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    Clinical Trial Results:
    A multi-center, double-blind, randomized, placebo-controlled, dose-finding study in patients with active rheumatoid arthritis incompletely controlled on stable MTX doses to investigate efficacy and safety of SC BT061

    Summary
    EudraCT number
    2010-018485-24
    Trial protocol
    CZ   ES   DE   HU   LV  
    Global end of trial date
    16 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Dec 2021
    First version publication date
    25 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    979
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01481493
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biotest AG
    Sponsor organisation address
    Landsteinerstr. 5, Dreieich, Germany, 63303
    Public contact
    Daniela Zipp, Biotest AG, +49 6103 801 255 , daniela.zipp@biotest.com
    Scientific contact
    Daniela Zipp, Biotest AG, +49 6103 801 255 , daniela.zipp@biotest.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Is to investigate dose-response information on efficacy. Primary efficacy variable is ACR20 (at Week 13).
    Protection of trial subjects
    The patient had to give written consent to participate in the trial by signing and dating the informed consent form (ICF) before screening. Any new and relevant information that evolved during the course of the trial concerning the investigational medicinal product (IMP), alternative treatments, or the risk/benefit ratio was communicated to the patient. After SC administration the patient was asked to stay at the investigational site for at least 2 hours to cover the potential risk of a type I hypersensitivity reaction. Therefore, intensive care measures had to be available. Patients should be informed that such reactions are possible and prompt medical attention should be sought if allergic reactions occur. After administration of the last dose of the IMP patients were observed for a 12-week follow-up period on a regular outpatient basis. All these patients had in addition a safety follow-up visit at Week 24. Treatment is discontinued if at least one of the following three criteria are met for two consecutive weekly assessments. • CD3CD4 cell count ≤ 200 cells/μl or • CD3CD4 cell count < 50% of individual baseline count or • Total lymphocyte count < 50% of individual baseline count The treatment will be discontinued for male patients in case: • TSH, follicle-stimulating hormone (FSH), luteinizing hormone (LH) or testoste-rone levels are outside the normal range and • The investigator assesses these changes as compared to baseline as clinically relevant for 2 consecutive measurements. Other reasons for treatment discontinuation are: • Prolonged lymphopenia at two consecutive weekly visits • Lymphopenia is defined as < 1000 lymphocytes / μl (< 1.000 * 109 lymphocytes / l) in a whole blood specimen. • Anaphylactic or other serious allergic reaction Patients withdrawn from treatment should be followed up for at least 2 additional weeks and should . In case of an AE, the withdrawn patient should be followed up until the AE is resolved or in a steady state.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Dec 2010
    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
    Spain: 1
    Country: Number of subjects enrolled
    Czech Republic: 49
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Latvia: 10
    Country: Number of subjects enrolled
    Poland: 56
    Worldwide total number of subjects
    128
    EEA total number of subjects
    128
    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)
    101
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The Screening period was up to 6 weeks for each subject. The screening started on 21-DEC-2010 and ended on 04-FEB-2013 (2 year and 2 months). The active sites were in Czech Republic, Germany, Spain, Italy, Poland, Hungary and Latvia. In total, 128 patients was randomized onto the study. Of which 127 patients received study treatment.

    Pre-assignment
    Screening details
    Main inclusion criteria: Adult patients (18–75 years, both gender) with active RA (duration of ≥ 12months) with functional class I-III incompletely controlled on methotrexate (MTX), with a history of at least one traditional disease modifying antirheumatic drug (DMARD) with an inadequate response despite ≥ 3 months of treatment and who signed ICF.

