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    Clinical Trial Results:
    A two-part placebo-controlled study to evaluate the safety, tolerability and preliminary efficacy of BVS857 in patients with spinal and bulbar muscular atrophy (SBMA) Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2013-002608-15
    Trial protocol
    		 IT   DK   DE  
    Global end of trial date
    13 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2018
    First version publication date
    11 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBVS857X2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02024932
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    13 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of BVS857 in patients with SBMA  To evaluate the preliminary efficacy of BVS857 on thigh muscle volume (TMV) by MRI in patients with SBMA after 12 weeks of dosing (Part B only)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    37
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    28
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 2 parts, Part A and Part B. In Part A, Cohort 1 participants received open-label BVS857. Cohort 2 participants were randomized to double-blind BVS857 or double-blind placebo in a 2:1 ratio.

    Pre-assignment
    Screening details
    		 In Part B, Cohort 3 was not enrolled. Cohort 4 participants received open-label BVS857. Cohort 5 participants were randomized to double-blind BVS857 or double-blind placebo in a ratio of 18:10.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BVS857 Part A Open label (Cohort 1)
    Arm description
    		 Participants received single doses of 0.01 mg/kg BVS857 intravenously (i.v.) on day 1, 0.01 mg/kg BVS857 subcutaneously (s.c.) on day 15, 0.03 mg/kg BVS857 s.c. on day 29, 0.06 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BVS857
    Investigational medicinal product code
    BVS857
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Participants received single doses of 0.01 mg/kg BVS857 intravenously (i.v.) on day 1, 0.01 mg/kg BVS857 subcutaneously (s.c.) on day 15, 0.03 mg/kg BVS857 s.c. on day 29, 0.06 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57.

    Arm title
    		 BVS857 Part A double blind (Cohort 2)
    Arm description
    		 Participants received single doses of 0.03 mg/kg BVS857 i.v. on day 1, 0.03 mg/kg BVS857 s.c. on day 15, 0.06 mg/kg BVS857 s.c. on day 29, 0.10 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57. (BVS857 concentrations differed on days 43 and 57.)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BVS857
    Investigational medicinal product code
    BVS857
    Other name
    Pharmaceutical forms
    Solution for injection, Solution for infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Participants received single doses of 0.03 mg/kg BVS857 i.v. on day 1, 0.03 mg/kg BVS857 s.c. on day 15, 0.06 mg/kg BVS857 s.c. on day 29, 0.10 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57. (BVS857 concentrations differed on days 43 and 57.)

    Arm title
    		 Placebo Part A double blind (Cohort 2)
    Arm description
    		 Participants received single doses of matching placebo i.v. on day 1 and matching placebo s.c. on days 15, 29, 43 and 57.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Participants received single doses of matching placebo i.v. on day 1 and matching placebo s.c. on days 15, 29, 43 and 57.

    Arm title
    		 BVS857 Part B open-label (Cohort 4)
    Arm description
    		 Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BVS857
    Investigational medicinal product code
    BVS857
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks.

    Arm title
    		 BVS857 Part B double blind (Cohort 5)
    Arm description
    		 Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BVS857
    Investigational medicinal product code
    BVS857
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks.

    Arm title
    		 Placebo Part B double blind (Cohort 5)
    Arm description
    		 Participants received matching placebo i.v. to BVS857 weekly for 12 weeks.
    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 received matching placebo i.v. to BVS857 weekly for 12 weeks.

    Number of subjects in period 1
    		BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) Placebo Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5) Placebo Part B double blind (Cohort 5)
    Started
    2
    4
    2
    2
    18
    9
    Safety analysis set
    2
    4
    2
    2
    18
    9
    Pharmacokinetic (PK) analysis set
    2
    4
    0 [1]
    2
    18
    0 [2]
    Pharmacodynamic (PD) analysis set
    2
    4
    2
    2
    18
    9
    Completed
    0
    1
    2
    0
    16
    9
    Not completed
    2
    3
    0
    2
    2
    0
         Adverse event, non-fatal
    2
    3
    -
    -
    2
    -
         Abnormal laboratory value
    -
    -
    -
    2
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: PK analysis does not apply to placebo participants.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: PK analysis does not apply to placebo participants.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BVS857 Part A Open label (Cohort 1)
    Reporting group description
    		 Participants received single doses of 0.01 mg/kg BVS857 intravenously (i.v.) on day 1, 0.01 mg/kg BVS857 subcutaneously (s.c.) on day 15, 0.03 mg/kg BVS857 s.c. on day 29, 0.06 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57.

