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    Clinical Trial Results:
    Efficacy and safety of a human normal immunoglobulin product for intravenous administration (IVIg) in the treatment of dermatomyositis (DM) and polymyositis (PM): prospective, randomised, double-blind, placebo-controlled study

    Summary
    EudraCT number
    2005-002463-88
    Trial protocol
    DE   AT   IT   HU   CZ  
    Global end of trial date
    06 Sep 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Aug 2016
    First version publication date
    08 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    L00133 IV 301 (ORF)
    Additional study identifiers
    ISRCTN number
    ISRCTN87782942
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Orfagen
    Sponsor organisation address
    3, avenue Hubert Curien, Toulouse CEDEX 1, France, 31035
    Public contact
    Clinical project manager, Orfagen, info@orfagen.com
    Scientific contact
    Clinical project manager, Orfagen, info@orfagen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000415-PIP01-08
    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
    03 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jun 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of the IVIg product as adjunctive treatment to conventional glucocorticosteroids (GS) and immunosuppressors (IS) in dermatomyositis (DM) and polymyositis (PM) patients with insufficient improvement of muscle strength.
    Protection of trial subjects
    At baseline, according to the “note for guidance on the clinical investigation of human normal immunoglobulin for intravenous administration” (CPMP/BPWG/388/95 rev.1), a pre-treatment serum sample was performed and stored at – 70°C until the sponsor allows its destruction (after clinical study report edition), for possible testing.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Oct 2006
    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
    Austria: 5
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    37
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A run-in period (observational period where patients received conventional therapies) aimed at ensuring that patients entered the randomised, active part of the study, only if they insufficiently improve their muscle strength under those conventional therapies.

    Pre-assignment period milestones
    Number of subjects started
    67 [1]
    Number of subjects completed
    44

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 6
    Reason: Number of subjects
    Inclusion period closed: 4
    Reason: Number of subjects
    Not enrollable in the following study period: 9
    Reason: Number of subjects
    Consent withdrawn by subject: 2
    Reason: Number of subjects
    Concomitant disease: 1
    Reason: Number of subjects
    Wrong diagnosis: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Subjects started a pre-assignement period that aimed at ensuring that patients entered the randomised, active part of the study only if they insufficiently improve their muscle strength under conventional thérapies. Enrolled subjects are defined as subjects who received at least once one of the study treatment
    Period 1
    Period 1 title
    Study Period I
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    L0133 Group
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    L0133
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2g/Kg (40 ml/Kg) per month, delivered in 2 consecutive days (1g/Kg daily or 20 ml/Kg daily). Test product had to be infused intravenously at an initial rate of 0.46 – 0.92 mL/Kg/hr (10 –20 drops per minute) for 20 – 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 1.85 mL/Kg/hr (40 drops / minute) for the remainder of the infusion. The entire time necessary to infuse 40 mL/Kg daily (or 1 mg/Kg daily of IVIg product) is about 11h (30 minutes at the rate of 0.46 – 0.92 mL/Kg/hr and about 10h30 at the rate of 1.85 mL/Kg/hr). Patients with abnormal renal parameters, history of myocardial and stroke and with blood viscosity abnormalities received the test product over 5 consecutive days (0.4 g/Kg daily or 8 ml/Kg daily).

    Arm title
    Placebo Group
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (NaCl 9‰) 40ml/Kg per month, delivered in 2 consecutive days (20mL/Kg daily). Patients with abnormal renal parameters, history of myocardial and stroke and with blood viscosity abnormalities will receive the test product during 5 consecutive days (8mL/Kg daily).

    Number of subjects in period 1
    L0133 Group Placebo Group
    Started
    22
    22
    Completed
    21
    22
    Not completed
    1
    0
         Adverse event, serious fatal
    1
    -
    Period 2
    Period 2 title
    Study period II
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    L0133 / L0133 Group
    Arm description
    Patients having received 6 months of active treatment (3 months of Period I, followed by 3 months of Period II)
    Arm type
    Experimental

    Investigational medicinal product name
    L0133
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2g/Kg (40 ml/Kg) per month, delivered in 2 consecutive days (1g/Kg daily or 20 ml/Kg daily). Test product had to be infused intravenously at an initial rate of 0.46 – 0.92 mL/Kg/hr (10 –20 drops per minute) for 20 – 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 1.85 mL/Kg/hr (40 drops / minute) for the remainder of the infusion. The entire time necessary to infuse 40 mL/Kg daily (or 1 mg/Kg daily of IVIg product) is about 11h (30 minutes at the rate of 0.46 – 0.92 mL/Kg/hr and about 10h30 at the rate of 1.85 mL/Kg/hr). Patients with abnormal renal parameters, history of myocardial and stroke and with blood viscosity abnormalities received the test product over 5 consecutive days (0.4 g/Kg daily or 8 ml/Kg daily).

