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    Clinical Trial Results:
    Prediction of response to Certolizumab Pegol treatment by functional MRI of the brain. A multi-center, randomized double-blind controlled study Prediction of response to Certolizumab-Pegol in RA (PreCePRA)

    Summary
    EudraCT number
    		 2013-000337-13
    Trial protocol
    		 DE   PT  
    Global end of trial date
    10 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2021
    First version publication date
    14 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PreCePra
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01864265
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Erlangen
    Sponsor organisation address
    Maximiliansplatz 2, Erlangen, Germany, 91054
    Public contact
    Clinical Trial Unit, Med. 3 , Universitätsklinikum Erlangen, +49 91318543014, juergen.rech@uk-erlangen.de
    Scientific contact
    Clinical Trial Unit, Med. 3 , Universitätsklinikum Erlangen, +49 91318543014, juergen.rech@uk-erlangen.de
    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
    18 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary parameter of interest is the proportion of patients who reach low disease activity according to the DAS28 (DAS28 < 3.2) during the first 12 weeks of study participation according their baseline CNS activity measured by functional MRI.
    Protection of trial subjects
    All patients must sign and date the most current IRB/IEC-approved written informed consent form (ICF)  Review patient eligibility and ensure that all inclusion and exclusion criteria are met.  Physical examination, including pulse rate, systolic and diastolic blood pressure (after the patient has been in a semi-supine position for at least 5 minutes), body temperature, body weight and physician’s global assessment of disease status  ECG: a 12-lead ECG with formal readings. Patients should be supine for 5 minutes before the recording is performed  TB testing will be performed according to local guidelines. In case of a positive TB test, requiring treatment for latent TB, the patient must be treated at a minimum of 4 weeks or even longer (according to national and international guidelines) before starting treatment with the TNF-inhibitor (Certolizumab-Pegol). If treatment of latent TB is required re-screening of the patient is possible.Blood samples for laboratory tests including High Sensitivity C-Reactive Protein, Erythrocyte Sedimentation Rate.  Rheumatoid factor and CCP-antibodies  Cytokines and Hormones of the hypothalamic-pituitary-adrenal/gonadal axis (IL-6, TNF, IFN-gamma, cortisol, ACTH und NPY) and urinalysis (specific gravity, pH, glucose, protein, ketones, bilirubin).  Hematology: Hematology includes complete blood count (RBC count, hemoglobin, heamatocrit, WBC count and differential, absolute  Pregnancy, any event with elevated risk of interaction with immunosuppressive therapy such as myocardial infarction, pulmonary embolism, apoplexy; medical emergencies requiring immediate treatment as an inpatient and / or surgery (severe traffic accident, ileus, etc.), and infectious diseases requiring anti-inflammatory therapy risking interaction with immunosuppressive therapy. It is incumbent upon the Investigator to consider continuation or discontinuation of therapy.
    Background therapy
    		 - Glucocorticoids treatment up to 10mg prednisolone per day will be allowed at study entry. - At screening- visit patients should have been treated without alterations of DMARD therapy (for at least three months) (i.e. Methotrexate) (with or without concomitant use of steroids).
    Evidence for comparator
    		 Study Rationale By using functional MRI we have recently shown that TNFi elicit rapid changes in brain function linked to the perception of RA. Functional MRI allows the detection of tiny changes in neuronal activity by measuring alterations of blood flow in the context of neuronal activation. TNFi rapidly reversed the widespread activation of brain centers involved in pain such as the thalamus and the somatosensoric cortex, as well as those involved in the control, of mood and emotions such as the limbic system. Moreover, as small phase I study with 10 patients with RA showed that high brain activity detected in the functional MRI predicts clinical response to Certolizumab Pegol after 1 month, suggesting the central nervous system activity may be used as a tool to predict response to TNFi . The rationale of this study is to test whether response to TNFi can be predicted by using functional MRI. Risk-Benefit considerations The introduction of TNF α antagonists represents a major advance in the drug treatment of RA. The therapeutic response to currently available TNF α antagonists is idiosyncratic. This is also true for tolerability and is in keeping with the well known idiosyncratic response to traditional DMARDs. Therefore, there remains a medical need for additional effective TNF α antagonists for the treatment of RA. The benefit of the protocol PreCePra are the potential future a availability of a predictor before treating patients and to predict that these patients treated with certolizumab pegol will respond to the TNF α blockade.
    Actual start date of recruitment
    01 Jun 2013
    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
    Portugal: 1
    Country: Number of subjects enrolled
    Germany: 105
    Country: Number of subjects enrolled
    Serbia: 50
    Worldwide total number of subjects
    156
    EEA total number of subjects
    106
    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)
    148
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patient recruitment was performed in the outpatient and inpatient ward of the Medizinische Klinik 3, Universitätsklinikum Erlangen, as well as in the participating centers.