    Reporting group title
    BVS857 Part A double blind (Cohort 2)
    Reporting group description
    		 Participants received single doses of 0.03 mg/kg BVS857 i.v. on day 1, 0.03 mg/kg BVS857 s.c. on day 15, 0.06 mg/kg BVS857 s.c. on day 29, 0.10 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57. (BVS857 concentrations differed on days 43 and 57.)

    Reporting group title
    Placebo Part A double blind (Cohort 2)
    Reporting group description
    		 Participants received single doses of matching placebo i.v. on day 1 and matching placebo s.c. on days 15, 29, 43 and 57.

    Reporting group title
    BVS857 Part B open-label (Cohort 4)
    Reporting group description
    		 Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks.

    Reporting group title
    BVS857 Part B double blind (Cohort 5)
    Reporting group description
    		 Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks.

    Reporting group title
    Placebo Part B double blind (Cohort 5)
    Reporting group description
    		 Participants received matching placebo i.v. to BVS857 weekly for 12 weeks.

    Reporting group values
    		 BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) Placebo Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5) Placebo Part B double blind (Cohort 5) Total
    Number of subjects
    		 2 4 2 2 18 9 37
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 1 3 1 2 12 9 28
        From 65-84 years
    		 1 1 1 0 6 0 9
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 67 ( 5.66 ) 56 ( 12.33 ) 59.5 ( 7.78 ) 41.5 ( 4.95 ) 57 ( 55.5 ) 54 ( 5.94 ) -
    Gender Categorical
    Units: Subjects
        Male
    		 2 4 2 2 18 9 37

    End points

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    End points reporting groups
    Reporting group title
    BVS857 Part A Open label (Cohort 1)
    Reporting group description
    		 Participants received single doses of 0.01 mg/kg BVS857 intravenously (i.v.) on day 1, 0.01 mg/kg BVS857 subcutaneously (s.c.) on day 15, 0.03 mg/kg BVS857 s.c. on day 29, 0.06 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57.

    Reporting group title
    BVS857 Part A double blind (Cohort 2)
    Reporting group description
    		 Participants received single doses of 0.03 mg/kg BVS857 i.v. on day 1, 0.03 mg/kg BVS857 s.c. on day 15, 0.06 mg/kg BVS857 s.c. on day 29, 0.10 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57. (BVS857 concentrations differed on days 43 and 57.)

    Reporting group title
    Placebo Part A double blind (Cohort 2)
    Reporting group description
    		 Participants received single doses of matching placebo i.v. on day 1 and matching placebo s.c. on days 15, 29, 43 and 57.

    Reporting group title
    BVS857 Part B open-label (Cohort 4)
    Reporting group description
    		 Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks.

    Reporting group title
    BVS857 Part B double blind (Cohort 5)
    Reporting group description
    		 Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks.

    Reporting group title
    Placebo Part B double blind (Cohort 5)
    Reporting group description
    		 Participants received matching placebo i.v. to BVS857 weekly for 12 weeks.

    Primary: Number of patients with adverse events (AEs), serious adverse events (SAEs) and deaths as a measure of safety and tolerability

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    End point title
    		 Number of patients with adverse events (AEs), serious adverse events (SAEs) and deaths as a measure of safety and tolerability [1]
    End point description
    Safety was monitored throughout the study.
    End point type
    Primary
    End point timeframe
    After 78 days in Part A and after 85 days in Part B.
    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: Descriptive summary statistics only were reported for this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) Placebo Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5) Placebo Part B double blind (Cohort 5)
    Number of subjects analysed
    2
    4
    2
    2
    18
    9
    Units: Participants
        Non-serious AEs
    2
    4
    2
    1
    17
    8
        SAEs
    0
    0
    0
    0
    0
    0
        Deaths
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of mild, moderate and severe adverse events as a measure of safety and tolerability

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    End point title
    		 Number of mild, moderate and severe adverse events as a measure of safety and tolerability [2]
    End point description
    Safety was monitored throughout the study.
    End point type
    Primary
    End point timeframe
    After 78 days in Part A and after 85 days in Part B.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive summary statistics only were reported for this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) Placebo Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5) Placebo Part B double blind (Cohort 5)
    Number of subjects analysed
    2
    4
    2
    2
    18
    9
    Units: Participants
        Mild
    1
    2
    2
    0
    5
    4
        Moderate
    1
    2
    0
    0
    11
    3
        Severe
    0
    0
    0
    0
    1
    1
    No statistical analyses for this end point

