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    Clinical Trial Results:
    The SYNBioSe Study A proof-of-concept study involving synergetic B-cell imunnomodulation in patients with refractory systemic lupus erythematosus

    Summary
    EudraCT number
    2014-000488-42
    Trial protocol
    NL  
    Global end of trial date
    31 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Nov 2021
    First version publication date
    29 Nov 2021
    Other versions
    Summary report(s)
    Synbiose-1 publication

    Trial information

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    Trial identification
    Sponsor protocol code
    P14.065
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02284984
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Leiden University Medical Center
    Sponsor organisation address
    Albinusdreef 2, Leiden, Netherlands, 2333 ZA
    Public contact
    Teng, Leiden University Medical Center, 31 715268157, y.k.o.teng@lumc.nl
    Scientific contact
    Teng, Leiden University Medical Center, 31 715268157, y.k.o.teng@lumc.nl
    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
    06 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In this proof-of-concept study the primary objective is to assess whether a combination treatment ofrituximab (anti-CD20) and belimumab (anti-BAFF) will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation, which portentially forms the basis of a new therapeutic approach in severe SLE.
    Protection of trial subjects
    Within the study safety and toxicity monitoring includes: - the recording of adverse events according to WHO Toxicity criteria - evaluation of the time to immune reconstitution of B-cells - the recording of infectious events, with special interest for serious infections, including herpes zoster and opportunistic infections - Serious hypersensitivity or infusion reactions - Malignancy - Suicidal thought, intent or behaviour In accordance to Good Clinical Practice (GCP) guidelines, serious adverse events and SUSARs will be reported to the METC. In order to guarantee the feasibility of the study, the principal investigators will meet every 3 months to evaluate all adverse events (AEs). For every AE the severity and relation to the study treatment will be recorded. An advice will be formulated when an AE or a series of AEs necessitates a protocol change or a consideration to terminate the study. The METC will advise to continue the study, to implement protocol changes or to terminate this study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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
    31 subjects were screened of which 16 patients were eligible for the study. 1 patient dropped out during screening while treated with intravenous methylprednisolone as remission induction treatment

    Pre-assignment
    Screening details
    the majority of SLE patients was female and had severe disease with major organ involvement. The median [range] SLEDAI was 18 [6-29] and 13 patients (81%) had active lupus nephritis (LN) with a median [range] proteinuria of 2.3 g/day [1e8.2]. One patient had transverse myelitis at inclusion and presented with paralysis of the lower extremities.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    n.a.

    Arms
    Arm title
    overall trial
    Arm description
    -
    Arm type
    single arm

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will be intravenously treated with Rituximab 1000mg on day 0 and day 14. Before every infusion of Rituximab patients will receive intravenous methylprednisolon 100mg together with oral acetaminophen 1000 mg and intravenous Tavegil 2 mg

    Investigational medicinal product name
    belimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will be intravenously treated with Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks. No pre-medication is administered.

    Number of subjects in period 1
    overall trial
    Started
    15
    Completed
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    sixteen patients(88% female) were included, with median age of 31 years[19;51]. All patients had refractory disease, of which 12(80%) had active LN at baseline. One patient experienced severe hypogammaglobulinemia at week 8 after completion of methylprednisolone and RTX, therefore BLM treatment was not initiated. This patient was excluded from the long-term follow-up study.

    Reporting group values
    overall trial Total
    Number of subjects
    15 15
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    31 (19 to 51) -
    Gender categorical
    Units: Subjects
        Female
    14 14
        Male
    1 1
    Subject analysis sets

    Subject analysis set title
    All subjects
    Subject analysis set type
    Full analysis
    Subject analysis set description
    15 subjects who completed the study were included in the analysis

    Subject analysis sets values
    All subjects
    Number of subjects
    15
    Age categorical
    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)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    31 (19 to 51)
    Gender categorical
    Units: Subjects
        Female
    14
        Male
    1

    End points

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    End points reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Subject analysis set title
    All subjects
    Subject analysis set type
    Full analysis
    Subject analysis set description
    15 subjects who completed the study were included in the analysis

    Primary: Reduction of pathogenic autoantibodies

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    End point title
    Reduction of pathogenic autoantibodies [1]
    End point description
    Anti-dsDNA levels of 268AU/mL[50;827] at baseline decreased at week 24 to 29.6[0;104.5](p=0.02) equal to a median decrease of 87%[-100;+3].
    End point type
    Primary
    End point timeframe
    - Reduction of pathogenic autoantibodies, i.e.. a sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start.
    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: This is a single-arm study with immunological endpoint compared to each subject's baseline value. In accordance to mail correspondence: "Please note that inserting the statistical analysis related to an endpoint is not mandatory. You can delete the statistical analysis, however you need to provide a justification in the correct field"
    End point values
    All subjects
    Number of subjects analysed
    15
    Units: IU/mL
        median (full range (min-max))
    29.6 (0 to 104.5)
    Attachments
    Primary endpoint adsDNA
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the complete study from 0-104 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    WHO
    Dictionary version
    1
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    -

    Serious adverse events
    All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 15 (26.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Hospitalisation
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 15 (73.33%)
    Injury, poisoning and procedural complications
    Infusion-related reaction
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Immune system disorders
    Hypogammglobulinemia
    Additional description: IgG < 4.0 g/L
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Infections and infestations
    Minor infection
    Additional description: Upper respiratory tract 9 (60.0) Lower respiratory tract 3 (20.0) Urinary tract 4 (26.7) Urogenital infection 2 (13.3) Sinusitis 1 (6.7) Influenza 1 (6.7) Herpes simplex 1 (6.7)
         subjects affected / exposed
    8 / 15 (53.33%)
         occurrences all number
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    As defined by the study protocol, sujects that faile study treatment were withdrawn from the study and no further follow-up was available. In total 8/15 subjects completed 104 weeks. Hence, 7 subjects no complete follow-up of 104 weeks was recorded

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29636274
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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