    Pre-assignment
    Screening details
    		 156 patients signed written informed consent. 13 patients did not meet inclusion-exclusion criteria or did not met inclusion exclusion criteria. 143 subjects reached baseline visit.

    Period 1
    Period 1 title
    Baseline
    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
    The password-protected and/or encrypted electronic master randomization list is kept by Clinical Site (pharmacist) in their secure system and is only accessible to the randomization list manager. No open key to the code will be available at the study centre, fMRI analyst, to the CRO monitors or to the project team at UCB-PHARMA, neither to the sponsor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 (high voxel count + CZP)
    Arm description
    		 fMRI: high voxel count; randomized to: Certolizumab Pegol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Certolizumab Pegol (Cimzia®)
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Loading dose: The recommended starting dose of Cimzia® for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. MTX should be continued during treatment with Cimzia® where appropriate. Maintenance dose: The recommended maintenance dose of Cimzia® for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia® where appropriate.

    Arm title
    		 Group 2 (low voxel count + CZP)
    Arm description
    		 fMRI: low voxel Count; randomized to: Certolizumab Pegol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Certolizumab Pegol (Cimzia®)
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Loading dose: The recommended starting dose of Cimzia® for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. MTX should be continued during treatment with Cimzia® where appropriate. Maintenance dose: The recommended maintenance dose of Cimzia® for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia® where appropriate.

    Arm title
    		 Group 3 (high or low voxel count + placebo)
    Arm description
    		 fMRI: high or low voxel Count; randomized to: placebo
    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
    one injection every two weeks until week 12

    Number of subjects in period 1
    		Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Started
    52
    52
    52
    Completed
    49
    48
    46
    Not completed
    3
    4
    6
         Physician decision
    -
    4
    6
         Protocol deviation
    3
    -
    -
    Period 2
    Period 2 title
    Treatment Period 1 (week 0 - 12)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 (high voxel count + CZP)
    Arm description
    		 fMRI: high voxel Count; randomized to: Certolizumab Pegol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Certolizumab Pegol (Cimzia®)
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Loading dose: The recommended starting dose of Cimzia® for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. MTX should be continued during treatment with Cimzia® where appropriate. Maintenance dose: The recommended maintenance dose of Cimzia® for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia® where appropriate.

    Arm title
    		 Group 2 (low voxel count + CZP)
    Arm description
    		 fMRI: low voxel Count; randomized to: Certolizumab Pegol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Certolizumab Pegol (Cimzia®)
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Loading dose: The recommended starting dose of Cimzia® for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. MTX should be continued during treatment with Cimzia® where appropriate. Maintenance dose: The recommended maintenance dose of Cimzia® for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia® where appropriate.