    Primary: Mean percent change from baseline in thigh muscle volume in Part B, Cohort 5

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    End point title
    		 Mean percent change from baseline in thigh muscle volume in Part B, Cohort 5 [3]
    End point description
    Thigh muscle volume was assessed by magnetic resonance imaging (MRI). Change from baseline was calculated from the ratio of the post-baseline mean value to the baseline mean value: [(Day 85/baseline) - 1)] x 100. A positive change from baseline indicates improvement.
    End point type
    Primary
    End point timeframe
    Baseline, Day 85
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B double blind (Cohort 5) Placebo Part B double blind (Cohort 5)
    Number of subjects analysed
    15
    9
    Units: Percent change
        geometric mean (standard deviation)
    0 ( 2.42 )
    -3.4 ( 4.79 )
    Statistical analysis title
    		 Change from BL in TMV in Part B, Cohort 5
    Comparison groups
    BVS857 Part B double blind (Cohort 5) v Placebo Part B double blind (Cohort 5)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0164
    Method
    		 ANCOVA
    Parameter type
    		 Geo-mean ratio
    Point estimate
    1.037
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.009
         upper limit
    		 1.065

    Secondary: Mean change from baseline in score on the adult myopathy assessment tool (AMAT) in Part B, Cohort 5

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    End point title
    		 Mean change from baseline in score on the adult myopathy assessment tool (AMAT) in Part B, Cohort 5 [4]
    End point description
    The AMAT rated physical function and muscle endurance, with higher scores indicating better performance. The tool includes 7 timed functional tasks rated on a scale from 0 - 21 and 6 endurance tasks rated on a scale from 0 - 24. The range for the total score was from 0 (worst) to 45 (best). A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B double blind (Cohort 5) Placebo Part B double blind (Cohort 5)
    Number of subjects analysed
    18
    9
    Units: score on a scale
        arithmetic mean (standard deviation)
    1 ( 4.2 )
    2.3 ( 1.87 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in total lean body mass (LBM) in Part B, Cohort 5

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    End point title
    		 Mean change from baseline in total lean body mass (LBM) in Part B, Cohort 5 [5]
    End point description
    LBM was assessed by dual-energy X-ray (DXA) absorptiometry. A positive change from baseline indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B double blind (Cohort 5) Placebo Part B double blind (Cohort 5)
    Number of subjects analysed
    17
    8
    Units: kilograms
        arithmetic mean (standard deviation)
    0.77 ( 1.556 )
    0.16 ( 1.199 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part A, Cohort 1

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part A, Cohort 1 [6]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1)
    Number of subjects analysed
    2
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.01 mg/kg BVS857 s.c.
    184 ( 6.36 )
        Day 15, 0.01 mg/kg BVS857 s.c.
    34.6 ( 48.9 )
        Day 29, 0.03 mg/kg BVS857 s.c.
    83.1 ( 20.3 )
        Day 43, 0.06 mg/kg BVS857 s.c.
    74.2 ( 16.1 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part A, Cohort 2

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part A, Cohort 2 [7]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1, 15
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A double blind (Cohort 2)
    Number of subjects analysed
    4
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.03 mg/kg BVS857 i.v. (n=4)
    393 ( 30.1 )
        Day 15, 0.03 mg/kg BVS857 s.c. (n=3)
    77.3 ( 46.5 )
        Day 29, 0.06 mg/kg BVS857 s.c. (n=2)
    113 ( 2.12 )
        Day 43, 0.10 mg/kg BVS857 s.c. (n=3)
    191 ( 19.2 )
        Day 57, 0.10 mg/kg BVS857 s.c. (n=1)
    232 ( 9999 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part A, Cohort 1

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part A, Cohort 1 [8]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1)
    Number of subjects analysed
    2
    Units: hours
    arithmetic mean (standard deviation)
        Day 1, 0.01 mg/kg BVS857 i.v. (n=2)
    4.04 ( 0.0566 )
        Day 15, 0.01 mg/kg BVS857 s.c. (n=1)
    12.1 ( 9999 )
        Day 29, 0.03 mg/kg BVS857 s.c.(n=2)
    18.1 ( 8.41 )
        Day 43, 0.06 mg/kg BVS857 s.c. (n=2)
    36 ( 16.8 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part A, Cohort 2

