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    Clinical Trial Results:
    Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme

    Summary
    EudraCT number
    		 2011-000572-33
    Trial protocol
    		 DE  
    Global end of trial date
    08 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions
    Summary report(s)
    		 CTR synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ParvOryx01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01301430
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oryx GmbH & Co. KG
    Sponsor organisation address
    Marktplatz 1, Baldham, Germany, 85598
    Public contact
    Dr. Bernard Huber (CEO), Oryx GmbH & Co. KG, +49 8106213110, info@oryx-medicine.com
    Scientific contact
    Dr. Ottheinz Krebs (COO), Oryx GmbH & Co. KG, +49 8106213110, info@oryx-medicine.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
    15 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • Local and systemic safety and tolerability of the IMP, • Maximum tolerated dose (MTD) of the IMP, • Viremia following administration of the IMP, • Virus shedding/persistence following administration of the IMP.
    Protection of trial subjects
    Sequential enrolment Sequential dose escalation Monitoring of safety data by Data Safety Monitoring Board (DSMB) Hospitalisation during and after administration of the IMP
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    21 Oct 2011
    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
    Germany: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    13
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 All patients were recruited in Germany; Recruitment period: overall first subject enrolled: 24.10.2011, overall last subject enrolled: 23.01.15, overall last visit of the last subject: 08.05.15.

    Pre-assignment
    Screening details
    		 Screening was performed within 14 days before the first dose of IMP. Main eligibility criteria: confirmation of disease, safety parameters (physical examination, vital signs, ECG, laboratory evaluations). All screened subjects enrolled the trial (no screening failures).

    Period 1
    Period 1 title
    Screening
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 Level 1
    Arm description
    		 Administration of IMP at the total dose of 1E06. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 1E06 pfu: 5E05 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 5E05 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 1 Level 2
    Arm description
    		 Administration of IMP at the total dose of 5E07. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 5E07 pfu: 2.5E07 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 2.5E07 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes.

    Arm title
    		 Group 1 Level 3
    Arm description
    		 Administration of IMP at the total dose of 1E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 1E09 pfu: 5E08 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 5E08 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 2 Level 2
    Arm description
    		 Administration of IMP at the total dose of 5E07. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Intracerebral use
    Dosage and administration details
    Total dose of 5E07 pfu: Daily 5E06 pfu on Days 1 to 5 intravenously over 2 hours, 2.5E07 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 2 Level 3
    Arm description
    		 Administration of IMP at the total dose of 1E09. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Intracerebral use
    Dosage and administration details
    Total dose of 1E09 pfu: Daily 1E08 pfu on Days 1 to 5 intravenously over 2 hours, 5E08 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 3 Level 4
    Arm description
    		 Administration of IMP at the total dose of 5E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 5E09 pfu: 2.5E09 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 2.5E09 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Number of subjects in period 1
    		Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4
    Started
    3
    3
    3
    3
    3
    3
    Completed
    3
    3
    3
    3
    3
    3
    Period 2
    Period 2 title
    Treatment & Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 Level 1
    Arm description
    		 Administration of IMP at the total dose of 1E06. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 1E06 pfu: 5E05 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 5E05 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 1 Level 2
    Arm description
    		 Administration of IMP at the total dose of 5E07. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 5E07 pfu: 2.5E07 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 2.5E07 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes.

    Arm title
    		 Group 1 Level 3
    Arm description
    		 Administration of IMP at the total dose of 1E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 1E09 pfu: 5E08 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 5E08 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 2 Level 2
    Arm description
    		 Administration of IMP at the total dose of 5E07. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Intracerebral use
    Dosage and administration details
    Total dose of 5E07 pfu: Daily 5E06 pfu on Days 1 to 5 intravenously over 2 hours, 2.5E07 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 2 Level 3
    Arm description
    		 Administration of IMP at the total dose of 1E09. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Intracerebral use
    Dosage and administration details
    Total dose of 1E09 pfu: Daily 1E08 pfu on Days 1 to 5 intravenously over 2 hours, 5E08 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Arm title
    		 Group 3 Level 4
    Arm description
    		 Administration of IMP at the total dose of 5E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ParvOryx
    Investigational medicinal product code
    ParvOryx
    Other name
    Parvovirus H-1 in visipaque/ringer solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use, Intracerebral use
    Dosage and administration details
    Total dose of 5E09 pfu: 2.5E09 pfu on Day 1 intratumorally (via intratumoral catheter) over 15 minutes, 2.5E09 pfu on Day 10 intratumorally (direct injection at several locations of the resection wall) over 15-30 minutes