    Arm title
    		 Group 3 (high or low voxel count + placebo)
    Arm description
    		 fMRI: high or low voxel Count; randomized to: placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline 0,9%
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    one Syringe every 2 weeks

    Number of subjects in period 2
    		Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Started
    49
    48
    46
    Completed
    48
    45
    46
    Not completed
    1
    3
    0
         Consent withdrawn by subject
    1
    -
    -
         Adverse event, non-fatal
    -
    3
    -
    Period 3
    Period 3 title
    Treatment Period 2 (week 12 - 24)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 (high voxel count + CZP)
    Arm description
    		 fMRI: high voxel Count; randomized to : Certolizumab Pegol; responder at week 12
    Arm type
    		 Experimental

    Investigational medicinal product name
    Certolizumab Pegol (Cimzia®)
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Maintenance dose: The recommended maintenance dose of Cimzia® for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia® where appropriate.

    Arm title
    		 Group 2 (low voxel count + CZP)
    Arm description
    		 fMRI: low voxel Count; randomized to : Certolizumab Pegol; responder at week 12
    Arm type
    		 Experimental

    Investigational medicinal product name
    Certolizumab Pegol (Cimzia®)
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Maintenance dose: The recommended maintenance dose of Cimzia® for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia® where appropriate.

    Arm title
    		 Group 3 (high or low voxel count + placebo)
    Arm description
    		 fMRI: high or low voxel Count; randomized to : placobo; non-responder at week 12; Certolizumab Pegol from week 12 to 24
    Arm type
    		 placebo -> experimental

    Investigational medicinal product name
    Certolizumab Pegol (Cimzia®)
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Loading dose: The recommended starting dose of Cimzia® for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. MTX should be continued during treatment with Cimzia® where appropriate. Maintenance dose: The recommended maintenance dose of Cimzia® for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia® where appropriate.

    Number of subjects in period 3
    		Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Started
    48
    45
    46
    Completed
    38
    35
    39
    Not completed
    10
    10
    7
         Lack of efficacy
    10
    10
    7

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Group 1 (high voxel count + CZP)
    Reporting group description
    		 fMRI: high voxel count; randomized to: Certolizumab Pegol

    Reporting group title
    Group 2 (low voxel count + CZP)
    Reporting group description
    		 fMRI: low voxel Count; randomized to: Certolizumab Pegol

    Reporting group title
    Group 3 (high or low voxel count + placebo)
    Reporting group description
    		 fMRI: high or low voxel Count; randomized to: placebo

    Reporting group values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo) Total
    Number of subjects
    		 52 52 52 156
    Age categorical
    Patients must be aged ≥ 18 years at time of consent
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.3 ± 10.8 56.5 ± 12.2 52.1 ± 12.0 -
    Gender categorical
    Units: Subjects
        Female
    		 38 37 33 108
        Male
    		 14 15 19 48
    ACPA
    Units: Subjects
        positive
    		 34 40 40 114
        negative
    		 18 12 12 42
    RF
    Units: Subjects
        positive
    		 35 38 36 109
        negative
    		 17 14 16 47
    Tender joints (28)
    Units: joints
        arithmetic mean (standard deviation)
    		 9.3 ± 6.4 11.3 ± 6.7 9.9 ± 6.2 -
    Swollen joints
    Units: joints
        arithmetic mean (standard deviation)
    		 7.0 ± 4.4 8.7 ± 6.3 8.0 ± 4.8 -
    Patient global VAS
    Units: mm
        arithmetic mean (standard deviation)
    		 57.2 ± 19.9 59.1 ± 17.8 57.6 ± 22.5 -
    Physician global VAS
    Units: mm
        arithmetic mean (standard deviation)
    		 46.0 ± 20.2 49.5 ± 19.2 53.1 ± 16.2 -
    Pain VAS
    Units: mm
        arithmetic mean (standard deviation)
    		 53.5 ± 18.0 57.1 ± 17.0 54.9 ± 22.7 -
    ESR
    Units: mm/h
        arithmetic mean (standard deviation)
    		 23.7 ± 19.0 25.2 ± 17.1 28.2 ± 23.2 -
    CRP
    Units: mg/l
        arithmetic mean (standard deviation)
    		 6.8 ± 12.7 7.9 ± 8.7 11.2 ± 16.5 -
    DAS28
    Units: none
        arithmetic mean (standard deviation)
    		 4.7 ± 1.0 5.0 ± 1.1 4.9 ± 1.0 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Group 1 (high voxel count + CZP)
    Reporting group description
    		 fMRI: high voxel count; randomized to: Certolizumab Pegol