    Period 1
    Period 1 title
    Controlled Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All study staff at the investigational site and study personnel at the sponsor / clinical research organization(s) involved in the conduct of the study remained blinded until study unblinding. Plasma concentrations of BT061 was determined at Biotest only after the blinded data review meeting (BDRM). The independent statistician, independent laboratory specialists and the IDRB members had access to such data before the BDRM. Unblinded personnel were not involved in any analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo group ( Group D) received weekly subcutaneous placebo for 12 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 ml placebo (0 mg/ml BT061) (2 vials) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (placebo) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

    Arm title
    BT061 25 mg
    Arm description
    BT061 25 mg Group received weekly subcutaneous 25 mg BT061 for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BT061 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    25 mg BT061 in 2 ml (1 ml 25mg/ml BT061 + 1 ml placebo 0 mg/ml BT061) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (BT061) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

    Arm title
    BT061 50 mg
    Arm description
    BT061 50 mg group received weekly subcutaneous 50 mg BT061 for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BT061 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50 mg BT061 in 2 ml (1 ml 50 mg/ml BT061 + 1 ml placebo 0 mg/ml BT061) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (BT061) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

    Arm title
    BT061 75 mg
    Arm description
    BT061 75 mg group received weekly subcutaneous 75 mg BT061 for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BT061 75 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    75 mg BT061 in 2 ml (1 ml 25 mg/ml BT061 + 1 ml 50 mg/ml BT061) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (BT061) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

    Number of subjects in period 1 [1]
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Started
    32
    32
    32
    31
    Completed
    28
    30
    27
    27
    Not completed
    4
    2
    5
    4
         Consent withdrawn by subject
    -
    -
    1
    2
         positive CMV IgM test
    -
    -
    -
    1
         patient absence
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    2
    -
         patient decision to withdraw from treatment
    -
    -
    1
    -
         positive EBV IgM test
    -
    1
    -
    -
         positive quantiferon test
    1
    -
    1
    -
         Protocol deviation
    2
    1
    -
    -
         Lack of efficacy
    -
    -
    -
    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: A total of 128 patients were randomized of which 127 patients were treated and included in the APTAS.For patient I0302 (75 mg BT061) the randomization did not lead to treatment due to a system error. Patient I0302 was screened on 16-APR-2012 and, according to the protocol, the Screening period was 6 weeks. On 28 MAY 2012 the 6-week Screening period was exceeded. The sub-investigator tried to randomize the patient on IWRS on time, but she could not because of a problem with IMP in IWRS.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo group ( Group D) received weekly subcutaneous placebo for 12 weeks.

    Reporting group title
    BT061 25 mg
    Reporting group description
    BT061 25 mg Group received weekly subcutaneous 25 mg BT061 for 12 weeks.

    Reporting group title
    BT061 50 mg
    Reporting group description
    BT061 50 mg group received weekly subcutaneous 50 mg BT061 for 12 weeks.

    Reporting group title
    BT061 75 mg
    Reporting group description
    BT061 75 mg group received weekly subcutaneous 75 mg BT061 for 12 weeks.

    Reporting group values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg Total
    Number of subjects
    32 32 32 31 127
    Age categorical
    Units: Subjects
        Adults (18- <40 years)
    2 4 5 4 15
        Adults (40-65 years)
    23 21 20 24 88
        Adults (>65 - 77 years)
    7 7 7 3 24
    Age continuous
    Units: years
        median (full range (min-max))
    58 (33 to 75) 54 (26 to 71) 56.5 (25 to 76) 54 (26 to 74) -
    Gender categorical
    Units: Subjects
        Female
    25 28 29 25 107
        Male
    7 4 3 6 20
    Subject analysis sets

    Subject analysis set title
    All patients treated analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least a single dose of study medication (IMP).

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients who received at least one dose of IMP and have at least one postbaseline assessment with respect to the efficacy parameters.

    Subject analysis set title
    Per-protocol (PP) analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the full analysis set without any major protocol violations as defined during the blinded data review meeting. Patients with major protocol deviations or incomplete documentation of relevant data will be excluded from the PP analysis. Patients who miss more than two doses of the IMP do not qualify for the perprotocol analysis set. In any case patients must have received the last two IMP injections of Week 11 and Week 12 to qualify for the PP set.

    Subject analysis set title
    PK analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients will be considered evaluable for PK analysis if they received at least one dose of BT061, and if they have at least one post-treatment plasma concentration measure of BT061.

