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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase II Study to Evaluate the Safety and Efficacy of RO7123520 as Adjunct Treatment in Patients with Moderately to Severely Active Rheumatoid Arthritis

    Summary
    EudraCT number
    		 2016-002126-36
    Trial protocol
    		 AT   DE   ES   IT  
    Global end of trial date
    06 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Nov 2019
    First version publication date
    20 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BP39261
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03001219
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    06 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of RO7123520 as adjunctive therapy in patients with RA who were inadequately responding to standard-of-care (methotrexate (MTX) and anti-TNF-a therapy).
    Protection of trial subjects
    All subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2016
    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
    Argentina: 9
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Guatemala: 3
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Mexico: 33
    Country: Number of subjects enrolled
    Peru: 9
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    118
    EEA total number of subjects
    16
    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)
    92
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult men and women with moderate to severe active rheumatoid arthritis (RA) who experience an inadequate response to disease-modifying anti-rheumatic drug (DMARD) therapy with MTX plus anti-TNF-a therapy.

    Pre-assignment
    Screening details
    		 Proof of Concept: Subjects received either placebo or 810 mg/dose of RO7123520. Extension Period Analysis: Subjects were given the option to continue in an optional extension period. Subjects received either 360 mg/dose or 810 mg/dose of RO7123520. Part 3 was not conducted due to early study termination.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Proof of Concept: Placebo
    Arm description
    		 Participants received placebo (IV saline matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously (IV) on Days 1, 14, 28, and 56.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Tablet, Powder for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Oral use, Subcutaneous use, Intramuscular use
    Dosage and administration details
    Subjects must have been on stable regimens of MTX (i.e. 5.0-25 mg/wk) for at least 4 weeks prior to randomization.

    Investigational medicinal product name
    Anti-TNF-alpha
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Subjects must have been on stable regimens of anti-TNF-alpha therapy at the recommended dose for at least 12 weeks prior to randomization.

    Arm title
    		 Proof of Concept: RO7123520 810mg/dose
    Arm description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO7123520
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Tablet, Powder for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Oral use, Subcutaneous use, Intramuscular use
    Dosage and administration details
    Subjects must have been on stable regimens of MTX (i.e. 5.0-25 mg/wk) for at least 4 weeks prior to randomization.

    Investigational medicinal product name
    Anti-TNF-alpha
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Subjects must have been on stable regimens of anti-TNF-alpha therapy at the recommended dose for at least 12 weeks prior to randomization.

    Arm title
    		 Extension Period Analysis: RO7123520 360mg/dose
    Arm description
    		 Participants received 360mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO7123520
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 360mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Tablet, Powder for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Oral use, Subcutaneous use, Intramuscular use
    Dosage and administration details
    Subjects must have been on stable regimens of MTX (i.e. 5.0-25 mg/wk) for at least 4 weeks prior to randomization.

    Investigational medicinal product name
    Anti-TNF-alpha
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Subjects must have been on stable regimens of anti-TNF-alpha therapy at the recommended dose for at least 12 weeks prior to randomization.

    Arm title
    		 Extension Period Analysis: RO7123520 810mg/dose
    Arm description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO7123520
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Solution for injection/infusion, Tablet, Powder for solution for injection/infusion
    Routes of administration
    Oral use, Subcutaneous use, Intramuscular use
    Dosage and administration details
    Subjects must have been on stable regimens of MTX (i.e. 5.0-25 mg/wk) for at least 4 weeks prior to randomization.

    Investigational medicinal product name
    Anti-TNF-alpha
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Subjects must have been on stable regimens of anti-TNF-alpha therapy at the recommended dose for at least 12 weeks prior to randomization.

