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    Clinical Trial Results:
    A Double Blind, Randomized, Placebo Controlled, Multi-Center Trial of Anti-TNFα Chimeric Monoclonal Antibody (Infliximab, Remicade®) in Combination with Methotrexate in Patients with Very Early Inflammatory Arthritis

    Summary
    EudraCT number
    2006-002787-26
    Trial protocol
    AT   NL   DE   ES   GR   GB  
    Global end of trial date
    31 Aug 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Nov 2018
    First version publication date
    01 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DINORA
    Additional study identifiers
    ISRCTN number
    ISRCTN21272423
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria, 1090
    Public contact
    Internal Medicine III, Rheumatology, Medical University of Vienna, 043 14040043010, josef.smolen@wienkav.at
    Scientific contact
    Internal Medicine III, Rheumatology, Medical University of Vienna, +43 14040043010, josef.smolen@wienkav.at
    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
    23 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to demonstrate that patients with very early arthritis have a higher probability of achieving a state of clinical remission at end of infliximab therapy if treated with infliximab plus MTX when compared to MTX monotherapy or supportive treatment only.
    Protection of trial subjects
    Personal data pseudonymized.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 May 2007
    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
    Spain: 1
    Country: Number of subjects enrolled
    Netherlands: 28
    Country: Number of subjects enrolled
    Austria: 29
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    70
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were eligible if they had symptom duration of 2 to 16 weeks with synovial swelling in at least 2 joints (66 joint count) of which a minimum of one joint must have been a metacarpophalangeal, proximal interpahalangeal or a metatarsophalangeal (MTP) joint. However, two MTP-joints were considered not sufficient for inclusion.

    Pre-assignment
    Screening details
    Two screening visits for symptom duration which must have been 2 weeks at least (subjects did not receive study treatment before 12 weeks of symptom duration) and 16 weeks at most. The 16 weeks included an observation period of at least 2 weeks, as reported by the subject.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor
    Blinding implementation details
    A “double-dummy-like” administration of study medication was pursued. Every patient was treated with tablets containing methotrexate or placebo and with infusions containing infliximab or placebo. The study medication code was kept blinded in patients who discontinued prematurely.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    IFX+MTX
    Arm description
    Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)
    Arm type
    Experimental

    Investigational medicinal product name
    Anti-TNFα chimeric monoclonal antibody infliximab (IFX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ifliximab is a chimeric IgG1 monoclonal antibody manufactured from a recombinant cell line cultured by continuous perfusion. Infliximab (IFX) was administered by intravenous infusions at a dose of 3 mg/kg at 0, 2 and 6 weeks, and at 5 mg/kg every 8 weeks thereafter.

    Investigational medicinal product name
    Methotrexate (MTX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate (MTX) was dosed orally according to a rapid dose escalation scheme: start at 10 mg/week and increased to 25 mg/week in three steps with 2-week intervals except in cases of intolerance.

    Arm title
    MTX monotherapy
    Arm description
    Methotrexate (MTX) monotherapy
    Arm type
    Experimental

    Investigational medicinal product name
    Methotrexate (MTX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate (MTX) was dosed orally according to a rapid dose escalation scheme: start at 10 mg/week and increased to 25 mg/week in three steps with 2-week intervals except in cases of intolerance.

    Arm title
    Placebo
    Arm description
    Placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Intravenous use
    Dosage and administration details
    A “double-dummy-like” administration of study medication was pursued. Every patient was treated with tablets containing methotrexate (MTX) or placebo and with infusions containing infliximab (IFX) or placebo.

    Number of subjects in period 1
    IFX+MTX MTX monotherapy Placebo
    Started
    38
    36
    16
    Completed
    14
    11
    7
    Not completed
    24
    25
    9
         Unable to comply with protocol
    -
    2
    -
         Accidental unblinding
    -
    -
    1
         Unknown
    3
    2
    -
         Lack of efficacy
    12
    9
    6
         Adverse event, non-fatal
    2
    1
    1
         Consent withdrawn by subject
    6
    9
    1
         Lost to follow-up
    1
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IFX+MTX
    Reporting group description
    Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)

    Reporting group title
    MTX monotherapy
    Reporting group description
    Methotrexate (MTX) monotherapy

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group values
    IFX+MTX MTX monotherapy Placebo Total
    Number of subjects
    38 36 16 90
    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
        arithmetic mean (standard deviation)
    52.1 ± 14.1 52.9 ± 14 54.4 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    26 28 9 63
        Male
    12 8 7 27