    Subject analysis sets values
    All patients treated analysis set Full analysis set Per-protocol (PP) analysis set PK analysis set
    Number of subjects
    127
    127
    89
    127
    Age categorical
    Units: Subjects
        Adults (18- <40 years)
    15
        Adults (40-65 years)
    88
        Adults (>65 - 77 years)
    24
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    107
        Male
    20

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo group ( Group D) received weekly subcutaneous placebo for 12 weeks.

    Reporting group title
    BT061 25 mg
    Reporting group description
    BT061 25 mg Group received weekly subcutaneous 25 mg BT061 for 12 weeks.

    Reporting group title
    BT061 50 mg
    Reporting group description
    BT061 50 mg group received weekly subcutaneous 50 mg BT061 for 12 weeks.

    Reporting group title
    BT061 75 mg
    Reporting group description
    BT061 75 mg group received weekly subcutaneous 75 mg BT061 for 12 weeks.

    Subject analysis set title
    All patients treated analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received at least a single dose of study medication (IMP).

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients who received at least one dose of IMP and have at least one postbaseline assessment with respect to the efficacy parameters.

    Subject analysis set title
    Per-protocol (PP) analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients of the full analysis set without any major protocol violations as defined during the blinded data review meeting. Patients with major protocol deviations or incomplete documentation of relevant data will be excluded from the PP analysis. Patients who miss more than two doses of the IMP do not qualify for the perprotocol analysis set. In any case patients must have received the last two IMP injections of Week 11 and Week 12 to qualify for the PP set.

    Subject analysis set title
    PK analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients will be considered evaluable for PK analysis if they received at least one dose of BT061, and if they have at least one post-treatment plasma concentration measure of BT061.

    Primary: ACR20 response at Week 13

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    End point title
    ACR20 response at Week 13
    End point description
    The primary objective of this study was to investigate dose-response information on efficacy using the ACR20 response criteria after 12 weeks of treatment at study Week 13 (one week after end of treatment). The impact of the IMP on rheumatoid arthritis (RA) disease activity was evaluated by the difference between pre-treatment (baseline) disease activity and one week post-treatment (Week 13) disease activity. An ACR20 response was defined as at least 20% improvement in both the tender joint count and the swollen joint count and at least 20% improvement in 3 of the 5 other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ).
    End point type
    Primary
    End point timeframe
    From baseline to study week 13 ( one week after 12 weeks of treatment)
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg All patients treated analysis set
    Number of subjects analysed
    32
    32
    32
    31
    127
    Units: subjects
        Response
    14
    18
    18
    15
    65
        No response
    18
    14
    14
    16
    62
    Statistical analysis title
    BT061 25 mg versus placebo
    Statistical analysis description
    The primary analysis is the final analysis of the 2 groups (BT061 25 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.
    Comparison groups
    BT061 25 mg v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    4.44
    Notes
    [1] - Wald X2 p-value = 0.3186 and Fisher 2-sided p-value = 0.4536. There was no statistically significant difference in ACR20 response rate versus placebo group.
    Statistical analysis title
    BT061 50 mg versus placebo
    Statistical analysis description
    The primary analysis is the final analysis of the 2 groups (BT061 50 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.
    Comparison groups
    BT061 50 mg v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    4.44
    Notes
    [2] - Wald X2 p-value = 0.3186 and Fisher 2-sided p-value = 0.4536. There was no statistically significant difference in ACR20 response rate versus placebo group.
    Statistical analysis title
    BT061 75 mg versus placebo
    Statistical analysis description
    The primary analysis is the final analysis of the 2 groups (BT061 75 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.
    Comparison groups
    BT061 75 mg v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    3.25
    Notes
    [3] - Wald X2 p-value = 0.7121 and Fisher 2-sided p-value = 0.8025. There was no statistically significant difference in ACR20 response rate versus placebo group.

