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    Clinical Trial Results:
    A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study of BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients with Severe Haemophilia A

    Summary
    EudraCT number
    		 2014-003880-38
    Trial protocol
    		 GB  
    Global end of trial date
    14 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Feb 2025
    First version publication date
    28 Feb 2025
    Other versions
    Summary report(s)
    		 BMN 270-201 Table screenshots

    Trial information

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    Trial identification
    Sponsor protocol code
    270-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02576795
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc
    Sponsor organisation address
    105 Digital Drive, Novato, CA, United States, 94949
    Public contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., medinfo@bmrn.com
    Scientific contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., medinfo@bmrn.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
    14 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To assess the safety of a single intravenous administration of a recombinant AAV5 encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. - To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII at or above 5% of normal activity (>=5 IU/dL) at 16 weeks after infusion. The kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals with hemophilia A were determined and correlated to an appropriate BMN 270 dose.
    Protection of trial subjects
    This study was conducted in accordance with the following: • European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC, for studies conducted within any European country • US Code of Federal Regulations (CFR) sections that address clinical research studies, and/or other national and local regulations, as applicable • ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (ICH E6) The study was conducted under a protocol reviewed and approved by an IEC and is conducted by scientifically and medically qualified persons. The benefits of the study were in proportion to the risks. The rights and welfare of the participants were respected and the investigators conducting the study did not find the hazards to outweigh the potential benefits.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 7 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    0
    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)
    15
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 5 sites in United Kingdom (Basingstoke, Cambridge, Birmingham, Royal London, & Guys and St. Thomas’s Trust, London).

    Pre-assignment
    Screening details
    		 21 subjects were screened.6 did not meet eligibility criteria for enrollment in study:5 were found to be adeno-associated virus5(AAV5)transduction inhibition(TI)/total antibody(TAb)+ve,&1 was assessed as being unable to comply with requirements of trial. 15 participants were enrolled were enrolled in 270-201 & received BMN 270 in 1 of 4 dose cohort

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BMN 270 6E12 vg/kg
    Arm description
    		 Cohort 1: 6E12 vector genomes (vg) per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valacocogene Roxaparvovec
    Investigational medicinal product code
    BMN 270-201
    Other name
    AAV5-hFVIII-SQ/BMN 270
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 270 was infused through the catheter using an appropriate infusion pump at a constant rate of 4 ml/min while monitoring the vital signs. 6E12 vector genomes (vg) per kilogram of body weight, given as a single intravenous dose (IV)

    Arm title
    		 BMN 270 2E13 vg/kg
    Arm description
    		 Cohort 2: 2E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valacocogene Roxaparvovec
    Investigational medicinal product code
    BMN 270-201
    Other name
    AAV5-hFVIII-SQ/BMN 270
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 270 was infused through the catheter using an appropriate infusion pump at a constant rate of 4 ml/min while monitoring the vital signs. 2E13 vg per kilogram of body weight, administered as a single intravenous dose (IV)

    Arm title
    		 BMN 270 4E13 vg/kg
    Arm description
    		 Cohort 4: 4E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valacocogene Roxaparvovec
    Investigational medicinal product code
    BMN 270-201
    Other name
    AAV5-hFVIII-SQ/BMN 270
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 270 was infused through the catheter using an appropriate infusion pump at a constant rate of 4 ml/min while monitoring the vital signs. 4E13 vg per kilogram, per kilogram of body weight, administered as a single intravenous dose (IV).