    Arm title
    L0133 / Placebo Group
    Arm description
    Patients having received 3 months of active treatment [Placebo during Period I (3months), followed by active during Period II (3 months)].
    Arm type
    Experimental

    Investigational medicinal product name
    L0133
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2g/Kg (40 ml/Kg) per month, delivered in 2 consecutive days (1g/Kg daily or 20 ml/Kg daily). Test product had to be infused intravenously at an initial rate of 0.46 – 0.92 mL/Kg/hr (10 –20 drops per minute) for 20 – 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 1.85 mL/Kg/hr (40 drops / minute) for the remainder of the infusion. The entire time necessary to infuse 40 mL/Kg daily (or 1 mg/Kg daily of IVIg product) is about 11h (30 minutes at the rate of 0.46 – 0.92 mL/Kg/hr and about 10h30 at the rate of 1.85 mL/Kg/hr). Patients with abnormal renal parameters, history of myocardial and stroke and with blood viscosity abnormalities received the test product over 5 consecutive days (0.4 g/Kg daily or 8 ml/Kg daily).

    Number of subjects in period 2
    L0133 / L0133 Group L0133 / Placebo Group
    Started
    21
    22
    Completed
    21
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    L0133 Group
    Reporting group description
    -

    Reporting group title
    Placebo Group
    Reporting group description
    -

    Reporting group values
    L0133 Group Placebo Group Total
    Number of subjects
    22 22 44
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    18 19 37
        From 65-84 years
    4 3 7
    Gender categorical
    Units: Subjects
        Female
    15 15 30
        Male
    7 7 14

    End points

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    End points reporting groups
    Reporting group title
    L0133 Group
    Reporting group description
    -

    Reporting group title
    Placebo Group
    Reporting group description
    -
    Reporting group title
    L0133 / L0133 Group
    Reporting group description
    Patients having received 6 months of active treatment (3 months of Period I, followed by 3 months of Period II)

    Reporting group title
    L0133 / Placebo Group
    Reporting group description
    Patients having received 3 months of active treatment [Placebo during Period I (3months), followed by active during Period II (3 months)].

    Primary: Treatment Response

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    End point title
    Treatment Response
    End point description
    Muscle strength intensity: as defined by the modified BMRC index which assigns the grades 0 to 11 to indicate the level of muscle power in 8 muscle groups (neck flexors, trapezius, deltoid, biceps, psoas, maximus and medius gluteus, and quadriceps). Treatment response was defined as an improvement from baseline of BMRC score at the end of Period I as follows: - Patients with baseline BMRC score between 24 and 40 included: at least 18 points improvement, - Patients with baseline BMRC score between 40.5 and 56 included: at least 12 points improvement, - Patients with baseline BMRC score between 56.5 and 72 included: at least 8 points improvement, Patients prematurely switched from Period I to Period II due to BMRC index aggravation were considered as non-responders.
    End point type
    Primary
    End point timeframe
    End of Period I, i.e. 84 days or earlier in case of significant deterioration of the muscle strength.
    End point values
    L0133 Group Placebo Group
    Number of subjects analysed
    22
    22
    Units: Patients
    8
    6
    Statistical analysis title
    Treatment response at the end of Period I
    Comparison groups
    L0133 Group v Placebo Group
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5174
    Method
    Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to study end
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Period I - L0133 Group
    Reporting group description
    -

    Reporting group title
    Period I - Placebo Group
    Reporting group description
    -

    Reporting group title
    Period II - L0133 / L0133 Group
    Reporting group description
    -

    Reporting group title
    Period II - L0133 / Placebo Group
    Reporting group description
    -

    Serious adverse events
    Period I - L0133 Group Period I - Placebo Group Period II - L0133 / L0133 Group Period II - L0133 / Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Period I - L0133 Group Period I - Placebo Group Period II - L0133 / L0133 Group Period II - L0133 / Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 22 (68.18%)
    12 / 22 (54.55%)
    11 / 21 (52.38%)
    14 / 22 (63.64%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Condition aggravated
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Face oedema
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sternal fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Accident
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Platelet count increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cardiac disorders
    Tachyarrhythmia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Congenital, familial and genetic disorders
    Congenital anomaly
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Essential tremor
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Autonomic nervous system imbalance
         subjects affected / exposed
    5 / 22 (22.73%)
    2 / 22 (9.09%)
    1 / 21 (4.76%)
    5 / 22 (22.73%)
         occurrences all number
    6
    4
    1
    8
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cataract
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Glaucoma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Renal and urinary disorders
    Urge incontinence
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    0
    1
    Pigmentation disorder
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Swelling face
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Purpura
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Adrenal disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Meningitis aseptic
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    1
    2
    Bronchitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2006
    Clarification / modifications of the study protocol following local Ethics Committeees assessment and National Authorities assessment.
    22 Dec 2006
    Modification in the pre-assignment Period. Changes in MTX dosage
    11 Sep 2007
    Modifications in the pre-assignement period. Extension of the Study period
    06 May 2008
    Co-investigators' changes in 4 centers. Addition of 2 centers.
    27 Oct 2008
    Modifications in the pre-assignement period. New study protocol template. Helsinki declaration update. Extension of the study period.
    06 May 2010
    Extension of study period
    06 Jan 2011
    Change of sponsor address

    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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