    Number of subjects in period 2
    		Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4
    Started
    3
    3
    3
    3
    3
    3
    Completed
    3
    3
    3
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 Level 1
    Reporting group description
    		 Administration of IMP at the total dose of 1E06. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 1 Level 2
    Reporting group description
    		 Administration of IMP at the total dose of 5E07. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 1 Level 3
    Reporting group description
    		 Administration of IMP at the total dose of 1E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 2 Level 2
    Reporting group description
    		 Administration of IMP at the total dose of 5E07. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 2 Level 3
    Reporting group description
    		 Administration of IMP at the total dose of 1E09. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 3 Level 4
    Reporting group description
    		 Administration of IMP at the total dose of 5E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group values
    		 Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4 Total
    Number of subjects
    		 3 3 3 3 3 3 18
    Age categorical
    Age categorical per group
    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)
    		 3 2 3 2 2 1 13
        From 65-84 years
    		 0 1 0 1 1 2 5
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.6 ( 10.1 ) 62.2 ( 8.5 ) 45.6 ( 1.8 ) 60.3 ( 11.4 ) 57.8 ( 7.6 ) 69.7 ( 7.2 ) -
    Gender categorical
    Gender characteristics per group
    Units: Subjects
        Female
    		 0 1 1 0 1 1 4
        Male
    		 3 2 2 3 2 2 14
    Subject analysis sets

    Subject analysis set title
    All groups, all dose levels
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Result pooled for all groups and all dose levels

    Subject analysis sets values
    		 All groups, all dose levels
    Number of subjects
    18
    Age categorical
    Age categorical per group
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    13
        From 65-84 years
    5
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender categorical
    Gender characteristics per group
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Group 1 Level 1
    Reporting group description
    		 Administration of IMP at the total dose of 1E06. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 1 Level 2
    Reporting group description
    		 Administration of IMP at the total dose of 5E07. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 1 Level 3
    Reporting group description
    		 Administration of IMP at the total dose of 1E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 2 Level 2
    Reporting group description
    		 Administration of IMP at the total dose of 5E07. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 2 Level 3
    Reporting group description
    		 Administration of IMP at the total dose of 1E09. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 3 Level 4
    Reporting group description
    		 Administration of IMP at the total dose of 5E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).
    Reporting group title
    Group 1 Level 1
    Reporting group description
    		 Administration of IMP at the total dose of 1E06. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 1 Level 2
    Reporting group description
    		 Administration of IMP at the total dose of 5E07. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 1 Level 3
    Reporting group description
    		 Administration of IMP at the total dose of 1E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 2 Level 2
    Reporting group description
    		 Administration of IMP at the total dose of 5E07. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 2 Level 3
    Reporting group description
    		 Administration of IMP at the total dose of 1E09. Day 1-5: 10% of the total dose intravenously, Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Reporting group title
    Group 3 Level 4
    Reporting group description
    		 Administration of IMP at the total dose of 5E09. Day 1: 50% of the total dose intratumorally (via catheter), Day 10: 50% of the total dose intracerebrally (direct injection at several locations in resection wall).

    Subject analysis set title
    All groups, all dose levels
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Result pooled for all groups and all dose levels

    Primary: Number of adverse events

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    End point title
    		 Number of adverse events [1]
    End point description
    End point type
    Primary
    End point timeframe
    Between first administration of the IMP and the last study visit (at month 6)
    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: Only descriptive statistical methods were employed in this trial (no confirmatory statistics)
    End point values
    		 Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4 All groups, all dose levels
    Number of subjects analysed
    3
    3
    3
    3
    3
    3
    18
    Units: unit
    19
    32
    25
    28
    23
    58
    185
    No statistical analyses for this end point

    Secondary: Progression-free survival at 6 months (6-m-PFS)

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    End point title
    		 Progression-free survival at 6 months (6-m-PFS)
    End point description
    End point type
    Secondary
    End point timeframe
    Between surgery and last study visit (at 6 months)
    End point values
    		 Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4 All groups, all dose levels
    Number of subjects analysed
    3
    3
    3
    3
    3
    3
    18
    Units: percent
        number (not applicable)
    66.6
    33.3
    0.0
    33.3
    0
    33.3
    27
    No statistical analyses for this end point

    Secondary: Overall survival at 6 months (6-m-OS)

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    End point title
    		 Overall survival at 6 months (6-m-OS)
    End point description
    End point type
    Secondary
    End point timeframe
    Between surgery and the last study visit (at month 6)
    End point values
    		 Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4 All groups, all dose levels
    Number of subjects analysed
    3
    3
    3
    3
    3
    3
    18
    Units: percent
        number (not applicable)
    100
    66.6
    100
    66.6
    100
    0.0
    72
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were documented between 1st administration of the IMP and the last follow-up visit (approx. 6 months after 1st administration of the IMP)
    Adverse event reporting additional description
    Adverse events were asked for at each contact with trial participants
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Group 1 Level 1
    Reporting group description
    		 Group 1 Level 1