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part A, Cohort 2 [9]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Day 1, 15
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A double blind (Cohort 2)
    Number of subjects analysed
    4
    Units: hours
    arithmetic mean (standard deviation)
        Day 1, 0.03 mg/kg BVS857 i.v. (n=4)
    2.53 ( 1.7 )
        Day 15, 0.03 mg/kg BVS857 s.c.(n=3)
    24.1 ( 0.1 )
        Day 29, 0.06 mg/kg BVS857 s.c. (n=2)
    24 ( 0 )
        Day 43, 0.10 mg/kg BVS857 s.c. (n=3)
    24 ( 0.2 )
        Day 57, 0.10 mg/kg BVS857 s.c. (n=1)
    48 ( 9999 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) in Part A, Cohort 1

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) in Part A, Cohort 1 [10]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1)
    Number of subjects analysed
    2
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.01 mg/kg BVS857 i.v.(n=2)
    4630 ( 1200 )
        Day 15, 0.01 mg/kg BVS857 s.c. (n=2)
    1060 ( 1500 )
        Day 29, 0.03 mg/kg BVS857 s.c.(n=2)
    2720 ( 870 )
        Day 43, 0.06 mg/kg BVS857 s.c.(n=2)
    5310 ( 4720 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) in Part A, Cohort 2

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) in Part A, Cohort 2 [11]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1, 15
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A double blind (Cohort 2)
    Number of subjects analysed
    4
    Units: H*ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.03 mg/kg BVS857 i.v.(n=4)
    9850 ( 4480 )
        Day 15, 0.03 mg/kg BVS857 s.c. (n=3)
    6480 ( 5850 )
        Day 29, 0.06 mg/kg BVS857 s.c. (n=2)
    7340 ( 5610 )
        Day 43, 0.10 mg/kg BVS857 s.c. (n=3)
    14400 ( 3320 )
        Day 57, 0.10 mg/kg BVS857 s.c. (n=1)
    28400 ( 9999 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part A, Cohort 1

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part A, Cohort 1 [12]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose
    Notes
    [12] - 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: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1)
    Number of subjects analysed
    2
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.01 mg/kg BVS857 i.v.(n=2)
    4620 ( 1200 )
        Day 15, 0.01 mg/kg BVS857 s.c. (n=1)
    2120 ( 9999 )
        Day 29, 0.03 mg/kg BVS857 s.c. (n=2)
    2720 ( 870 )
        Day 43, 0.06 mg/kg BVS857 s.c. (n=2)
    2210 ( 339 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part A, Cohort 2

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part A, Cohort 2 [13]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1, 15
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A double blind (Cohort 2)
    Number of subjects analysed
    4
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.03 mg/kg BVS857 i.v. (n=4)
    7980 ( 1710 )
        Day 15, 0.03 mg/kg BVS857 s.c. (n=3)
    2640 ( 1500 )
        Day 29, 0.06 mg/kg BVS857 s.c. (n=2)
    3880 ( 735 )
        Day 43, 0.10 mg/kg BVS857 s.c. (n=3)
    6390 ( 925 )
        Day 57, 0.10 mg/kg BVS857 s.c. (n=1)
    7360 ( 9999 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part B, Cohort 4

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part B, Cohort 4 [14]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1: pre-dose, 1, 4, 24, 48 hours post-dose
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B open-label (Cohort 4)
    Number of subjects analysed
    2
    Units: ng/mL
        arithmetic mean (standard deviation)
    2490 ( 799 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part B, Cohort 5

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) in Part B, Cohort 5 [15]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    18
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.06 mg/kg BVS857 i.v. (n=18)
    854 ( 669 )
        Day 36, 0.06 mg/kg BVS857 i.v. (n=16)
    790 ( 184 )
        Day 78, 0.06 mg/kg BVS857 i.v. (n=16)
    712 ( 218 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part B, Cohort 4

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part B, Cohort 4 [16]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1: pre-dose, 1, 4, 24, 48 hours post-dose
    Notes
    [16] - 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: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B open-label (Cohort 4)
    Number of subjects analysed
    2
    Units: hours
        arithmetic mean (standard deviation)
    1.08 ( 0.0707 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part B, Cohort 5