    Number of subjects in period 1
    		Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Started
    37
    72
    9
    97
    Completed
    35
    65
    4
    52
    Not completed
    2
    7
    5
    45
         Physician decision
    1
    -
    -
    1
         Consent withdrawn by subject
    -
    4
    4
    5
         Participant Non-Compliance
    -
    -
    -
    1
         Adverse event, non-fatal
    1
    1
    1
    1
         Protocol Deviation
    -
    1
    -
    1
         Study Termination by Sponsor
    -
    1
    -
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Proof of Concept: Placebo
    Reporting group description
    		 Participants received placebo (IV saline matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Proof of Concept: RO7123520 810mg/dose
    Reporting group description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Extension Period Analysis: RO7123520 360mg/dose
    Reporting group description
    		 Participants received 360mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Extension Period Analysis: RO7123520 810mg/dose
    Reporting group description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose Total
    Number of subjects
    		 37 72 9 97 118
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 28 59 5 78 92
        From 65-84 years
    		 9 13 4 19 26
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.7 ± 14.1 52.3 ± 12.3 56.6 ± 14.3 53.4 ± 12.8 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 32 66 6 87 104
        Male
    		 5 6 3 10 14
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 27 54 1 73 82
        Not Hispanic or Latino
    		 10 18 8 24 36
        Unknown or Not Reported
    		 0 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 7 12 0 16 19
        Asian
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 1 1 2 2 4
        White
    		 25 52 7 68 84
        More than one race
    		 2 4 0 6 6
        Unknown or Not Reported
    		 2 3 0 5 5

    End points

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    End points reporting groups
    Reporting group title
    Proof of Concept: Placebo
    Reporting group description
    		 Participants received placebo (IV saline matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Proof of Concept: RO7123520 810mg/dose
    Reporting group description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Extension Period Analysis: RO7123520 360mg/dose
    Reporting group description
    		 Participants received 360mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Extension Period Analysis: RO7123520 810mg/dose
    Reporting group description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Primary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events [1]
    End point description
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Primary
    End point timeframe
    Baseline to end of study (approximately 2 years)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Numbers provided are the percentage. No statistical analysis is performed on numbers/percentage of AEs.
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    70
    9
    97
    Units: Percent
        number (not applicable)
    48.6
    60.0
    66.7
    60.8
    No statistical analyses for this end point

    Primary: Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12

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    End point title
    		 Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12 [2]
    End point description
    The ACR50 is a composite measure defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Numbers provided are a proportion. No statistical analysis is performed on proportions for this endpoint.
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    72
    9
    97
    Units: Percent
        number (confidence interval 90%)
    16.2 (7.67 to 29.95)
    11.1 (5.86 to 19.48)
    0 (0 to 30.89)
    1.0 (0.07 to 5.28)
    No statistical analyses for this end point

    Primary: Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans

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    End point title
    		 Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans [3]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned due to early study termination due to futility (not due to safety issues).
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    67 [4]
    9 [5]
    94 [6]
    Units: g/cm^2
    arithmetic mean (standard deviation)
        Baseline
    1.02 ± 0.21
    2.51 ± 12.46
    1.17 ± 0.20
    2.06 ± 10.53
        Week 12
    -0.06 ± 0.20
    0.71 ± 5.50
    -0.01 ± 0.04
    0.58 ± 4.98
    Notes
    [4] - Week 12 n=59
    [5] - Week 12 n=6
    [6] - Week 12 n=72
    No statistical analyses for this end point

    Primary: Percentage of Participants With Anti-Drug Antibodies

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies [7] [8]
    End point description
    The immunogenicity population included participants with at least 1 pre-dose ADA assessment, grouped by treatment and dose level.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Numbers provided are the percentage. No statistical analysis is performed on numbers/percentage of AEs.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Numbers provided are the percentage. No statistical analysis is performed on numbers/percentage of ADAs.
    End point values
    		 Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    69
    Units: Percent
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12

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    End point title
    		 Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12
    End point description
    The CDAI for Rheumatoid Arthritis (RA) assesses the severity of the disease using clinical data. It consists of the Patient Global disease Activity (PGA) estimate and the Evaluator Global disease Activity (EGA) estimate, each of which represent assessments of disease activity on a scale of 1-10, with 10 being maximum activity. -9999 = Data was not reported for this arm at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    69 [9]
    9
    96 [10]
    Units: No Units
    arithmetic mean (standard deviation)
        Baseline
    37.05 ± 10.99
    37.38 ± 13.14
    30.89 ± 15.31
    32.17 ± 15.91
        Week 12
    -17.44 ± 15.11
    -14.44 ± 13.96
    -9999 ± 0
    -9999 ± 0
    Notes
    [9] - Week 12 n=65
    [10] - Week 12 n=97
    No statistical analyses for this end point