    Reporting group title
    Group 2 (low voxel count + CZP)
    Reporting group description
    		 fMRI: low voxel Count; randomized to: Certolizumab Pegol

    Reporting group title
    Group 3 (high or low voxel count + placebo)
    Reporting group description
    		 fMRI: high or low voxel Count; randomized to: placebo
    Reporting group title
    Group 1 (high voxel count + CZP)
    Reporting group description
    		 fMRI: high voxel Count; randomized to: Certolizumab Pegol

    Reporting group title
    Group 2 (low voxel count + CZP)
    Reporting group description
    		 fMRI: low voxel Count; randomized to: Certolizumab Pegol

    Reporting group title
    Group 3 (high or low voxel count + placebo)
    Reporting group description
    		 fMRI: high or low voxel Count; randomized to: placebo
    Reporting group title
    Group 1 (high voxel count + CZP)
    Reporting group description
    		 fMRI: high voxel Count; randomized to : Certolizumab Pegol; responder at week 12

    Reporting group title
    Group 2 (low voxel count + CZP)
    Reporting group description
    		 fMRI: low voxel Count; randomized to : Certolizumab Pegol; responder at week 12

    Reporting group title
    Group 3 (high or low voxel count + placebo)
    Reporting group description
    		 fMRI: high or low voxel Count; randomized to : placobo; non-responder at week 12; Certolizumab Pegol from week 12 to 24

    Primary: Low disease activity (DAS28 < 3.2) at week 12, proportion

    		 Close Top of page
    End point title
    		 Low disease activity (DAS28 < 3.2) at week 12, proportion
    End point description
    Proportion of patients who reach low disease activity (DAS28 < 3.2) during the first 12 weeks according their screening CNS activity measured by fMRI
    End point type
    Primary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: subjects
    17
    14
    12
    Statistical analysis title
    		 Comparison DAS28 < 3.2 Group 1 vs. 3
    Statistical analysis description
    Comparison DAS28 < 3.2 between group 1 and group 3
    Comparison groups
    Group 1 (high voxel count + CZP) v Group 3 (high or low voxel count + placebo)
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.6433
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - Chi squared
    Statistical analysis title
    		 Comparison DAS28 < 3.2 Group 2 vs. 3
    Comparison groups
    Group 2 (low voxel count + CZP) v Group 3 (high or low voxel count + placebo)
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1515
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Low disease activity (DAS28 < 3.2) at week 24, proportion

    		 Close Top of page
    End point title
    		 Low disease activity (DAS28 < 3.2) at week 24, proportion
    End point description
    Proportion of patients who reach low disease activity (DAS28 < 3.2) during the first 24 weeks according their screening CNS activity measured by fMRI
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: subjects
    24
    17
    21
    Statistical analysis title
    		 Low disease activity (DAS28 < 3.2)
    Comparison groups
    Group 1 (high voxel count + CZP) v Group 2 (low voxel count + CZP) v Group 3 (high or low voxel count + placebo)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.25
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [2] - Chi-squared

    Secondary: Remission (DAS28 < 2.6) at week 12, proportion

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    End point title
    		 Remission (DAS28 < 2.6) at week 12, proportion
    End point description
    Proportion of patients who reach remission (DAS28 < 2.6) during the first 12 weeks according their screening CNS activity measured by fMRI
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    48
    40
    46
    Units: subjects
    12
    13
    6
    No statistical analyses for this end point