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) in Part B, Cohort 5 [17]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    18
    Units: hours
    arithmetic mean (standard deviation)
        Day 1, 0.06 mg/kg BVS857 i.v. (n=18)
    2.39 ( 1.54 )
        Day 36, 0.06 mg/kg BVS857 i.v. (n=16)
    1.73 ( 1.2 )
        Day 78, 0.06 mg/kg BVS857 i.v. (n=16)
    1.49 ( 1.04 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) in Part B, Cohort 5

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) in Part B, Cohort 5 [18]
    End point description
    Serum samples were obtained for PK assessment.
    End point type
    Secondary
    End point timeframe
    Day 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.
    Notes
    [18] - 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: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    18
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 36, 0.06 mg/kg BVS857 i.v. (n=1)
    13100 ( 9999 )
        Day 78, 0.06 mg/kg BVS857 i.v. (n=15)
    28000 ( 13500 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857:The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part B, Cohort 4

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857:The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part B, Cohort 4 [19]
    End point description
    Serum samples were obtained for the PK assessment.
    End point type
    Secondary
    End point timeframe
    Days 1: pre-dose, 1, 4, 24, 48 hours post-dose
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B open-label (Cohort 4)
    Number of subjects analysed
    2
    Units: H*ng/mL
        arithmetic mean (standard deviation)
    40600 ( 1270 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857:The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part B, Cohort 5

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857:The area under the plasma concentration-time curve from zero to 48 hours (AUC0_48h) in Part B, Cohort 5 [20]
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.
    Notes
    [20] - 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: All arms do not apply to this end point.
    End point values
    		 BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    18
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1, 0.06 mg/kg BVS857 i.v. (n=18)
    19400 ( 4160 )
        Day 36, 0.06 mg/kg BVS857 i.v.(n=16)
    19600 ( 5240 )
        Day 78, 0.06 mg/kg BVS857 i.v. (n=16)
    18100 ( 5850 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUCtau)

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUCtau) [21]
    End point description
    Serum samples were obtained for PK assessment. This PK parameter was not analyzed in either Part A or Part B because there were insufficient data points after Cmax. Therefore, this parameter could not be calculated.
    End point type
    Secondary
    End point timeframe
    Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    Units: ng*h/mL
    Notes
    [22] - This PK parameter was not analyzed.
    [23] - This PK parameter was not analyzed.
    [24] - This PK parameter was not analyzed.
    [25] - This PK parameter was not analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The terminal elimination half-life (T1/2)

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The terminal elimination half-life (T1/2) [26]
    End point description
    Serum samples were obtained for PK assessment. This PK parameter was not analyzed in either Part A or Part B because there were insufficient data points after Cmax. Therefore, this parameter could not be calculated.
    End point type
    Secondary
    End point timeframe
    Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.
    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: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    0 [27]
    0 [28]
    0 [29]
    0 [30]
    Units: ng*h/mL
    Notes
    [27] - This PK parameter was not analyzed.
    [28] - This PK parameter was not analyzed.
    [29] - This PK parameter was not analyzed.
    [30] - This PK parameter was not analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to infinity (AUCinf)

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    End point title
    		 Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to infinity (AUCinf) [31]
    End point description
    Serum samples were obtained for PK assessment. This PK parameter was not analyzed in either Part A or Part B because there were insufficient data points after Cmax. Therefore, this parameter could not be calculated.
    End point type
    Secondary
    End point timeframe
    Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.
    Notes
    [31] - 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: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    0 [32]
    0 [33]
    0 [34]
    0 [35]
    Units: hour
    Notes
    [32] - This PK parameter was not analyzed.
    [33] - This PK parameter was not analyzed.
    [34] - This PK parameter was not analyzed.
    [35] - This PK parameter was not analyzed.
    No statistical analyses for this end point

    Secondary: Compare dose normalized log-transformed AUCinf following IV and SC administrations