    Arm title
    		 BMN 270 6E13 vg/kg
    Arm description
    		 Cohort 3: 6E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valacocogene Roxaparvovec
    Investigational medicinal product code
    BMN 270-201
    Other name
    AAV5-hFVIII-SQ/BMN 270
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 270 was infused through the catheter using an appropriate infusion pump at a constant rate of 4 ml/min while monitoring the vital signs. 6E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV)

    Number of subjects in period 1
    		BMN 270 6E12 vg/kg BMN 270 2E13 vg/kg BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg
    Started
    1
    1
    6
    7
    Completed
    1
    1
    5
    7
    Not completed
    0
    0
    1
    0
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BMN 270 6E12 vg/kg
    Reporting group description
    		 Cohort 1: 6E12 vector genomes (vg) per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 2E13 vg/kg
    Reporting group description
    		 Cohort 2: 2E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 4E13 vg/kg
    Reporting group description
    		 Cohort 4: 4E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 6E13 vg/kg
    Reporting group description
    		 Cohort 3: 6E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group values
    		 BMN 270 6E12 vg/kg BMN 270 2E13 vg/kg BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg Total
    Number of subjects
    		 1 1 6 7 15
    Age categorical
    Age at enrollment, n (%) Full Analysis Set (FAS): All enrolled participants who receive study drug and have at least one Baseline and post-Baseline assessment.
    Units: Subjects
        18 to < 40 years
    		 1 0 5 6 12
        40 to < 60 years
    		 0 1 1 1 3
    Gender categorical
    FAS population
    Units: Subjects
        Male
    		 1 1 6 7 15
    Race
    FAS population
    Units: Subjects
        Asian
    		 1 0 0 1 2
        Black or African American
    		 0 0 1 0 1
        White
    		 0 1 5 6 12
    Ethnicity
    FAS population.
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0
        Not Hispanic or Latino
    		 1 1 6 7 15
        Unknown or Not Reported
    		 0 0 0 0 0
    Baseline bleed counts (treated bleeds)
    FAS population
    Units: Subjects
        0 bleeds/year
    		 0 0 1 1 2
        > 0 to 4
    		 1 1 2 1 5
        > 4 to 10
    		 0 0 0 1 1
        > 10
    		 0 0 3 4 7
    History of previous diseases
    FAS population Liver Disease(LD) Some subjects may have multiple conditions. So the sum of subjects with HepB, HepC, HIV, LD and subjects without history of HepB/HepC/HIV/LD may not total to the overall number of subjects within the arm. In BMN 270-4E13 vg/kg Arm: 4 out of 6 subjects had no history of HepB/HepC/HIV/LD. One subject had multiple conditions (ie Hep B, Hep C and Liver Disease). Due to system limitation, it is reported as 2 in below table. In Total, 10 out of 15 subjects had no history of HepB/HepC/HIV/LD. Due to system limitations, it is showing as 8 in below table.
    Units: Subjects
        Hepatitis B
    		 0 0 1 0 1
        Hepatitis C
    		 0 1 2 2 5
        HIV
    		 0 0 0 0 0
        Liver disease
    		 0 0 1 0 1
        Subjects without History of HepB/HepC/HIV/LD
    		 1 0 2 5 8
    Number of target joints
    FAS population
    Units: Subjects
        n=0
    		 0 0 3 1 4
        n=1
    		 0 0 1 3 4
        n=2
    		 0 1 0 2 3
        n=3
    		 1 0 0 0 1
        n>3
    		 0 0 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    BMN 270 6E12 vg/kg
    Reporting group description
    		 Cohort 1: 6E12 vector genomes (vg) per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 2E13 vg/kg
    Reporting group description
    		 Cohort 2: 2E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 4E13 vg/kg
    Reporting group description
    		 Cohort 4: 4E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 6E13 vg/kg
    Reporting group description
    		 Cohort 3: 6E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Primary: Number of Participants with Treatment-emergent Adverse Events