    Secondary: Remission (DAS28 < 2.6) at week 24, proportion

    		 Close Top of page
    End point title
    		 Remission (DAS28 < 2.6) at week 24, proportion
    End point description
    Proportion of patients who reach remission (DAS28 < 2.6) during the first 24 weeks according their screening CNS activity measured by fMRI
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    38
    28
    39
    Units: subjects
    19
    8
    10
    Statistical analysis title
    		 Remission at week 24
    Comparison groups
    Group 1 (high voxel count + CZP) v Group 2 (low voxel count + CZP) v Group 3 (high or low voxel count + placebo)
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 other [3]
    P-value
    		 < 0.009
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - Chi squared

    Secondary: DAS28 at week 12, mean

    		 Close Top of page
    End point title
    		 DAS28 at week 12, mean
    End point description
    Mean DAS28 at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    3.3 ± 1.2
    3.8 ± 1.4
    4.1 ± 1.5
    No statistical analyses for this end point

    Secondary: DAS28 at week 24, mean

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    End point title
    		 DAS28 at week 24, mean
    End point description
    Mean DAS28 at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    2.79 ± 1.11
    3.2 ± 1.11
    3.11 ± 0.95
    No statistical analyses for this end point

    Secondary: SF-36 emotional well-being at week 12, mean

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    End point title
    		 SF-36 emotional well-being at week 12, mean
    End point description
    Mean SF-36 emotional well-being at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    72.2 ± 18.8
    59.2 ± 24.9
    66.5 ± 21.1
    No statistical analyses for this end point

    Secondary: SF-36 emotional well-being at week 24, mean

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    End point title
    		 SF-36 emotional well-being at week 24, mean
    End point description
    Mean SF-36 emotional well-being at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    38
    28
    39
    Units: AU
        arithmetic mean (standard deviation)
    73.8 ± 18.7
    65.4 ± 19.1
    72.6 ± 18.7
    No statistical analyses for this end point

    Secondary: DAS28 at week 24, median

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    End point title
    		 DAS28 at week 24, median
    End point description
    Median DAS28 at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        median (inter-quartile range (Q1-Q3))
    2.43 (1.86 to 3.84)
    2.89 (2.20 to 3.82)
    3.34 (2.76 to 4.11)
    No statistical analyses for this end point

    Secondary: SF-36 energy/fatigue at week 12, mean

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    End point title
    		 SF-36 energy/fatigue at week 12, mean
    End point description
    Mean SF-36 energy/fatigue at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    54.1 ± 22.3
    45.9 ± 24.7
    54.9 ± 22.9
    No statistical analyses for this end point

    Secondary: SF-36 energy/fatigue at week 24, mean

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    End point title
    		 SF-36 energy/fatigue at week 24, mean
    End point description
    Mean SF-36 energy/fatigue at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    58.2 ± 22.6
    51.4 ± 19.3
    63.1 ± 19.6
    No statistical analyses for this end point

    Secondary: SF-36 general health at week 12, mean

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    End point title
    		 SF-36 general health at week 12, mean
    End point description
    Mean SF-36 general health at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    53.5 ± 15.6
    47.9 ± 21.4
    50.6 ± 16.3
    No statistical analyses for this end point

    Secondary: SF-36 general health at week 24, mean

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    End point title
    		 SF-36 general health at week 24, mean
    End point description
    Mean SF-36 general health at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    59.9 ± 16.0
    51.7 ± 15.4
    52.5 ± 14.7
    No statistical analyses for this end point

    Secondary: SF-36 health change at week 12, mean

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    End point title
    		 SF-36 health change at week 12, mean
    End point description
    Mean SF-36 health change at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    76.8 ± 27.3
    64.0 ± 27.4
    60.2 ± 27.7
    No statistical analyses for this end point

    Secondary: SF-36 health change at week 24, mean

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    End point title
    		 SF-36 health change at week 24, mean
    End point description
    Mean SF-36 health change at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    84.6 ± 23.0
    68.0 ± 28.6
    73.7 ± 25.6
    No statistical analyses for this end point

