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    Clinical Trial Results:
    Optimal utilisation of biologic drugs in Behçet’s Disease: a randomised controlled trial of infliximab (IFX) verses alpha interferon (aIFN), with genotyping and metabolomic profiling, towards a stratified medicines approach to treatment.

    Summary
    EudraCT number
    2014-005390-36
    Trial protocol
    GB  
    Global end of trial date
    21 Sep 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Oct 2021
    First version publication date
    10 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UoL001109
    Additional study identifiers
    ISRCTN number
    ISRCTN49793874
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    Clinical Directorate 2nd Floor, Block C, Waterhouse Building 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Miss Charlotte Rawcliffe, Liverpool Clinical Trials Centre, +44 151 794 8167, c.rawcliffe@liverpool.ac.uk
    Scientific contact
    Miss Charlotte Rawcliffe, Liverpool Clinical Trials Centre, +44 151 794 8167, c.rawcliffe@liverpool.ac.uk
    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
    20 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to underpin clinically effective prescribing of the biologic drugs infliximab (IFX) and alpha interferon (aIFN) for Behçet’s Disease (BD). The primary objective of the study is to undertake a randomised controlled trial to compare IFX versus aIFN in patients with BD who are unresponsive to standard oral therapy.
    Protection of trial subjects
    Consent was obtained prior to each patient participating in the trial, after a full explanation had been given of the treatment options, including the conventional and generally accepted methods of treatment. Age and stage-of-development specific Patient Information and Consent Leaflets were also implemented and patient assent obtained where appropriate. The right of patients to refuse their consent to participate in the trial without giving reasons would have been respected. The study also had a Trial Steering Committee (TSC) and Independent Safety and Data Monitoring Committee (ISDMC). The ISDMC was responsible for safeguarding the interests of trial participants, assessing the safety and efficacy of the interventions during the trial and for monitoring the overall progress and conduct of the clinical trial. The TSC was responsible for monitoring and supervising the progress of the trial, considering recommendations from the IDSMC and advising the TMG on all aspects of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2015
    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
    United Kingdom: 79
    Worldwide total number of subjects
    79
    EEA total number of subjects
    79
    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)
    78
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment took place over 43 months from 8recruiting centres, the first patient was randomised on 21st June 2016 and the last patient was randomised on 18th February 2020.

    Pre-assignment
    Screening details
    161 patients were screened prior to randomisation. 82 patients did not enter the study, 58 of which were due to not meeting the inclusion/exclusion criteria, 4 declined to participate and 10 were due to 'Other' reasons.

    Period 1
    Period 1 title
    Intervention Phase (Overall Period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    There was partial blinding in this study. Assessing clinicians were blinded to therapy, documenting the disease activity and potential AEs. Patients, nurses and the clinician responsible for prescribing the study drug were not blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Infliximab
    Arm description
    Infliximab Intravenous Infusion (Remicade)
    Arm type
    Experimental

    Investigational medicinal product name
    Infliximab
    Investigational medicinal product code
    L04AB02
    Other name
    Infliximab Intravenous Infusion
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Patients received Remicade at a standard dose of 5mg/kg at weeks 0, 2 and 6 as loading then every 8 weeks for the remaining length of the trial.

    Arm title
    Alpha interferon
    Arm description
    Alpha interferon (Roferon-A) pre-filled syringes
    Arm type
    Experimental

    Investigational medicinal product name
    Interferon alfa-2a
    Investigational medicinal product code
    L03AB04
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received Remicade at a standard dose of 5mg/kg at weeks 0, 2 and 6 as loading then every 8 weeks for the remaining length of the trial.

    Number of subjects in period 1 [1]
    Infliximab Alpha interferon
    Started
    37
    37
    Completed
    31
    29
    Not completed
    6
    8
         Adverse event, non-fatal
    1
    2
         Other
    3
    2
         Clinician decision (Not adverse event)
    1
    2
         Inadequate response
    1
    1
         Reason missing
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 5 Patients withdrew consent and data are presented on 74 patients included in the final statistical analysis report.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Infliximab
    Reporting group description
    Infliximab Intravenous Infusion (Remicade)

    Reporting group title
    Alpha interferon
    Reporting group description
    Alpha interferon (Roferon-A) pre-filled syringes