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    End point title
    		 Number of Participants with Treatment-emergent Adverse Events [1]
    End point description
    Adverse events (AEs) with onset or worsening after the investigational product were included. Participants with more than one AE of the same category were counted only once for that category. Serious adverse event (SAE) Safety analysis Population: The Safety analysis population was defined as all enrolled participants who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Approximately Up to 7 years after dosing.
    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: Subject incidence was summarized descriptively in each reporting groups.
    End point values
    		 BMN 270 6E12 vg/kg BMN 270 2E13 vg/kg BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg
    Number of subjects analysed
    1
    1
    6
    7
    Units: Participants
    number (not applicable)
        Participants with any AE
    1
    1
    6
    7
        AEs leading to dose adjustment during infusion
    0
    0
    0
    0
        AEs leading to dose interruption during infusion
    0
    0
    0
    0
        AEs leading to study drug discontinuation
    0
    0
    0
    0
        Participants with any SAE
    1
    0
    3
    5
        Participants with any treatment-related AE
    1
    0
    6
    7
        Treatment-related SAEs
    0
    0
    1
    0
        Participants with any AE of Grade >= 3
    1
    1
    1
    2
        Participants who died
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participant with Median FVIII Activity Levels >=5 IU/dL Using Chromogenic Substrate Assay (CSA)

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    End point title
    		 Number of Participant with Median FVIII Activity Levels >=5 IU/dL Using Chromogenic Substrate Assay (CSA) [2]
    End point description
    Responder/Non responder status, where a responder was defined as a participant with median FVIII activity of >= 5 IU/dL during Week 13-16 post-BMN 270 infusion. FAS Population
    End point type
    Primary
    End point timeframe
    Week 13-16 post-BMN 270 infusion
    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: Incidence of subject defined in the endpoint was summarized descriptively in each reporting groups.
    End point values
    		 BMN 270 6E12 vg/kg BMN 270 2E13 vg/kg BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg
    Number of subjects analysed
    1
    1
    6
    7
    Units: participants
        number (not applicable)
    0
    0
    5
    7
    No statistical analyses for this end point

    Primary: Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion

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    End point title
    		 Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion [3]
    End point description
    Values for FVIII activity were excluded from analysis if obtained within 72 hours since the last infusion of exogenous FVIII replacement therapy FVIII activity levels below the Lower limit of quantitation (LLOQ) will be imputed with 0 IU/dL Q1: 25% Percentile; Q3: 75% Percentile FAS Population Neither participant in either the 6E12 vg/kg or 2E13 vg/kg cohort reached ≥ 5 IU/dL as of Weeks 13-16. Hence, these arms are not included for this endpoint. Efficacy results in this section are presented by dose cohort, with a primary focus on the 6E13 vg/kg and 4E13 vg/kg dose cohorts. One participant was dosed in each of the two lowest dose cohorts (6E12 vg/kg and 2E13 vg/kg) as part of the dose escalation scheme in Part 1 of the study. Neither participant showed an appreciable FVIII response following BMN 270 dosing at these dose levels
    End point type
    Primary
    End point timeframe
    Week 13-16 post-BMN 270 infusion
    Notes
    [3] - 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: FVIII activity was summarized descriptively in each reporting groups.
    End point values
    		 BMN 270 6E12 vg/kg BMN 270 2E13 vg/kg BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg
    Number of subjects analysed
    1
    1
    6
    7
    Units: IU/dL
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    16.30 (11.05 to 19.90)
    50.40 (31.30 to 64.95)
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment during Week 5 and Beyond

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    End point title
    		 Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment during Week 5 and Beyond [4]
    End point description
    ABR= [Number of bleeding episodes during calculation period] / [Total number of days during the calculation period] ×365.25 A bleeding episode (treated) was defined as a bleed or symptoms associated with the development of a bleed (or multiple bleeds occurring in the same day) requiring FVIII replacement treatment within 72 hours of the start of the bleed. The baseline values for the secondary efficacy endpoints were based on the historical data prior to study enrollment. Annualized bleeding rate (ABR) FAS Population
    End point type
    Secondary
    End point timeframe
    Week 5 and Beyond (approximately 7 years post Infusion).
    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: Efficacy results in this section are presented by dose cohort, with a primary focus on the 6E13 vg/kg and 4E13 vg/kg dose cohorts. One participant was dosed in each of the two lowest dose cohorts (6E12 vg/kg and 2E13 vg/kg) as part of the dose escalation scheme in Part 1 of the study. Neither participant showed an appreciable FVIII response following BMN 270 dosing at these dose levels.
    End point values
    		 BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg
    Number of subjects analysed
    6
    7
    Units: bleeds/year
    arithmetic mean (standard deviation)
        ABR at Week 5 and Beyond
    1.58 ( 1.97 )
    0.75 ( 1.43 )
    No statistical analyses for this end point