    Secondary: Change From Baseline in Disease Activity Score 28 (DAS28) at Week 12

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    End point title
    		 Change From Baseline in Disease Activity Score 28 (DAS28) at Week 12
    End point description
    The DAS28 is a combined index for measuring disease activity in RA; the "28" refers to the number of joints included in the assessment. The index includes swollen and tender joint counts, acute phase response, and general arthritis disease activity status. An overall disease activity score of 5.1 or greater implies active disease, less than 3.2 implies low disease activity, and less that 2.6 implies disease remission. -9999 = Data was not reported for this arm at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    72
    9
    97
    Units: No Units
    arithmetic mean (standard deviation)
        Baseline
    6.29 ± 0.78
    6.28 ± 1.03
    5.42 ± 1.63
    5.82 ± 1.28
        Week 12
    -1.62 ± 1.28
    -1.15 ± 1.06
    -9999 ± 0
    -9999 ± 0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving DAS28 Remission at Week 12

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    End point title
    		 Percentage of Participants Achieving DAS28 Remission at Week 12
    End point description
    The DAS28 is a combined index for measuring disease activity in RA; the "28" refers to the number of joints included in the assessment. The index includes swollen and tender joint counts, acute phase response, and general arthritis disease activity status. An overall disease activity score of 5.1 or greater implies active disease, less than 3.2 implies low disease activity, and less that 2.6 implies disease remission. -9999 = Data was not reported for this arm at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    72
    9
    97
    Units: Percent
        number (not applicable)
    0
    1.4
    -9999
    -9999
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving CDAI Remission at Week 12

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    End point title
    		 Percentage of Participants Achieving CDAI Remission at Week 12
    End point description
    The CDAI for Rheumatoid Arthritis (RA) assesses the severity of the disease using clinical data. It consists of the Patient Global disease Activity (PGA) estimate and the Evaluator Global disease Activity (EGA) estimate, each of which represent assessments of disease activity on a scale of 1-10, with 10 being maximum activity. CDAI remission is defined as a score of less than or equal to 2.8. -9999 = Data was not reported for this arm at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    72
    9
    97
    Units: Percent
        number (not applicable)
    0
    1.4
    -9999
    -9999
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving ACR20 Response at Week 12

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    End point title
    		 Percentage of Participants Achieving ACR20 Response at Week 12
    End point description
    The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    72
    9
    97
    Units: Percent
        number (confidence interval 90%)
    43.2 (29.55 to 57.94)
    27.8 (19.42 to 37.88)
    0 (0.00 to 30.89)
    11.3 (6.66 to 18.32)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving ACR70 Response at Week 12

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    End point title
    		 Percentage of Participants Achieving ACR70 Response at Week 12
    End point description
    The ACR70 is a composite measure defined as both improvement of 70% in the number of tender and number of swollen joints, and a 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    72
    9
    97
    Units: Percent
        number (confidence interval 90%)
    0 (0.00 to 9.15)
    1.4 (0.10 to 7.04)
    0 (0.00 to 30.89)
    0 (0.00 to 3.65)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Simple Disease Activity Index (SDAI) Score at Week 12

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    End point title
    		 Change From Baseline in Simple Disease Activity Index (SDAI) Score at Week 12
    End point description
    The SDAI consists of 5 parameters used to assess RA disease activity: 28-joint count assessments of tenderness and swelling, participant and investigator global assessments, and CRP levels. A composite score is produced, with remission defined as an SDAI of <3.3, low disease activity as ≤11, moderate disease activity as ≤26 and high disease activity as >26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37 [11]
    69 [12]
    9 [13]
    96 [14]
    Units: No Units
    arithmetic mean (standard deviation)
        Baseline
    38.84 ± 10.58
    39.02 ± 14.55
    31.23 ± 15.25
    34.08 ± 16.69
        Week 12
    -17.48 ± 14.48
    -14.99 ± 15.19
    -15.33 ± 18.24
    -13.15 ± 14.56
    Notes
    [11] - Week 12 n=34
    [12] - Week 12 n=65
    [13] - Week 12 n=6
    [14] - Week 12 n=80
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12

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    End point title
    		 Change From Baseline in the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12
    End point description
    The HAQ-DI is a 20-item, validated questionnaire used to assess difficulty in performing activities of daily living. The questionnaire assesses eight domains of physical functioning: Dressing and Grooming (2 items), Hygiene (3 items), Arising (2 items), Reach (2 items), Eating (3 items), Grip (3 items), Walking (2 items), Common Daily Activities (3 items). The questions assess usual abilities ranging from 0 “without any difficulty” to 3 “unable to do.” A lower HAQ-DI score indicates better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    37
    70 [15]
    9 [16]
    96 [17]
    Units: No Units
    arithmetic mean (standard deviation)
        Baseline
    1.63 ± 0.64
    1.61 ± 0.76
    1.29 ± 0.70
    1.59 ± 0.71
        Week 12
    -0.15 ± 0.52
    -0.24 ± 0.51
    -0.21 ± 0.74
    -0.21 ± 0.49
    Notes
    [15] - Week 12 n=65
    [16] - Week 12 n=6
    [17] - Week 12 n=81
    No statistical analyses for this end point

