
    4 / 7 (57.14%)
         occurrences all number
    0
    3
    11
    8
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    3
    1
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    4
    0
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    1
    Inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    Malaise
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Application site scab
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Facial pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infusion site reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Nodule
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Nipple pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    2
    6
    2
    4
    Cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    1
    Asthma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Depression
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Depressive symptom
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Intentional self-injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stress
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    1
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    1
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    1
    0
    2
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    2
    Electrocardiogram QT Prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Heart rate irregular
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Clavicle fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Concussion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fibula fracture
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Post procedural complication
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Repetitive strain injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 5 (80.00%)
    9 / 9 (100.00%)
    8 / 8 (100.00%)
    7 / 7 (100.00%)
         occurrences all number
    25
    45
    25
    32
    Dizziness
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    3 / 7 (42.86%)
         occurrences all number
    2
    1
    1
    3
    Dizziness postural
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    3 / 7 (42.86%)
         occurrences all number
    1
    2
    1
    6
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    0
    3
    Eosinophilia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    2
    Lymphopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Leukocytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    2
    Leukopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Monocytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear disorder
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Motion sickness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Vertigo
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 5 (40.00%)
    5 / 9 (55.56%)
    8 / 8 (100.00%)
    7 / 7 (100.00%)
         occurrences all number
    2
    7
    16
    15
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 9 (44.44%)
    6 / 8 (75.00%)
    7 / 7 (100.00%)
         occurrences all number
    0
    9
    10
    12
    Abdominal pain upper
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 9 (11.11%)
    6 / 8 (75.00%)
    3 / 7 (42.86%)
         occurrences all number
    1
    1
    7
    3
    Abdominal pain
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 9 (33.33%)
    3 / 8 (37.50%)
    2 / 7 (28.57%)
         occurrences all number
    5
    4
    3
    2
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 9 (33.33%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    4
    2
    1
    Constipation
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    2
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    6
    1
    Abdominal distension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gingival recession
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Tongue disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 9 (44.44%)
    7 / 8 (87.50%)
    7 / 7 (100.00%)
         occurrences all number
    1
    12
    14
    9
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    3 / 7 (42.86%)
         occurrences all number
    0
    3
    1
    3
    Alopecia
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Rash erythematous
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    0
    2
    Skin exfoliation
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    1
    Eczema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Generalised erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash generalised
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Microalbuminuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 9 (33.33%)
    5 / 8 (62.50%)
    2 / 7 (28.57%)
         occurrences all number
    6
    3
    5
    3
    Arthralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 9 (33.33%)
    4 / 8 (50.00%)
    4 / 7 (57.14%)
         occurrences all number
    0
    4
    8
    6
    Myalgia
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    4
    2
    1
    Pain in extremity
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Arthritis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 5 (40.00%)
    6 / 9 (66.67%)
    4 / 8 (50.00%)
    5 / 7 (71.43%)
         occurrences all number
    5
    10
    7
    11
    Gastroenteritis
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 9 (33.33%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    4
    4
    1
    Influenza
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 9 (55.56%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    5
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    3
    1
    Onychomycosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    1
    Body tinea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Bronchitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gingival abscess
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Herpes virus infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vaginal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    5 / 5 (100.00%)
    9 / 9 (100.00%)
    8 / 8 (100.00%)
    7 / 7 (100.00%)
         occurrences all number
    434
    646
    210
    622
    Hyperglycaemia
         subjects affected / exposed
    5 / 5 (100.00%)
    9 / 9 (100.00%)
    7 / 8 (87.50%)
    7 / 7 (100.00%)
         occurrences all number
    118
    380
    360
    215
    Decreased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Iron deficiency
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Metabolic disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Increased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2014
    Amend_01: Addition of unblinded Pharmacy Monitor to table summarising blinding status of personnel; endpoint in table updated to include insulin measurement for 7 days before all outpatient visits; endpoint of glucose added when performing Mixed Meal Tolerance test and clamp procedures; clarification of time period for collecting information in the screening period; removal of T Cell Receptor complexes and clarification of CD3 requirements throughout protocol; change of volume required to purge the Intravenous infusion line and total volume filled into syringe, and removal of “micopore” from description; the following changes to the Time and Events Tables: clarification that insulin should be recorded for 7 days before all outpatient visits; addition of Day 6 to footnote; clarification that glucose will be collected in addition to C-peptide during the hyperglycaemic clamp procedure; addition of Electrocardiograms at 6 hours post start of infusion clarification of which Electrocardiograms will be triplicate or single measures; addition of T Cell Receptor deep sequencing at 24 months to Biomarker Assay Table; clarification that Mixed Meal Tolerance test will be at least 7 days prior to the first dose of study drug; clarification that c-peptide and glucose samples will be shipped within 3 weeks of collection; clarification that the hyperglycaemic range of 180-240 milligram per deciLiter during 140 minutes for consistency with blood sampling time points.
    02 Apr 2014
    Amend_02: Hyperglycaemic events is included in the follow up endpoints and the Time and Events table to be consistent with the applicable secondary objective; rephrased “Immuno-Assay for syphilis test” in order to allow for different types of tests; increased the overage volume required to remain in the syringe for infusion; clarified the start of Adverse Events recording.