    Secondary: Annualized Factor VIII Utilization during Week 5 and Beyond

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    End point title
    		 Annualized Factor VIII Utilization during Week 5 and Beyond [5]
    End point description
    Annualized FVIII use (IU/kg/yr.) =[Sum of FVIII use (IU/kg) during calculation period] / [Total number of days during the calculation period] ×365.25 FAS Population
    End point type
    Secondary
    End point timeframe
    Week 5 and Beyond (approximately 7 years post Infusion)
    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: Efficacy results in this section are presented by dose cohort, with a primary focus on the 6E13 vg/kg and 4E13 vg/kg dose cohorts. One participant was dosed in each of the two lowest dose cohorts (6E12 vg/kg and 2E13 vg/kg) as part of the dose escalation scheme in Part 1 of the study. Neither participant showed an appreciable FVIII response following BMN 270 dosing at these dose levels.
    End point values
    		 BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg
    Number of subjects analysed
    6
    7
    Units: IU/kg/yr
    arithmetic mean (standard deviation)
        Annualized FVIII Usage at Week 5 and Beyond
    331.65 ( 360.19 )
    228.72 ( 311.68 )
    No statistical analyses for this end point

    Secondary: Annualized Factor VIII Infusion Rate during Week 5 and Beyond

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    End point title
    		 Annualized Factor VIII Infusion Rate during Week 5 and Beyond [6]
    End point description
    Annualized FVIII infusion rate (count/yr.) = [Number of FVIII replacement infusions during calculation period] / [Total number of days during the calculation period] ×365.25 FAS population
    End point type
    Secondary
    End point timeframe
    Week 5 and Beyond (approximately 7 years post Infusion)
    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: Efficacy results in this section are presented by dose cohort, with a primary focus on the 6E13 vg/kg and 4E13 vg/kg dose cohorts. One participant was dosed in each of the two lowest dose cohorts (6E12 vg/kg and 2E13 vg/kg) as part of the dose escalation scheme in Part 1 of the study. Neither participant showed an appreciable FVIII response following BMN 270 dosing at these dose levels.
    End point values
    		 BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg
    Number of subjects analysed
    6
    7
    Units: Infusions/ year
    arithmetic mean (standard deviation)
        Annualized FVIII infusion rate Week 5 and Beyond
    10.25 ( 9.06 )
    6.38 ( 8.19 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately up to 7 years after dosing.
    Adverse event reporting additional description
    AEs with onset or worsening after the investigational product were included Subjects with more than one AE of the same PT were counted only once for that Preferred term (PT) AEs were graded for severity using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version v4.03 Safety analysis Population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    BMN 270 6E12 vg/kg
    Reporting group description
    		 Cohort 1: 6E12 vector genomes (vg) per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 2E13 vg/kg
    Reporting group description
    		 Cohort 2: 2E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 4E13 vg/kg
    Reporting group description
    		 Cohort 4: 4E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    BMN 270 6E13 vg/kg
    Reporting group description
    		 Cohort 3: 6E13 vg per kilogram, per kilogram of body weight, given as a single intravenous dose (IV) valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

    Reporting group title
    Overall
    Reporting group description
    		 Valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A.