    Secondary: ACR50 Response

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    End point title
    ACR50 Response
    End point description
    ACR50 response was derived using last observation carried forward and Non-responder Imputation. An ACR50 response was defined as at least 50% improvement in both the tender joint count and the swollen joint count and at least 50% improvement in 3 of the 5 other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ).
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg All patients treated analysis set
    Number of subjects analysed
    32
    32
    32
    31
    127
    Units: subjects
        Response
    4
    7
    4
    11
    26
        No response
    28
    25
    28
    20
    101
    Statistical analysis title
    BT061 25 mg versus placebo
    Statistical analysis description
    The final analysis of the 2 groups (BT061 25 mg and placebo) of ACR50 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.
    Comparison groups
    BT061 25 mg v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    7.5
    Notes
    [4] - Wald X2 p-value = 0.3256 and Fisher 2-sided p-value = 0.5092. There was no statistically significant difference in ACR50 response rate versus placebo group.
    Statistical analysis title
    BT061 50 mg versus placebo
    Statistical analysis description
    The primary analysis is the final analysis of the 2 groups (BT061 50 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.
    Comparison groups
    BT061 50 mg v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05 [5]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    4.4
    Notes
    [5] - Wald X2 p-value = 1.0000 and Fisher 2-sided p-value = 1.0000. There was no statistically significant difference in ACR50 response rate versus placebo group.
    Statistical analysis title
    BT061 75 mg versus placebo
    Statistical analysis description
    The primary analysis is the final analysis of the 2 groups (BT061 75 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.
    Comparison groups
    BT061 75 mg v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.07
         upper limit
    13.85
    Notes
    [6] - Wald X2 p-value = 0.0390 and Fisher 2-sided p-value = 0.0413. There was statistically significant difference in ACR50 response rate versus placebo group.

    Secondary: ACR 70 Response

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    End point title
    ACR 70 Response
    End point description
    ACR70 response was derived using last observation carried forward and Non-responder Imputation. An ACR70 response was defined as at least 70% improvement in both the tender joint count and the swollen joint count and at least 70% improvement in 3 of the 5 other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ).
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg All patients treated analysis set
    Number of subjects analysed
    32
    32
    32
    31
    127
    Units: subjects
        Response
    0
    1
    1
    2
    4
        No response
    32
    31
    31
    29
    123
    No statistical analyses for this end point

    Secondary: Hybrid ACR Scores

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    End point title
    Hybrid ACR Scores
    End point description
    The hybrid ACR is derived at each post-baseline visit from the 7 core set items (components: the tender joint count and the swollen joint count and other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ)) by the following steps: 1. For each component: „Bound %change‟ = percentage improvement (defined above) provided this is >-100%; -100% otherwise (Thus, a deterioration can never go beyond -100%.) 2. „Mean %change‟ = mean of the 7 „bound %change‟ values classified as <20, 20-<50, 50-<70 or 70+. 3. ACR status = „not ACR20‟ or „ACR20 but not ACR50‟ or „ACR50 but not ACR70‟ or „ACR70‟ based on the definitions of ACR20, ACR50 and ACR70.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    31
    32
    32
    30
    Units: scores
        median (full range (min-max))
    19.99 (5.8 to 70.0)
    37.26 (6.5 to 73.0)
    30.30 (-0.1 to 72.7)
    29.91 (-62.2 to 70.0)
    No statistical analyses for this end point

    Secondary: DAS28 scores

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    End point title
    DAS28 scores
    End point description
    Disease activity score for 28 joints (DAS28) combines information from swollen joints, tender joints, acute phase response, and general health into one continuous measure of RA inflammation. DAS28 criteria are a modified version of DAS, which has a reduced and non-graded joint count. It consists of a 28 tender joint count (range 0 to 28), a 28 swollen joint count (range 0 to 28), ESR, and an optional general health assessment on a VAS (range 0 to 100), which will be assessed for this study. DAS28 has a continuous scale ranging from 0 to 10. The level of disease activity is interpreted as low (DAS28 ≤ 3.2), moderate (3.2 < DAS28 ≤ 5.1), and high (DAS28 > 5.1). Higher DAS28 scores means worse disease activity.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: scores
        median (full range (min-max))
    5.03 (1.8 to 7.1)
    4.25 (1.9 to 7)
    4.97 (3.1 to 6.4)
    4.91 (1.9 to 7.3)
    No statistical analyses for this end point