    Secondary: Serum RO7123520 Concentration

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    End point title
    		 Serum RO7123520 Concentration
    End point description
    All enrolled participants were included in the PK population.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 1 hour post infusion (duration of infusion: approximately 1 hour) on Days 1, 14, 28, 56; Pre-dose (0 hour) on Days 84, 112
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    Units: No Units
    Notes
    [18] - No PK analysis was performed due to an insufficient number of available participant samples.
    [19] - No PK analysis was performed due to an insufficient number of available participant samples.
    [20] - No PK analysis was performed due to an insufficient number of available participant samples.
    [21] - No PK analysis was performed due to an insufficient number of available participant samples.
    No statistical analyses for this end point

    Secondary: Synovial Fluid RO7123520 Concentration

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    End point title
    		 Synovial Fluid RO7123520 Concentration
    End point description
    All enrolled participants were included in the PK population.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Days 1, 84
    End point values
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Number of subjects analysed
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    Units: No Units
    Notes
    [22] - No PK analysis was performed due to an insufficient number of available participant samples.
    [23] - No PK analysis was performed due to an insufficient number of available participant samples.
    [24] - No PK analysis was performed due to an insufficient number of available participant samples.
    [25] - No PK analysis was performed due to an insufficient number of available participant samples.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through end of study (approximately 2 years)
    Adverse event reporting additional description
    The safety population included participants who received at lease one dose of study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Proof of Concept: Placebo
    Reporting group description
    		 Participants received placebo (IV saline matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Proof of Concept: RO7123520 810mg/dose
    Reporting group description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Extension Period Analysis: RO7123520 360mg/dose
    Reporting group description
    		 Participants received 360mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Reporting group title
    Extension Period Analysis: RO7123520 810mg/dose
    Reporting group description
    		 Participants received 810mg of RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

    Serious adverse events
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 70 (1.43%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 70 (1.43%)
    0 / 9 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 70 (0.00%)
    0 / 9 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Proof of Concept: Placebo Proof of Concept: RO7123520 810mg/dose Extension Period Analysis: RO7123520 360mg/dose Extension Period Analysis: RO7123520 810mg/dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 37 (27.03%)
    10 / 70 (14.29%)
    6 / 9 (66.67%)
    17 / 97 (17.53%)
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 70 (0.00%)
    0 / 9 (0.00%)
    0 / 97 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Computerised tomogram abnormal
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 70 (1.43%)
    1 / 9 (11.11%)
    1 / 97 (1.03%)
         occurrences all number
    3
    1
    1
    1
    Dizziness
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 70 (1.43%)
    1 / 9 (11.11%)
    1 / 97 (1.03%)
         occurrences all number
    2
    1
    1
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 70 (0.00%)
    0 / 9 (0.00%)
    0 / 97 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    3 / 97 (3.09%)
         occurrences all number
    0
    0
    1
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Neck mass
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    1 / 97 (1.03%)
         occurrences all number
    0
    0
    1
    1
    Infections and infestations
    Chronic tonsillitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Laryngitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    1 / 97 (1.03%)
         occurrences all number
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    2 / 97 (2.06%)
         occurrences all number
    0
    0
    1
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    0 / 9 (0.00%)
    9 / 97 (9.28%)
         occurrences all number
    0
    0
    0
    12
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 70 (5.71%)
    0 / 9 (0.00%)
    0 / 97 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 70 (5.71%)
    0 / 9 (0.00%)
    0 / 97 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 70 (0.00%)
    1 / 9 (11.11%)
    0 / 97 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2016
    Modified inclusion/exclusion criteria
    09 May 2017
    Clarified total study duration, modified safety outcome measures, modified inclusion/exclusion criteria
    28 Mar 2018
    Inclusion criteria modified, allowed concomitant treatment with non-biological agents, modified allowed dose range for MTX, expanded age range for eligible population

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was prematurely terminated due to a lack of efficacy of the investigational drug. There were no serious safety issues or adverse events contributing to the decision to terminate early.
    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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