    Serious adverse events
    		 BMN 270 6E12 vg/kg BMN 270 2E13 vg/kg BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    3 / 6 (50.00%)
    5 / 7 (71.43%)
    9 / 15 (60.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acinic cell carcinoma of salivary gland
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery dissection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint stiffness
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 BMN 270 6E12 vg/kg BMN 270 2E13 vg/kg BMN 270 4E13 vg/kg BMN 270 6E13 vg/kg Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acinic cell carcinoma of salivary gland
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Haemangioma of liver
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Haemangioma of skin
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Melanocytic naevus
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    3
    3
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    0
    1
    3
    Fatigue
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    6 / 15 (40.00%)
         occurrences all number
    1
    0
    2
    4
    7
    Hangover
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Influenza like illness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    4 / 15 (26.67%)
         occurrences all number
    0
    1
    2
    1
    4
    Pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Puncture site swelling
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    4 / 15 (26.67%)
         occurrences all number
    1
    0
    2
    2
    5
    Swelling
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Vaccination site pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    3
    4
    Reproductive system and breast disorders
    Epididymal cyst
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Sexual dysfunction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    6 / 15 (40.00%)
         occurrences all number
    0
    1
    3
    5
    9
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Nasal congestion
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    4 / 15 (26.67%)
         occurrences all number
    0
    1
    2
    2
    5
    Productive cough
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    1
    0
    2
    3
    Snoring
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    0
    1
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    2
    Depressed mood
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Euphoric mood
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Insomnia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    4 / 15 (26.67%)
         occurrences all number
    0
    0
    1
    3
    4
    Panic attack
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    5 / 6 (83.33%)
    7 / 7 (100.00%)
    13 / 15 (86.67%)
         occurrences all number
    2
    0
    8
    9
    19
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    5 / 6 (83.33%)
    3 / 7 (42.86%)
    9 / 15 (60.00%)
         occurrences all number
    1
    0
    5
    4
    10
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    1
    0
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    0
    2
    3
    Blood urine present
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Coagulation factor VIII level decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Coagulation factor VIII level increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    0
    0
    2
    Thrombin time prolonged
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Weight increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    4
    4
    Injury, poisoning and procedural complications
    Back injury
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Fall
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    2
    3
    Foot fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Head injury
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Joint dislocation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Joint injury
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    5
    5
    Ligament sprain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    2
    1
    3
    Limb injury
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    2
    Muscle strain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Post-traumatic pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Procedural pain
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    1
    0
    2
    Thermal burn
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Traumatic haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Nervous system disorders
    Aura
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    3
    3
    Carotid artery dissection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Headache
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    3 / 6 (50.00%)
    4 / 7 (57.14%)
    8 / 15 (53.33%)
         occurrences all number
    1
    0
    34
    10
    45
    Hypoaesthesia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Lethargy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Loss of consciousness
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Migraine
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    12
    12
    Paraesthesia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    3
    1
    5
    Parosmia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Sleep deficit
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Typical aura without headache
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    0
    3
    Neutrophilia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Splenomegaly
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    Thrombocytosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Ear pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    External ear inflammation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    5
    0
    0
    5
    Eyelid oedema