    Reporting group values
    Infliximab Alpha interferon Total
    Number of subjects
    37 37 74
    Age categorical
    Number of patients to fall into the age categories defined below.
    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 (inter-quartile range (Q1-Q3))
    38.9 (31.8 to 48.7) 39.3 (31.6 to 46.5) -
    Gender categorical
    Units: Subjects
        Female
    24 26 50
        Male
    13 11 24
    Ethnicity
    Units: Subjects
        White - British
    34 30 64
        Caribbean
    0 1 1
        Black - Other
    1 0 1
        Other
    0 1 1
        White - European
    1 1 2
        White - Other
    0 2 2
        White and Black Caribbean
    0 1 1
        Pakistani
    1 1 2
    Smoking Status
    Units: Subjects
        Missing
    0 1 1
        Current Smoker
    8 6 14
        Ex-smoker
    17 9 26
        Never smoked
    12 21 33
    Alcohol Status
    Units: Subjects
        Missing
    0 1 1
        None
    14 11 25
        Sporadic
    18 18 36
        Regular
    5 7 12
    Steriod Use
    Units: Subjects
        Missing
    1 0 1
        No
    18 18 36
        Yes
    18 19 37
    Ocular
    Units: Subjects
        Missing
    11 8 19
        Primary
    10 7 17
        Other
    16 22 38
    Oral
    Units: Subjects
        Missing
    12 7 19
        Primary
    12 15 27
        Other
    13 15 28
    Genital
    Units: Subjects
        Missing
    12 7 19
        Primary
    11 14 25
        Other
    14 16 30
    Musculoskeletal
    Units: Subjects
        Missing
    16 13 29
        Primary
    10 10 20
        Other
    11 14 25
    Previous septic arthritis in the last 12 months
    Units: Subjects
        No
    37 37 74
    Previous septic arthritis in prosthetic joint ever
    Units: Subjects
        No
    37 37 74
    Malignancy
    Units: Subjects
        No
    36 37 73
        Yes
    1 0 1
    Urine catheter
    Units: Subjects
        No
    37 37 74
    Heart Failure
    Units: Subjects
        No
    37 37 74
    Skin Rash
    Units: Subjects
        No
    23 23 46
        Yes
    14 14 28

    End points

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    End points reporting groups
    Reporting group title
    Infliximab
    Reporting group description
    Infliximab Intravenous Infusion (Remicade)

    Reporting group title
    Alpha interferon
    Reporting group description
    Alpha interferon (Roferon-A) pre-filled syringes

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Set on the Intention to treat principle retaining patients in their randomised groups irrespective of any protocol deviations.

    Primary: Modified Behçet’s Disease Activity Index (BDAI) after 3 months of treatment

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    End point title
    Modified Behçet’s Disease Activity Index (BDAI) after 3 months of treatment
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 3 months of treatment
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    35
    34
    Units: Score
        median (inter-quartile range (Q1-Q3))
    -2 (-3.5 to -0.5)
    -2 (-4 to 0)
    Statistical analysis title
    mod BDAI - baseline to 3 months
    Statistical analysis description
    A Bayesian Linear Regression Model
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Bayesian Linear Regression
    Parameter type
    alone parameter
    Point estimate
    0.13
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25

    Secondary: Modified Behçet’s Disease Activity Index (BDAI) after 6 months of treatment

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    End point title
    Modified Behçet’s Disease Activity Index (BDAI) after 6 months of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months of treatment.
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    32
    32
    Units: BDAI
        median (inter-quartile range (Q1-Q3))
    -1.5 (-4 to 0)
    -3 (-5.25 to -1)
    Statistical analysis title
    Modified BDAI - baseline to 6 months
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    Method
    Bayesian Linear Regression
    Parameter type
    Model parameter
    Point estimate
    0.05
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [1] - Bayesian linear regression Model

    Secondary: Original BDAI after 3 months of treatment

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    End point title
    Original BDAI after 3 months of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    35
    34
    Units: BDAI
        median (inter-quartile range (Q1-Q3))
    -1 (-2 to 0.5)
    -1 (-2 to 0)
    Statistical analysis title
    Original BDAI -Baseline to 3 month
    Comparison groups
    Alpha interferon v Infliximab
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Bayesian Linear Regression
    Parameter type
    Linear regression parameter
    Point estimate
    0.12
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25

    Secondary: Significant improvement in vitreous haze after 3 months

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    End point title
    Significant improvement in vitreous haze after 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    3 months of treatment.
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    37
    37
    Units: Vitreous haze score
        number (not applicable)
    0
    1
    No statistical analyses for this end point

    Secondary: Significant improvement in ulcer severity score (USS) after 3 and 6 months of treatment

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    End point title
    Significant improvement in ulcer severity score (USS) after 3 and 6 months of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    19
    25
    Units: Ulcer severity score
        median (inter-quartile range (Q1-Q3))
    -13.0 (-25.0 to 0)
    -7.0 (-21.0 to 0)
    Statistical analysis title
    Ulcer severity score
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.76
    Method
    Fisher exact
    Parameter type
    Exact test - non aplicable
    Confidence interval
    Notes
    [2] - Test performed is a Fisher exact test based on patients with at least 20% reduction.