    Secondary: SF-36 pain at week 12, mean

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    End point title
    		 SF-36 pain at week 12, mean
    End point description
    Mean SF-36 pain at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    63.9 ± 21.8
    50.1 ± 24.1
    53.2 ± 20.4
    No statistical analyses for this end point

    Secondary: SF-36 pain at week 24, mean

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    End point title
    		 SF-36 pain at week 24, mean
    End point description
    Mean SF-36 pain at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    67.1 ± 21.4
    59.5 ± 24.2
    63.5 ± 22.5
    No statistical analyses for this end point

    Secondary: SF-36 physical functioning at week 12, mean

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    End point title
    		 SF-36 physical functioning at week 12, mean
    End point description
    Mean SF-36 physical functioning at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    69.4 ± 22.4
    53.8 ± 27.5
    67.9 ± 24.6
    No statistical analyses for this end point

    Secondary: SF-36 physical functioning at week 24, mean

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    End point title
    		 SF-36 physical functioning at week 24, mean
    End point description
    Mean SF-36 physical functioning at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    72.8 ± 21.5
    63.6 ± 26.5
    69.2 ± 25.7
    No statistical analyses for this end point

    Secondary: DAS28 at week 12, median

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    End point title
    		 DAS28 at week 12, median
    End point description
    Median DAS28 at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    48
    40
    46
    Units: AU
        median (inter-quartile range (Q1-Q3))
    3.1 (2.35 to 3.85)
    3.29 (2.79 to 4.19)
    3.71 (3.01 to 4.33)
    No statistical analyses for this end point

    Secondary: BOLD signal at week 12, mean

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    End point title
    		 BOLD signal at week 12, mean
    End point description
    Mean BOLD signal at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    48
    40
    46
    Units: cm3
        arithmetic mean (standard deviation)
    2364 ± 3756.80
    1376.08 ± 2362.60
    1395.15 ± 2325.67
    No statistical analyses for this end point

    Secondary: BOLD signal at week 24, mean

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    End point title
    		 BOLD signal at week 24, mean
    End point description
    Mean BOLD signal at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    38
    28
    39
    Units: 12872.02
        arithmetic mean (standard deviation)
    1787.13 ± 2487.46
    1102.62 ± 1665.20
    1934.03 ± 3976.96
    No statistical analyses for this end point

    Secondary: BOLD signal at week 12, median

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    End point title
    		 BOLD signal at week 12, median
    End point description
    Median BOLD signal at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    48
    38
    46
    Units: voxel
    48
    38
    46
    No statistical analyses for this end point

    Secondary: BOLD signal at week 24, median

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    End point title
    		 BOLD signal at week 24, median
    End point description
    Median BOLD signal at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    38
    28
    39
    Units: 2446.00
        median (inter-quartile range (Q1-Q3))
    824.76 (241.50 to 1625.17)
    707.56 (76.44 to 1477.28)
    327 (26.67 to 3175.25)
    No statistical analyses for this end point

    Secondary: SF-36 role limitation physical at week 12, mean

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    End point title
    		 SF-36 role limitation physical at week 12, mean
    End point description
    Mean SF-36 role limitation physical at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    50.0 ± 41.8
    38.9 ± 46.5
    48.1 ± 44.4
    No statistical analyses for this end point

    Secondary: SF-36 role limitation physical at week 24, mean

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    End point title
    		 SF-36 role limitation physical at week 24, mean
    End point description
    Mean SF-36 role limitation physical at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    59.6 ± 42.3
    52.7 ± 43.7
    63.2 ± 40.3
    No statistical analyses for this end point

    Secondary: SF-36 social functioning at week 12, mean

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    End point title
    		 SF-36 social functioning at week 12, mean
    End point description
    Mean SF-36 social functioning at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    83.9 ± 21.4
    67.2 ± 29.6
    79.3 ± 21.7
    No statistical analyses for this end point