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    End point title
    		 Compare dose normalized log-transformed AUCinf following IV and SC administrations [36]
    End point description
    Serum samples were obtained for PK assessment. This PK parameter was not analyzed in either Part A or Part B because there were insufficient data points after Cmax. Therefore, this parameter could not be calculated.
    End point type
    Secondary
    End point timeframe
    In Part A: days 1 and 15, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose.
    Notes
    [36] - 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: All arms do not apply to this end point.
    End point values
    		 BVS857 Part A Open label (Cohort 1) BVS857 Part A double blind (Cohort 2) BVS857 Part B open-label (Cohort 4) BVS857 Part B double blind (Cohort 5)
    Number of subjects analysed
    0 [37]
    0 [38]
    0 [39]
    0 [40]
    Units: ng*h/mL
    Notes
    [37] - This PK parameter was not analyzed.
    [38] - This PK parameter was not analyzed.
    [39] - This PK parameter was not analyzed.
    [40] - This PK parameter was not analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Study Part 1: BVS857 (cohort 1)
    Reporting group description
    		 Study Part 1: BVS857 (cohort 1)

    Reporting group title
    Study Part 1: Placebo (cohort 2)
    Reporting group description
    		 Study Part 1: Placebo (cohort 2)

    Reporting group title
    Study Part 1: BVS857 (cohort 2)
    Reporting group description
    		 Study Part 1: BVS857 (cohort 2)

    Reporting group title
    Study Part 2: BVS857 0.1 mg/kg i.v. (cohort 4)
    Reporting group description
    		 Study Part 2: BVS857 0.1 mg/kg i.v. (cohort 4)

    Reporting group title
    Study Part 2: BVS857 0.06 mg/kg i.v. (cohort 5)
    Reporting group description
    		 Study Part 2: BVS857 0.06 mg/kg i.v. (cohort 5)

    Reporting group title
    Study Part 2: Placebo (cohort 5)
    Reporting group description
    		 Study Part 2: Placebo (cohort 5)