    Secondary: EULAR Response

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    End point title
    EULAR Response
    End point description
    The EULAR response is defined at each post-baseline visit in terms of Disease Activity Scores (DAS28) change from baseline. If the score is missing it will be derived using LOCF. If DAS28 at endpoint ≤ 3.2, the response was categorized based on improvement (reduction) in DAS28 from baseline >1.2 (Good), > 0.6 and ≤ 1.2 (Moderate) and ≤ 0.6 (None). If DAS28 at endpoint > 3.2 and ≤ 5.1, the response was categorized based on improvement (reduction) in DAS28 from baseline >1.2 (Moderate), > 0.6 and ≤ 1.2 (Moderate) and ≤ 0.6 (None). If DAS28 at endpoint > 5.1, the response was categorized based on improvement (reduction) in DAS28 from baseline >1.2 (Moderate), > 0.6 and ≤ 1.2 (None) and ≤ 0.6 (None).
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: subjects
        Good Response
    1
    6
    1
    5
        Moderate Response
    18
    20
    20
    20
        None
    13
    6
    11
    6
    No statistical analyses for this end point

    Secondary: CDAI scores

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    End point title
    CDAI scores
    End point description
    Clinical Disease Activity Index (CDAI) was calculated at each post-baseline visit as the sum of the number of tender joints (t28) from the 28 joints shaded on the CRF, the number of swollen joints (sw28), the disease activity (patient‟s global assessment) and the disease activity (physician‟s global assessment).
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: scores
        median (full range (min-max))
    22.65 (4.3 to 44.3)
    13.05 (1.7 to 46.5)
    21.35 (4.7 to 40.6)
    18.4 (1.6 to 49.7)
    No statistical analyses for this end point

    Secondary: SDAI Scores

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    End point title
    SDAI Scores
    End point description
    The Simplified Disease Activity Index (SDAI) was calculated at each post-baseline visit as the sum of the Clinical Disease Activity Index (CDAI) and the C-reactive protein (CRP) (in mg/dL). If any components of the SDAI are missing then the score will be missing. If the score is missing it will be derived using LOCF.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: scores
        median (full range (min-max))
    23.8 (4.4 to 47.4)
    13.8 (1.8 to 46.8)
    21.95 (4.8 to 40.7)
    19 (1.7 to 56)
    No statistical analyses for this end point

    Secondary: Tender Joint count change from Baseline

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    End point title
    Tender Joint count change from Baseline
    End point description
    Single Component of ACR for RA assesses: 68 joints for tenderness. Mean levels and percentage changes from baseline were plotted against weeks since start of treatment by treatment group. Minus percentage changes from baseline means improvement and plus change means worsening.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -38.71 ± 38.48
    -56.09 ± 31.37
    -47.22 ± 25.67
    -46.16 ± 36.33
    No statistical analyses for this end point

    Secondary: Swollen Joint Count change from Baseline

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    End point title
    Swollen Joint Count change from Baseline
    End point description
    Single Component of ACR for RA assesses: 68 joints for swollenness. Mean levels and percentage changes from baseline were plotted against weeks since start of treatment by treatment group. Minus percentage changes from baseline means improvement and plus change means worsening.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -42.80 ± 34.28
    -67.90 ± 27.28
    -59.89 ± 27.56
    -60.52 ± 37.81
    No statistical analyses for this end point

    Secondary: C-reactive protein change from Baseline

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    End point title
    C-reactive protein change from Baseline
    End point description
    Mean levels of C-reactive protein (CRP in mg/L) and percentage changes from baseline will be plotted against weeks since start of treatment by treatment group.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: Percent change
        arithmetic mean (standard deviation)
    31.85 ± 179.58
    10.33 ± 83.99
    41.98 ± 160.30
    37.11 ± 154.61
    No statistical analyses for this end point

    Secondary: ESR change from Baseline

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    End point title
    ESR change from Baseline
    End point description
    Erythrocyte Sedimentation Rate (ESR) Mean levels and percentage changes from baseline will be plotted against weeks since start of treatment by treatment group.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -36.72 ± 32.23
    -43.49 ± 26.62
    -28.08 ± 40.20
    -43.46 ± 33.83
    No statistical analyses for this end point

    Secondary: Change of VAS for Global Disease Activity (Investigator) from Baseline