    Secondary: SF-36 social functioning at week 24, mean

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    End point title
    		 SF-36 social functioning at week 24, mean
    End point description
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    84.9 ± 19.2
    80.5 ± 22.4
    84.6 ± 20.0
    No statistical analyses for this end point

    Secondary: SF-36 role limitation emotional at week 12, mean

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    End point title
    		 SF-36 role limitation emotional at week 12, mean
    End point description
    Mean SF-36 role limitation emotional at week 12
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    42
    46
    46
    Units: AU
        arithmetic mean (standard deviation)
    71.4 ± 37.2
    47.6 ± 45.5
    62.0 ± 41.5
    No statistical analyses for this end point

    Secondary: SF-36 role limitation emotional at week 24, mean

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    End point title
    		 SF-36 role limitation emotional at week 24, mean
    End point description
    Mean SF-36 role limitation emotional at week 24
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Group 1 (high voxel count + CZP) Group 2 (low voxel count + CZP) Group 3 (high or low voxel count + placebo)
    Number of subjects analysed
    34
    32
    39
    Units: AU
        arithmetic mean (standard deviation)
    72.5 ± 37.1
    57.0 ± 44.0
    66.7 ± 41.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Enrollment (signature ICF) until week 24 (visit 6)
    Adverse event reporting additional description
    All physical examination findings, vital sign abnormalities, clinical laboratory abnormalities, and ECG changes will be captured as AEs when deemed medically significant by the investigator. Adverse events will be assessed during all visits except Visit 1.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Randomized patients
    Reporting group description
    		 -

    Serious adverse events
    		 Randomized patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 138 (4.35%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tongue neoplasm
         subjects affected / exposed
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Coronary arterial stent insertion
         subjects affected / exposed
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Otitis media chronic
         subjects affected / exposed
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2.5%
    Non-serious adverse events
    		 Randomized patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 138 (52.17%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 138 (3.62%)
         occurrences all number
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 138 (0.72%)
         occurrences all number
    3
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    3 / 138 (2.17%)
         occurrences all number
    5
    Injection site reaction
         subjects affected / exposed
    2 / 138 (1.45%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    3 / 138 (2.17%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 138 (4.35%)
         occurrences all number
    7
    nausea
         subjects affected / exposed
    3 / 138 (2.17%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 138 (1.45%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 138 (2.17%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    2 / 138 (1.45%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 138 (1.45%)
         occurrences all number
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    28 / 138 (20.29%)
         occurrences all number
    40
    Oral herpes
         subjects affected / exposed
    4 / 138 (2.90%)
         occurrences all number
    4
    Respiratory tract infection
         subjects affected / exposed
    3 / 138 (2.17%)
         occurrences all number
    7
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 138 (1.45%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 138 (2.17%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2013
    Changes were made due to the deficiency letter of the local ethic.
    17 Dec 2013
    -Additional lab sample for RF/anti-CCP has been added - WOMAC score has been deleted - 2 new sides have been added
    02 May 2014
    - change of address of study aDMINISTRATION - more detailed explanation in the study synopsis has been made (page 8) - correct numeration in "table of contents have been made" - changes in "schedule of assessments" have been made - another side has been added
    10 Dec 2014
    Due to the addition of new countries several changes were needed to harmonize different requirements of each country and to explain things in more detail.
    17 Nov 2015
    - changes of wording have been made
    10 Mar 2017
    - wording has been changed. - table of contents have been adapted - figure has been changed for consistency - -detailed explanation of treatment diagram has been addeed - address for SAE reporting has been changed
    19 Jul 2017
    -wording has been changed - change of Subject infomration "Cimzia"
    21 Sep 2017
    - wording has been changed - change of Principle investigator Erlangen
    12 Nov 2017
    - change in study administration - wording has been changed

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

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