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Photophobia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Scleral discolouration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    0
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Colitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Constipation
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    1
    1
    3
    Crohn's disease
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    0
    3
    Diarrhoea
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    4 / 7 (57.14%)
    6 / 15 (40.00%)
         occurrences all number
    1
    3
    0
    7
    11
    Dyspepsia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    2
    3
    Dysphagia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Inguinal hernia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    4
    5
    Rectal haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Toothache
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    4
    5
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    5 / 15 (33.33%)
         occurrences all number
    0
    0
    1
    7
    8
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    2
    1
    3
    Hepatitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    Hepatomegaly
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    2
    3
    Actinic keratosis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    1
    0
    2
    Eczema
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Idiopathic guttate hypomelanosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Leukoderma
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Purpura
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Rash
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    1
    0
    2
    Rosacea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin disorder
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin reaction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin striae
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    Renal colic
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Renal cyst
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    5 / 6 (83.33%)
    6 / 7 (85.71%)
    13 / 15 (86.67%)
         occurrences all number
    2
    1
    9
    16
    28
    Arthritis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    0
    1
    2
    Arthropathy
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    7 / 15 (46.67%)
         occurrences all number
    6
    1
    5
    4
    16
    Back pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    3 / 6 (50.00%)
    3 / 7 (42.86%)
    6 / 15 (40.00%)
         occurrences all number
    0
    0
    6
    4
    10
    Bursitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    2
    3
    Joint range of motion decreased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Joint stiffness
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    1
    0
    2
    Joint swelling
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    0
    2
    3
    Neck mass
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    5 / 7 (71.43%)
    6 / 15 (40.00%)
         occurrences all number
    0
    0
    3
    5
    8
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    0
    2
    Synovitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    0
    0
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    4 / 15 (26.67%)
         occurrences all number
    0
    1
    2
    1
    4
    Conjunctivitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Diarrhoea infectious
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Ear infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    2
    3
    Epididymitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    3
    3
    Furuncle
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Hordeolum
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Influenza
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    1
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    0
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    3 / 6 (50.00%)
    5 / 7 (71.43%)
    10 / 15 (66.67%)
         occurrences all number
    1
    3
    4
    8
    16
    Oral herpes
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    Pericoronitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Pharyngitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    4
    4
    Rhinitis
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    4 / 15 (26.67%)
         occurrences all number
    1
    1
    3
    1
    6
    Sputum purulent
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Tinea infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Tonsillitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    6 / 15 (40.00%)
         occurrences all number
    2
    1
    2
    3
    8
    Viral infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    Viral pharyngitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    4
    0
    0
    0
    4
    Increased appetite
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Iron deficiency
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Polydipsia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2015
    Amendment 1: 1. Receipt of any vector or gene transfer agent was added to the exclusion criteria. 2. The inclusion criterion definition of "severe" was changed from "FVIII levels have ever declined to 1 IU/dL or less" to a "FVIII baseline level is 1 IU/dL or less".
    26 May 2015
    Amendment 2: 1. HIV positive patients and patients with any evidence of active infection or any immunosuppressive disorder were excluded from the study. 2. Study stopping criteria were changed to temporarily stop enrollment when triggered, rather than allowing enrollment to continue while additional analyses were performed. 3. Requirement of a FVIII Treatment Washout period was removed.
    06 Nov 2015