    Reporting group title
    Group 1 Level 2
    Reporting group description
    		 Group 1 Level 2

    Reporting group title
    Group 1 Level 3
    Reporting group description
    		 Group 1 Level 3

    Reporting group title
    Group 2 Level 2
    Reporting group description
    		 Group 2 Level 2

    Reporting group title
    Group 2 Level 3
    Reporting group description
    		 Group 2 Level 3

    Reporting group title
    Group 3 Level 4
    Reporting group description
    		 Group 3 Level 4

    Serious adverse events
    		 Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
         number of deaths (all causes)
    0
    1
    0
    2
    0
    2
         number of deaths resulting from adverse events
    0
    1
    0
    1
    0
    2
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fistula
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    Hydrocephalus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    Epilepsy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 2.5%
    Non-serious adverse events
    		 Group 1 Level 1 Group 1 Level 2 Group 1 Level 3 Group 2 Level 2 Group 2 Level 3 Group 3 Level 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    2
    0
    0
    1
    Procedural complication
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    2
    0
    0
    2
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    3
    1
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    2 / 3 (66.67%)
         occurrences all number
    2
    4
    0
    2
    5
    2
    Epilepsy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    8
    0
    0
    1
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    2
    1
    2
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    0
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2012
    This amendment (approved by the PEI on 22nd February 2012 and by the EC on 7th February 2012) concerned the timing of the determinations of viral shedding and antibody determinations, and also regulated the exact timing of the Day 28 visit such as to avoid difficulties arising through week-ends etc.
    13 Sep 2012
    This amendment (approved by the PEI on 13th September 2012 and by the EC on 27th September 2012) concerned the up-dating of the IB only.
    13 May 2013
    This amendment (approved by the PEI on 2nd May 2013 and by the EC on 10th April 2013) was planned before the start of the trial and was aimed at informing the higher federal authority (PEI) and the responsible EC on the safety-related findings obtained from Group I. On the basis of these findings the sponsor additionally proposed the following protocol changes: (i) a reduction in the intervals between inclusions of individual subjects in a given dose group; these intervals were no longer considered necessary, as there had been no safety issues; (ii) an increase of the highest dose (introduction of Group III); and (iii) an increase in the number of blood samples required for viral genome analysis. However, only changes (ii) and (iii) were approved. These were implemented; change (i) was not.
    15 Jul 2013
    This amendment (approved by the PEI on 15th July 2013 and by the EC on 19th July 2013) introduced parallel, rather than serial, treatment of patients in Groups II and III , again as there had been no relevant safety issues.
    04 Oct 2013
    This amendment (approved by the PEI on 4th October 2013 and by the EC on 16 September 2013) concerned the up-dating of the IB and IMPD.
    14 Nov 2013
    This amendment (approved by the PEI on 14th November 2013 and by the EC on 28th October 2013) allowed flexibility in respect of the minimum intervals between inclusions of the subjects of the 3rd dose level in Group II on the basis of pharmacokinetic data.
    14 Mar 2014
    This amendment (confirmed by the PEI on 25th March 2014; EC approval was not required) instituted a temporary halt to recruitment because of a SUSAR.
    29 Jun 2014
    This amendment (approved by the PEI on 29th June 2014 and by the EC on 22nd June 2014) ended the temporary halt to recruitment instituted by Amendment no. 7.
    30 Sep 2014
    This amendment (approved by the PEI on 30th September 2014 and by the EC on the same day) concerned the up-dating of the IB only.
    18 Dec 2014
    This amendment (approved by the PEI on 18th December 2014; EC approval was not necessary) concerned the up-dating of the IMPD only.
    08 May 2015
    This amendment (approved by the PEI on 8th May 2015; EC approval was not necessary) concerned the up-dating of the IMPD only.
    08 May 2015
    This amendment (approved by the PEI on 1st July 2015; EC approval was not necessary) concerned the up-dating of the IMPD only.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Feb 2014
    The trial was interrupted due to a SUSAR (main diagnoses: hydrocephalus and decreased consciousness). Since the causality between the event and the IMP could not be excluded the case was reported to the competent authority and the leading ethics committee. After an intense discussion between involved parties, the sponsor decided to temporary stop patients’ recruitment until clarification of the case. Based a thorough evaluation of different aspects of the event, performed by the sponsor in cooperation with the competent authority, no change in the positive risk-benefit-assessment of the trial and of the IMP was concluded. Hence, the trial recruitment was resumed. No similar adverse events were ever since observed.
    29 Jul 2014

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/22436661
    http://www.ncbi.nlm.nih.gov/pubmed/28967558
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