    Secondary: Significant improvement in number of genital ulcers after 3 and 6 months of treatment

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    End point title
    Significant improvement in number of genital ulcers after 3 and 6 months of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    11
    10
    Units: genital ulcers
        median (inter-quartile range (Q1-Q3))
    -17 (-24 to 0)
    -11 (-29 to 0)
    Statistical analysis title
    genital ulcers, baseline to 3 months
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Exact test - no parameter estimate
    Confidence interval
    Notes
    [3] - Fisher test performed on proportion with at least 20% reduction

    Secondary: Significant improvement in Likert pain score after 3 and 6 months of treatment

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    End point title
    Significant improvement in Likert pain score after 3 and 6 months of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    13
    16
    Units: Likert pain score
        median (inter-quartile range (Q1-Q3))
    -1 (-2 to 0)
    -0.5 (-2.5 to 1.0)
    Statistical analysis title
    Likert paint score - baseline to 3 months
    Statistical analysis description
    Analysis conducted using a fishers test based on the proportion with at least 20% improvement.
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Exact test - no parameter specified
    Confidence interval

    Secondary: Use of prednisolone (or equivalent glucocorticoid) at 6 months

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    End point title
    Use of prednisolone (or equivalent glucocorticoid) at 6 months
    End point description
    Analyses performed on the
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    37
    37
    Units: Patients
    12
    11
    Statistical analysis title
    Use of prednisolone
    Statistical analysis description
    Analysis conducted using a logistical regression model including treatment, timepoints and a treatment by timepoints interaction
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    74
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.891
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    30.477
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.629

    Secondary: Quality of life scores at 3 and 6 months compared to baseline

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    End point title
    Quality of life scores at 3 and 6 months compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    33
    29
    Units: EQ5D VAS
        median (inter-quartile range (Q1-Q3))
    10 (0 to 20)
    10 (-5 to 20)
    Statistical analysis title
    Quality ofLife (EQ5D)
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8318
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Exact test - no parameter specified
    Confidence interval

    Secondary: Physician’s Global Assessment of disease activity at 3 and 6 months

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    End point title
    Physician’s Global Assessment of disease activity at 3 and 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    Infliximab Alpha interferon
    Number of subjects analysed
    31
    29
    Units: Disease Activity score
        median (inter-quartile range (Q1-Q3))
    -2.0 (-4.0 to -1.0)
    -1.0 (-3.0 to 0.0)
    Statistical analysis title
    Clinician perception disease activity
    Comparison groups
    Infliximab v Alpha interferon
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.421
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    non-parametric test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Full study period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Infliximab
    Reporting group description
    -