    Amendment 3: 1. Changes to participant management, including the use of prophylactic CS, were made in the event that a participant develops ALT elevated 1.5x above his baseline after BMN 270 dosing. 2. Planned major surgery during the 16-week period following BMN 270 infusion was added as an exclusion criterion. 3. To reduce participant burden and limit blood volume requirements, a “smart rescreening” option was added for participants who are successfully screened but did not undergo Baseline assessments and Infusion within the 28 + 14 day window required by the protocol.
    02 Sep 2016
    Amendment 4: 1. The requirement for prophylactic CS was removed, and the threshold for starting reactive CS has been changed from ALT >= 1.5x baseline value to >= 1.5x ULN 2. Cohort 4 was added to the study 3. The enrollment stopping criterion related to serum ALT levels has been changed from a 5-fold increase from baseline after BMN 270 administration to: ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of BMN 270 in the absence of a definitive alternate etiology for the increase. 4. Changes to the frequency of vector shedding assessments were made (less frequently before Week 16, more frequently after Week 16). 5. The enrollment stopping criterion around vector shedding was modified. Enrollment in the study was to be halted if there is persistent detection (defined as 3 consecutive positive samples) of AAV vector DNA in the semen of a participant more than 52 weeks after BMN 270 administration. 6. Stopping criterion regarding Grade 2 related events has been changed to trigger a DRB review of safety data to determine whether an enrollment halt is warranted, rather than triggering an automatic enrollment halt. 7. Testing of von Willebrand factor antigen was added. 8. Testing of creatine phosphokinase (CPK) was added to routine blood chemistry assessments. 9. An exploratory Direct Thrombin assay was added.
    14 Feb 2017
    Amendment 5: 1. Frequency of local laboratory testing of ALT and FVIII during Weeks 1-20 was reduced. 2. The frequency of PBMC collection was increased. 3. Participants are now required to continue to provide semen samples for PCR analysis through Week 12, even if they have already had 3 consecutive negative results in semen prior to that timepoint. 4. Language was added to allow exploratory fractionation of collected samples (such as plasma, PBMCs, and red blood cells).
    21 Dec 2017
    Amendment 6: 1. The frequency of liver function and FVIII testing was increased during the Years 2-5 follow-up period. Testing will be performed every 4 weeks (+ 2 weeks) during Year 2, and every 6 weeks (± 2 weeks) during years 3-5. 2. Exploratory biomarker sampling was extended beyond Week 24 to permit further analysis of exploratory endpoints during the study.
    10 Oct 2018
    Amendment 7: 1. Efavirenz, lamivudine, and experimental hemophilia treatments (emicizumab, fitusiran, and concizumab) were added to the prohibited concomitant medications. 2. ABO testing was added. 3. Participants are being advised to abstain from blood or sperm donation after BMN 270 infusion until there is no further evidence of vector shedding. 4. Twice weekly evaluation of liver tests (LTs) was added during times when a participant’s ALT is >= 3x ULN. 5. An abbreviated visit schedule was made available during Years 2-5 for participants who are considered to have not responded to BMN 270 therapy to reduce participant burden in participants who had not achieved FVIII activity at least 5 IU/dL by Week 52. 6. Language concerning when to consider restarting FVIII prophylaxis following BMN 270 infusion was modified to emphasize that the decision should be made on clinical grounds (eg, bleeding episodes) rather than on FVIII activity levels.
    31 Jan 2019
    Amendment 8: 1. An optional liver biopsy substudy was added to the protocol.
    19 Jun 2020
    Amendment 9: 1. The duration of the study was extended from 5 years to 7 years post-infusion. 2. Language was added to permit the use of mobile nursing (MN) services, provided that the participant consents and that the site can implement the use of such services. 3. Lamivudine was removed as a prohibited medication. 4. The occurrence of events of Hy’s law was added as an event of special interest (EOSI) for purposes of expedited safety reporting. 5. The development of anti-FVIII inhibitory antibodies (inhibitors) was added as an EOSI for purposes of expedited safety reporting. 6. Language was added concerning the use of liver biopsy sample information from samples collected outside of the liver biopsy substudy. 7. Vector shedding and contraception use language was updated to change the determination of a “clear” result from negative to below the limit of detection, to better reflect regulatory guidance and to align 270-201 with other studies in the BMN 270 program. 8. Given possible travel and site restrictions caused by COVID-19, language was added to allow an investigator to document verbal confirmation by a participant that has signed and dated the written informed consent when the investigator cannot obtain a copy of the signed informed consent prior to initiating study procedures.
    24 Aug 2021
    Amendment 10: 1. Changes were made to enhance screening for potential malignancies (including hepatic cancers) after dosing with BMN 270. 2. Malignancy (except non-melanoma skin cancer) was added as an EOSI. 3. Language was added concerning the use of the SARS-CoV-2 vaccines. 4. Guidance concerning the use of reactive CS for ALT elevations was updated. 5. The definition of treatment failure was changed. 6. Frequency of several laboratory assessments after Year 1 was decreased: • FVIII Antigen BDD Assay reduced to Q12W after Year 1 through Year 5, and Q26W in Years 6-7. • AAV5 TAb reduced to End of Year Visits only after Year 1 • FVIII TAb reduced to End of Year Visits only after Year 1

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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