    End points

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    End points reporting groups
    Reporting group title
    IFX+MTX
    Reporting group description
    Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)

    Reporting group title
    MTX monotherapy
    Reporting group description
    Methotrexate (MTX) monotherapy

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Primary: Clinical remission

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    End point title
    Clinical remission
    End point description
    End point type
    Primary
    End point timeframe
    At week 54
    End point values
    IFX+MTX MTX monotherapy Placebo
    Number of subjects analysed
    38 [1]
    36 [2]
    16 [3]
    Units: Number of patients in clinical remission
        Clinical remission
    12
    5
    0
        No clinical remission
    26
    31
    16
    Notes
    [1] - Intention to treat
    [2] - Intention to treat
    [3] - Intention to treat
    Statistical analysis title
    Primary endpoint
    Comparison groups
    IFX+MTX v MTX monotherapy v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During study period
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Conducted by Janssen
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    IFX+MTX
    Reporting group description
    Anti-TNFα chimeric monoclonal antibody infliximab (IFX) in combination with methotrexate (MTX)

    Reporting group title
    MTX monotherapy
    Reporting group description
    Methotrexate (MTX) monotherapy

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Serious adverse events
    IFX+MTX MTX monotherapy Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 38 (15.79%)
    3 / 36 (8.33%)
    3 / 16 (18.75%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertensive episode one hour after the last infusion with study drug
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haematuria, followed by a diagnosis of bladder cancer
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction more than half a year after last study drug
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Fainted during blood collection, prior to administration of study drug
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Significant flare of disease activity
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Biliary pancreatitis in a time after the study medication
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Significantly raised transaminase levels
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MTX pneumonitis (opportunistic) infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.03%
    Non-serious adverse events
    IFX+MTX MTX monotherapy Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 38 (89.47%)
    32 / 36 (88.89%)
    13 / 16 (81.25%)
    Vascular disorders
    Diseases of ciculatory system
         subjects affected / exposed
    6 / 38 (15.79%)
    7 / 36 (19.44%)
    3 / 16 (18.75%)
         occurrences all number
    8
    10
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Social circumstances
    External causes of morbidity
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Diseases of genitourinary system (pregnancy, childbirth and puerperium)
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 36 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    2
    4
    0
    General disorders and administration site conditions
    Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified
         subjects affected / exposed
    11 / 38 (28.95%)
    11 / 36 (30.56%)
    5 / 16 (31.25%)
         occurrences all number
    21
    22
    6
    Injury, poisoning and procedural complications
    Injury, poisoning and certain other consequences of external causes
         subjects affected / exposed
    6 / 38 (15.79%)
    3 / 36 (8.33%)
    0 / 16 (0.00%)
         occurrences all number
    10
    3
    0
    Blood and lymphatic system disorders
    Disease of blood and blood-forming organs and certain disorders involving the immune mechanism
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Diseases of respiratory system
         subjects affected / exposed
    23 / 38 (60.53%)
    16 / 36 (44.44%)
    4 / 16 (25.00%)
         occurrences all number
    33
    32
    5
    Nervous system disorders
    Disease of the nervous system
         subjects affected / exposed
    6 / 38 (15.79%)
    9 / 36 (25.00%)
    2 / 16 (12.50%)
         occurrences all number
    9
    13
    2
    Eye disorders
    Diseases of the eye and adnexa
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    3
    0
    Skin and subcutaneous tissue disorders
    Diseases of the skin and subcutaneous tissue
         subjects affected / exposed
    12 / 38 (31.58%)
    8 / 36 (22.22%)
    5 / 16 (31.25%)
         occurrences all number
    18
    14
    8
    Musculoskeletal and connective tissue disorders
    Diseases of musculoskeletal system and connective tissue
         subjects affected / exposed
    15 / 38 (39.47%)
    9 / 36 (25.00%)
    6 / 16 (37.50%)
         occurrences all number
    26
    16
    8
    Endocrine disorders
    Endocrine, nutritional and metabolic diseases
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 36 (13.89%)
    2 / 16 (12.50%)
         occurrences all number
    2
    7
    2
    Metabolism and nutrition disorders
    Diseases of the digestive system
         subjects affected / exposed
    15 / 38 (39.47%)
    17 / 36 (47.22%)
    5 / 16 (31.25%)
         occurrences all number
    29
    35
    10
    Infections and infestations
    Infections
         subjects affected / exposed
    19 / 38 (50.00%)
    9 / 36 (25.00%)
    3 / 16 (18.75%)
         occurrences all number
    30
    22
    4

    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.
    None reported
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