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    End point title
    Change of VAS for Global Disease Activity (Investigator) from Baseline
    End point description
    Mean levels and percentage changes from baseline for ACR component (VAS for global disease activity (investigator)) will be plotted against weeks since start of treatment by treatment group.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -39.49 ± 28.93
    -49.75 ± 32.84
    -40.56 ± 30.18
    -42.11 ± 31.36
    No statistical analyses for this end point

    Secondary: Change of VAS for Global Disease Activity (Patient) from Baseline

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    End point title
    Change of VAS for Global Disease Activity (Patient) from Baseline
    End point description
    Mean levels and percentage changes from baseline for ACR component (VAS for global disease activity (patient)) will be plotted against weeks since start of treatment by treatment group.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -25.88 ± 27.03
    -19.09 ± 44.67
    -21.55 ± 41.28
    -31.04 ± 43.71
    No statistical analyses for this end point

    Secondary: Change of VAS for Patient’s Pain from Baseline

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    End point title
    Change of VAS for Patient’s Pain from Baseline
    End point description
    Mean levels and percentage changes from baseline for ACR component (VAS for Patient’s Pain) will be plotted against weeks since start of treatment by treatment group.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -22.48 ± 37.82
    -21.03 ± 39.60
    -25.16 ± 39.23
    -40.27 ± 30.39
    No statistical analyses for this end point

    Secondary: Change of Health Assessment Questionnaire from Baseline

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    End point title
    Change of Health Assessment Questionnaire from Baseline
    End point description
    Mean levels and percentage changes from baseline for ACR component (Health Assessment Questionnaire) will be plotted against weeks since start of treatment by treatment group.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -20.67 ± 40.62
    -0.63 ± 96.15
    -20.99 ± 32.15
    14.27 ± 196.78
    No statistical analyses for this end point

    Secondary: Change of FACIT-Fatigue Questionnaire Total Score from Baseline

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    End point title
    Change of FACIT-Fatigue Questionnaire Total Score from Baseline
    End point description
    Mean levels and percent changes of Functional Assessment Of Chronic Illness Therapy (FACIT) - Fatigue Questionnaire were plotted against weeks since start of treatment by treatment group.
    End point type
    Secondary
    End point timeframe
    From baseline to study Week 13
    End point values
    Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Number of subjects analysed
    32
    32
    32
    31
    Units: percent change
        arithmetic mean (standard deviation)
    23.57 ± 50.69
    15.19 ± 47.91
    25.51 ± 34.08
    22.25 ± 39.88
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signed informed consent to the end of follow up (up to 30 weeks)
    Adverse event reporting additional description
    Only serious nontreatment- emergent AEs that were related to study procedures have been collected. An AE that occurs from the time the patient receives his/her first dose of study drug until his/her final follow up visit, was treatment-emergen AE (TEAE). All TEAEs will be collected.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    All Patients Treated Analysis Set
    Reporting group description
    The All Patients Treated Analysis Set (APTAS) was defined as those patients who are randomised to treatment and receive at least one dose of study medication (BT061 or placebo). The APTAS has been used for all safety analyses. Patients who received the wrong treatment in error were analyzed as treated for safety analyses.

    Reporting group title
    Placebo
    Reporting group description
    Subjects in Placebo group received sc. 2 ml placebo once weekly (0 mg BT061) for 12 weeks.

    Reporting group title
    BT061 25 mg
    Reporting group description
    Subjects in BT061 25 mg group received sc. 1 ml placebo plus 1 ml BT061 25mg/ml once weekly (25 mg BT061) for 12 weeks.

    Reporting group title
    BT061 50 mg
    Reporting group description
    Subjects in BT061 25 mg group received sc. 1 ml placebo plus 1 ml BT061 50 mg/ml once weekly (50 mg BT061) for 12 weeks.

    Reporting group title
    BT061 75 mg
    Reporting group description
    Subjects in BT061 75 mg group received sc. 1 ml BT061 25mg/ml plus 1 ml BT061 50mg/ml once weekly (75 mg BT061) for 12 weeks.