    Reporting group title
    aIFN
    Reporting group description
    -

    Serious adverse events
    Infliximab aIFN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 37 (5.41%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure inadequately controlled
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Infliximab aIFN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 37 (32.43%)
    17 / 37 (45.95%)
    Investigations
    ALT Increased
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 37 (8.11%)
         occurrences all number
    2
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 37 (10.81%)
         occurrences all number
    3
    4
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 37 (5.41%)
    10 / 37 (27.03%)
         occurrences all number
    3
    14
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 37 (10.81%)
         occurrences all number
    3
    6
    flu like symptoms
         subjects affected / exposed
    2 / 37 (5.41%)
    5 / 37 (13.51%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 37 (16.22%)
         occurrences all number
    2
    6
    Nausea
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 37 (8.11%)
         occurrences all number
    3
    4
    Vomiting
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 37 (8.11%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Chest Infection
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Infections and infestations
    Chest Infection
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 37 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Feb 2015
    Several changes to the protocol as part of the MHRA approval, to include; • A change to the wording of the main exclusion criteria (section 1 and section 5.2) and precautions required (section 7.7.2) to detail the requirements for participants of child bearing potential to use effective contraception. • A change to the schedule of assessments (section 8) and changes to the glossary were made. • Patient information sheet was amended to reduce the amount of blood sample required.
    17 Dec 2015
    • General - updated trial start date. • Sections 1 and 5.2 – corrections to the objectives of the trial and confirmation of the number of trial sites. • Exclusion criteria updated to include Multiple Sclerosis and HIV patients. • Section 4.1 – overall design updated to reflect timing of assessments as per standard care practice. • Section 4.3 – secondary end points changes to genital ulcer measure with a reduction of 20% considered to be clinically significant. • Section 6 – Enrolment/baseline update to screening log information. Update to randomisation instructions relating to the online enrolment and randomisation system TARDIS. • Section 6.1- screening assessments to be completed within 35 days prior to the first dose of treatment. HIV added. • Section 6.1- symptom directed assessment removed from baseline assessment and the inclusion of a chest X-ray. Addition of screening for alterations in mood/suicide ideation (as known to be a side effect of Roferon treatment). • Section 7- Study treatment, the standardised use of methotrexate has been removed from the trial for clarity. Concomitant immunosuppressants will now be administered at the clinician discretion on a case by case basis. • Section 8.1 amendments were made to the schedule of assessments. • Section 8.2 Electronic CRF updated relating to assessment of efficacy. • Section 8.4.2.2. Further information detailing the collection of urine samples for metabolomics analyses. • Section 8.7. Trial closure has been amended as being when the last patient has completed their final study visit. • Section 9.2. Updated procedure for generating randomisation code lists. • Section 13. Update to clarify the method of data capture as utilising electronic CRF’s. • Quality control procedures at site for primary and secondary endpoints as a consequence of the use of an eCRF platform at sites. • The removal of minimisation techniques for randomisation. • Section 16. Oversight committee members’ inf
    25 Jan 2016
    Several changes to the protocol as part of the MHRA approval, to include; • A change to the wording of the overall design (section 4.1) as per the ISDMC recommendation. New wording; This is a randomised, two-arm, parallel, open-label design comparing the efficacies of infliximab vs alpha interferon. The population is patients with refractory disease eligible for the first biologic drug. • Primary outcome wording changed to match section 9 of the protocol. New wording; Primary Outcome: Modified Behçet’s Disease Activity Index (BDAI) after 3 months of treatment (Week 12 visit), with 20% change in means being defined as the zone of equivalence of treatment.
    28 Oct 2016
    • Change to randomisation directions. • Section 7.2.2 – “Target dose of azathioprine is 2.5 mg/kg” added as per ISDMC recommendation. • Section 7.2.1 – Update to provide sites with more information about the IMP. • Section 7.3.2 – Wording added as per ISDMC recommendation “Immunosuppressant’s will be discontinued in Arm B”. • Section 8.1 – Schedule of assessments – New column added to detail the assessments required at Week 36 for patients who swap treatment arms at 12 weeks. • Section 8.2 – Wording changed to include the mandatory visit (Week 36) for patients who swap treatment at Week 12. • Section 8.4.3.2 – Change to amount of urine to be collected at each visit. • Section 9.2 - Additional details were provided in order to make the randomisation procedure more clearly to the reader. • Section 9.3.2 - Week 26 replaced with Week 24. • Section 9.6.1 - Priors were given explicitly as this was missed in the previous version of the protocol. • Section 9.6.2 - Corrected sample amount and added “at each trial visit” to make the collection clearer • Changes to Remicade SmPC. • Changes to Roferon SmPC for notification purposes only • Update to Staff members. Patient Information Sheet • IRAS number added – to comply with HRA guidance. • New wording to make clear that urine sample is required at visit Week 36 if patients swap treatment at Week 12. Informed Consent Form • IRAS number added – to comply with HRA guidance. • New wording to make clear that urine sample is required at visit Week 36 if patients swap treatment at Week 12. GP Letter • IRAS number added – to comply with HRA guidance
    16 May 2017
    Exclusion Criteria added (section 5.2) • Point 8 Evidence for active Tuberculosis (TB testing using local standard practise) • New Wording Section 6.1 – If in the opinion of the Principle Investigator, the patient requires a biologic drug, whether a prior immunosuppressive agent has been given or not, that the patient will be eligible for a biologic under normal standard of care and SSBEH_D054/01 Bio Behçet’s Final Statistical Analysis Report 20/09/2021 Page 14 of 73 therefore may be included in the trial. (Patients previously receiving a prior biologic agent will, currently, not be eligible for the trial) If, in the opinion of the Principle Investigator, the disease is so severe that the benefit of starting the biologic before receiving all screening test results outweighs the risk of not starting it, that patient will remain eligible for the trial, in line with normal practise. • New Wording Section 4.1 – This is a randomised, two-arm, parallel design comparing the efficacies of the infliximab vs alpha interferon. (Previous Wording – This is a randomised, two-arm, parallel, open label design comparing the efficacies of infliximab vs alpha interferon • New Wording Section 6.1 – Section 6.1 Eligibility assessments for entry into the trial will be performed within 42 days prior to the first dose of treatment.(Previous Wording- Eligibility assessments for entry into the trial will be performed within 35 days prior to the first dose of treatment). • Changes to the wording randomisation procedure – New Wording After a patient has been screened and their details entered onto MACRO 4 database by the trial site the randomisation can be performed on the TARDIS website. The clinician must confirm eligibility by signing a paper eligibility Case Report Form (CRF) which trial site staff will email or fax to LCTU along with a copy of the Informed Consent Form. This will confirm eligibility of the patient along with the stratification factors, which will

    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.
    The primary outcome is conducted using a Bayesian approach using priors derived from clinical expertise. As such, the primary outcome is assessed based on a posterior distribution which accounts for both prior information and study data.
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    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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