    Serious adverse events
    		 Study Part 1: BVS857 (cohort 1) Study Part 1: Placebo (cohort 2) Study Part 1: BVS857 (cohort 2) Study Part 2: BVS857 0.1 mg/kg i.v. (cohort 4) Study Part 2: BVS857 0.06 mg/kg i.v. (cohort 5) Study Part 2: Placebo (cohort 5)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Study Part 1: BVS857 (cohort 1) Study Part 1: Placebo (cohort 2) Study Part 1: BVS857 (cohort 2) Study Part 2: BVS857 0.1 mg/kg i.v. (cohort 4) Study Part 2: BVS857 0.06 mg/kg i.v. (cohort 5) Study Part 2: Placebo (cohort 5)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    2 / 2 (100.00%)
    4 / 4 (100.00%)
    1 / 2 (50.00%)
    17 / 18 (94.44%)
    8 / 9 (88.89%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Hypotension
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Administration site hypersensitivity
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Asthenia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Catheter site extravasation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Feeling hot
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Infusion site erythema
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Infusion site pruritus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Injection site erythema
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 2 (0.00%)
    3 / 4 (75.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    5
    0
    0
    0
    Injection site rash
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injection site swelling
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Puncture site pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Therapeutic response unexpected
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Choking
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Investigations
    Blood potassium increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Neutralising antibodies positive
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Weight increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Fibula fracture
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Road traffic accident
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 2 (50.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Wound
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    2 / 4 (50.00%)
    0 / 2 (0.00%)
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    11
    0
    Headache
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    3 / 18 (16.67%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    4
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Presyncope
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Eustachian tube dysfunction
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Eye disorders
    Eyelid haematoma
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Glaucoma
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ocular discomfort
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    8
    0
    Scleral hyperaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gingival pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lip disorder
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Lip oedema
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Oesophagitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Periodontal disease
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sensitivity of teeth
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    0
    1
    2
    Pruritus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin discolouration
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin irritation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Back pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Exostosis of jaw
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Joint stiffness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Muscle spasms
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Myalgia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Spinal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 2 (100.00%)
    1 / 4 (25.00%)
    0 / 2 (0.00%)
    4 / 18 (22.22%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    1
    0
    5
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 2 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2013
    The purpose of this amendment was to address FDA comments regarding temporary and permanent dosing discontinuation due to adverse events. The amendment redefined the conditions leading to temporary discontinuation of study treatment. The amendment also stipulated permanent dosing discontinuation due to elevated liver function tests
    19 Aug 2014
    The purpose of this amendment was to address clinical issues that had come to light upon analysis of data from the first 2 patients enrolled in the trial. As per protocol, these patients were dosed open-label (BVS857 s.c.). Both patients experienced a mild injection site skin reaction subsequent to the 0.06 mg/kg s.c. dose, triggering patient discontinuation. This amendment stipulated modifications in the dosing regimen in Part A and clarified that patients had to be withdrawn in the event of severe or persistent and recurrent infusion- and injection-site skin reactions. It was also determined that the 0.01 mg/kg dose (both i.v. and s.c.) was associated with very low PK exposure levels, and this dose was therefore to be eliminated. The third planned interim analysis in Part B was clarified to state that early futility was the primary purpose of this analysis, and that it was to be performed when approximately18 patients had completed the study, instead of 12, in order to provide sufficient power for the statistical test based on the futility criterion at the interim analysis. Moreover, the criterion for claiming the preliminary efficacy of BVS857 at the end of the study was also clarified and the statistical tests were adjusted to it. Plans for development of BVS857 include application to selected central nervous system (CNS) disorders. Therefore, determination of BVS857’s CNS penetration was explored via an optional lumbar puncture with cerebrospinal fluid examination of PK at baseline and Visit 19 in Part B.
    06 Feb 2015
    This amendment was to allow the use of i.v. administration route for Part B in the event that (1) the s.c. route did not provide sufficient exposure to trigger the expected PD effect and/or did not show clear dose proportionality of exposure, or (2) the planned s.c. dosing schemes resulted in severe or recurrent injection site reactions. If Part B was performed using i.v. route of administration under this amendment, the first two patients were to receive 12 weekly i.v. doses of open-label BVS857 0.1 mg/kg. A safety review was to be performed after the first two patients had completed 3 weekly doses of open-label i.v. BVS857 prior to proceeding with the rest of the planned randomized cohort. BVS857 0.1 mg/kg i.v. was expected to be safe based on the following: 1) established single MTD of 0.1 mg/kg i.v. in healthy volunteers (including insulin resistant patients), which was not expected to accumulate upon weekly dosing. 2) SBMA patients had lower circulating IGF-1 compared to healthy volunteers, allowing for a wider margin for supplementation. 3) Based on simulations, total IGF-1-like activity following BVS857 0.1 mg/kg weekly i.v. for 12 weeks was not expected to exceed the established exposure cap (400 ng/mL).
    31 Mar 2015
    The purpose of this amendment was to make administrative updates to clarify sample numbering and appropriate QMT equipment. AMAT, DXA and TMV assessments at week 6 were added to the exploratory objectives following request for clarification from German radiation agency (BfS).
    20 Jul 2015
    The purpose of this amendment was to decrease the i.v. dose to be used in Cohort 5 of Part B. Following the review of safety data of Cohort 4 (first two patients in Part B dosed open-label) after the first 3 i.v. doses, a study stopping rule was met, with both patients having a total IGF-1-like activity greater than 400 ng/mL after the first dose. Accordingly, the dose for Cohort 5 was lowered as follows: 1) Patients with baseline body weight ≤ 100 kg were to receive BVS857 or placebo at 0.06 mg/kg i.v. weekly (i.e., lowered by 40%). The total dose was capped at 6 mg (i.e., patients with baseline body weight >100 kg were to receive 6 mg i.v. weekly). 2) PK and IGF-1 analysis were reviewed in an ongoing manner by an unblinded PK bioanalyst and blinded pharmacokineticist for the first 48 hours of Week 1 in each patient. Patients who had total IGF-1-like activity ≥ 400 ng/mL or Cmax ≥ 2.3 µg/mL would have their weekly doses reduced to 0.05 mg/kg i.v. weekly (5 mg maximum; i.e., further reduction by 17%) as soon as this was determined, and at the latest in time for the Week 6 dose. The dose could be further reduced to 0.04 mg/kg i.v. weekly (4 mg maximum dose) if a patient continued to reach these criteria following the dose reduction. Due to the absence of AEs associated with total IGF-1-like activity ≥ 400 ng/mL, planned dose reduction by 40% (from 0.1 mg/kg to 0.06 g/kg), and planned ongoing review of PK and IGF-1 data with online changes to dose levels, the criteria surrounding total IGF-1-like activity and Cmax levels were shifted from Study Stopping Rules to instructions for ermitted Dose Adjustments for Cohort 5.
    09 Nov 2015
    The purpose of this amendment was to add two follow-up visits to the end of the treatment period, at 4 and 8 weeks after the last dose, to assess whether efficacy, if any, was sustained after weekly doses over 12 weeks. This amendment provided valuable information for possible future dosing regimens.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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