    Serious adverse events
    All Patients Treated Analysis Set Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 127 (4.72%)
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         number of deaths (all causes)
    1
    0
    1
    0
    0
         number of deaths resulting from adverse events
    1
    0
    1
    0
    0
    Vascular disorders
    Hypertension
    Additional description: UNCONTROLLED HYPERTENSION: onset on study day 23, duration of 9 days and resolved. Severity was severe.
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocolitis
    Additional description: Enterocolitis: onset on study day 142, duration of 6 days and resolved; Severity was moderate.
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
    Additional description: Acute Gastritis: onset on study day 142, duration of 6 days and resolved; Severity was moderate.
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
    Additional description: RA EXACERBATION
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    EXTREMITIES GANGRENE
    Additional description: GANGRENE OF TOES OF THE LEFT: onset on study day 157, duration of 9 days and resulted in death. Severity was severe.
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    PNEUMONIA
    Additional description: PNEUMONIA BILATERAL: onset on study day 67, duration of 13 days and resolved. Severity was moderate.
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All Patients Treated Analysis Set Placebo BT061 25 mg BT061 50 mg BT061 75 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 127 (62.99%)
    20 / 32 (62.50%)
    16 / 32 (50.00%)
    25 / 32 (78.13%)
    21 / 31 (67.74%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    0
    4
    0
    Reproductive system and breast disorders
    Spermatocele
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Varicocele
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Blood albumin decreased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    0
    2
    Cytomegalovirus test positive
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    1
    1
    Epstein-Barr virus antibody positive
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Mycobacteriun tuberculosis complex test positiv
         subjects affected / exposed
    5 / 127 (3.94%)
    3 / 32 (9.38%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    5
    3
    1
    1
    0
    Protein total decreased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Epstein-Barr virus test positive
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    0
    0
    1
    Rib fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Nervous system disorders
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    8 / 127 (6.30%)
    3 / 32 (9.38%)
    3 / 32 (9.38%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    9
    4
    3
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Sicca syndrome
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    1
    1
    Dyspepsia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Glossodynia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    1
    2
    0
    Steatorrhoea
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    3 / 127 (2.36%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    3
    2
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Rash papular
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Haematuria
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Haemoglobinuria
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Leukocyturia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    0
    2
    Back pain
         subjects affected / exposed
    6 / 127 (4.72%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    3 / 32 (9.38%)
    1 / 31 (3.23%)
         occurrences all number
    7
    1
    1
    4
    1
    Bone pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Bursitis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    3
    0
    0
    0
    3
    Muscle spasms
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Osteopenia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Rheumatoid arthritis
         subjects affected / exposed
    8 / 127 (6.30%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    4 / 31 (12.90%)
         occurrences all number
    10
    3
    0
    2
    5
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Acute tonsillitis
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    1
    0
    1
    Bronchitis
         subjects affected / exposed
    4 / 127 (3.15%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    4
    0
    2
    1
    1
    Cystitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Dysentery
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Herpes simplex
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
         occurrences all number
    4
    0
    0
    1
    3
    Herpes zoster
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Laryngitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    12 / 127 (9.45%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    4 / 32 (12.50%)
    4 / 31 (12.90%)
         occurrences all number
    12
    2
    2
    4
    4
    Oral herpes
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    1
    1
    Sepsis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Tracheitis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    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
    06 Dec 2011
    Modification of some Incl./ Excl. criteria, incorporation of non-substantial amendments, refined diagnostic for cronic infectious disease hepatitis B,
    15 Dec 2011
    inclusion of two additional substudies for measurement of plasma concentration, numbers of CD3+/ CD4+ lymphocytes, level of CD4 expression,ocupancy of CD4 receptors, measuring the activation of Treg cells and functional capacity of CD4 T cells.
    19 Jan 2012
    Batch extension / Placebo
    31 Aug 2012
    Optional increase in size of patient population by an additional 0-40 patients in order to obtail sufficient data on PK/PD assessments and T-reg activation prior to interim analysis; PK/ PD assessments are part of the main study, explanation when data on the optional additioanl contingent will be evaluated.
    16 Oct 2013
    Cancellation of part II of the study in favour of a lager follow-on trial with a longer treatment duration

    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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    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
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