    18 Jun 2014
    Amend_03: The third medical monitor has changed, therefore contact information for the replacement is included. The eligibility inclusion criterion was changed from two to one positive autoantibody associated with Type 1 Diabetes Mellitus
    28 Jul 2014
    Amend_3.1: Clarified that within each cohort administration of study treatment for the first three patients will be staggered by at least three days across each centre.
    11 Feb 2015
    Amend_04: To increase flexibility for patients, dosing on Day 4, 5 & 6 may be performed on an out-patient basis if the Investigator is satisfied with the clinical status of the patient; clarification that if the infusion needs to be reduced or temporarily stopped the Investigator should first consult with the Medical Monitor who will consult the Sponsor, unless there is an immediate safety hazard, in this case the Investigator can inform the Medical Monitor afterwards; clarified that insulin use is to be recorded prior to each visit and phone call; clarification that the decision to replace a patient is to be based on the reason for withdrawal; inclusion criteria amended; screen failure data are to be collected; assessments following patient withdrawal clarified; clarified that infusion kits are supplied to sites; assessment of Epstein Barr Virus reactivation now conducted at 6 weeks after the first active dose; blinding status amended to clarify that only the patient is blinded and not site staff; requirement for pharmacy staff to document that investigational product shipping conditions were 2-8°C included; anti-emetic added as a permitted concomitant medication, window of ± 1 day added to Day 14, 21 visits & Week 4 telephone call; Dosing and Follow-up amended to include a phone call at Week 4 to discuss Adverse Events (AEs) with patient and addition of assessments at Week 6; endpoints amended to reflect the change to visits at Week 4 and Week 6; Detail for Vitals, Electrocardiogram and Pharmacokinetic and Pharmacodynamic Monitoring over the Infusion Period amended to include Electrocardiogram at 3 hours and to clarify that assessments may stop at 3 hours post dose; clarification of cytokine release syndrome adverse events grading system and stopping criteria in Section; Cytokine Release Syndrome (CRS) AEs; clarification on requirements for bilirubin samples included
    18 Aug 2015
    Amend_05:The assay for screening Epstein Barr Virus ImmunoglobulinG and ImmunoglobulinM assessment was clarified in exclusion criterion and in the Risk Management section; exclusion criterion was split into two exclusion criterias to clarify Epstein Barr Virus ImmunoglobulinM, ImmunoglobulinG and Viral load requirements for the interpretation of the results: a footnote was added to Table; Stopping Criteria for Cytokine Release Syndrome-Adverse Events to provide further clarification regarding when individual stopping criteria are met; the dose preparation section was updated to clarify that an additional maximum of 30 minutes is allowed for dose preparation tasks and that if 6 hours is exceeded, the syringe and infusion materials must be replaced; Epstein Barr Virus serology samples to assess ImmunoglobulinG and ImmunoglobulinM included for Day -1 in the Time and Events Table; Dosing and Follow-Up.
    12 Sep 2016
    Amend_06: Clarifications were made to the exploratory biomarker objectives and endpoints. Significant changes were: the addition of Th17 cells to the objective to assess the effect of otelixizumab on circulating lymphocytes; the addition of viral antigens to the endpoints to assess the effect of otelixizumab on the frequency of cytokine-producing antigen specific T cells; the addition of transcriptomic gene expression changes to the objective to assess the effect of otelixizumab on the clonal repertoire of circulating T cell populations; and clarification that the suppression activity of circulating T lymphocytes may be further evaluated by adapting assay conditions, possibly through adding and/or blocking of stimuli. The Time and Events table was updated to show requirement for telephone calls at Month 36, 48 and 60. Month 24 exploratory biomarkers are now being routinely collected and are not subject to the results of Month 12 biomarker analysis. In addition, it was clarified that Month 24 exploratory biomarker samples will be collected and only analysed after review of safety endpoints from Month 12 and not efficacy endpoints as previously stated. Minor clarifications related to the Month 12 Interim Analyses were included.
    11 Sep 2017
    Amend_07: All details of how the currently used Ensure powder (Abbott) is prepared has been removed from the Mixed Meal Tolerance Test. This has been amended because the manufacturer (Abbott) has discontinued the currently used powder and the new product has a slightly different formulation.
    26 Oct 2017
    Amend_08: Data which emerged from an interim analysis carried out in this study showed a prompt regain of immune competence observed in treated subjects and consequent rapid resolution of Epstein Barr Virus reactivation, both clinically and virologically. The long term EBV related Post-Transplant Lymphoproliferative Disorder risk, as observed in solid organ transplant on a chronic immune suppression therapy, is negligible. Therefore, all references to month 48 and 60 have been removed as no patient currently enrolled in the study has reached month 48 of follow up. For the patients who have yet to complete their 24 month visit, this visit will be treated as a final visit and for those who have gone past month 24, they will be followed up with a final communication or visit (final follow up) upon approval of this protocol amendment. Data from the literature identified a causal relationship between the degree of immunosuppression and an increased incidence of Epstein Barr Virus related Post Transplant Lymphoprolerative Disorders and for this reason a long-term follow-up was implemented at the start of the study.

    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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