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    Clinical Trial Results:
    A 24-Week Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose Finding Study to Evaluate the Efficacy and Safety of 3 Doses of Namilumab (20 mg, 80 mg and 150 mg) in Combination with Methotrexate (MTX) in Subjects with Moderate to Severe Rheumatoid Arthritis (RA) NEXUS

    Summary
    EudraCT number
    		 2013-002805-76
    Trial protocol
    		 GB   DE   CZ   ES   BG  
    Global end of trial date
    05 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2017
    First version publication date
    01 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M1-1188_202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02379091
    WHO universal trial number (UTN)
    		 U1111-1151-6931
    Other trial identifiers
    		 NRES: 14/SC/1252, JapicCTI: JapicCTI-152979, RNEC: 153300410A0071
    Sponsors
    Sponsor organisation name
    Takeda Development Center Americas Inc.
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL, United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.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
    05 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to establish proof of concept and identify the optimal efficacious dose for namilumab in RA in patients with an inadequate response to methotrexate (MTX-IR) and in patients with an inadequate response to one tumor necrosis factor (TNF)-inhibitor (TNF-IR).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Czech Republic: 35
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 9
    Worldwide total number of subjects
    108
    EEA total number of subjects
    66
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    101
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 28 investigative sites in Bulgaria, Czech Republic, Japan, Poland, Russian Federation, Spain and the United Kingdom from 17 December 2014 to 05 December 2016.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of moderate to severe Rheumatoid Arthritis were enrolled equally in one of 4 treatment groups: placebo or 20, 80, 150 mg/mL namilumab.

    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
    		 Investigator, Monitor, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Namilumab placebo-matching, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Namilumab placebo-matching, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 weeks.

    Arm title
    		 Namilumab 20 mg/mL
    Arm description
    		 Namilumab 20 mg/mL, subcutaneous (SC) injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Namilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Namilumab 20 mg/mL, subcutaneous (SC) injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks.

    Arm title
    		 Namilumab 80 mg/mL
    Arm description
    		 Namilumab 80 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Namilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Namilumab 80 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks.

    Arm title
    		 Namilumab 150 mg/mL
    Arm description
    		 Namilumab 150 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant was discontinued from the study. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Namilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Namilumab 150 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks.

    Number of subjects in period 1
    		Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Started
    27
    28
    25
    28
    Full Analysis set
    26
    28
    24
    28
    Completed
    15
    18
    18
    14
    Not completed
    12
    10
    7
    14
         Pretreatment Event/Adverse Event
    -
    2
    -
    1
         Study Termination
    7
    2
    5
    8
         Voluntary Withdrawal
    2
    5
    2
    4
         Principal Investigator Discretion
    -
    1
    -
    -
         Lost to follow-up
    -
    -
    -
    1
         Lack of efficacy
    3
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Namilumab placebo-matching, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 20 mg/mL
    Reporting group description
    		 Namilumab 20 mg/mL, subcutaneous (SC) injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 80 mg/mL
    Reporting group description
    		 Namilumab 80 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 150 mg/mL
    Reporting group description
    		 Namilumab 150 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant was discontinued from the study. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL Total
    Number of subjects
    		 27 28 25 28 108
    Age Categorical
    Units: Subjects
        < 45 years
    		 9 11 7 7 34
        45 to 64 years
    		 15 16 17 19 67
        65 to 74 years
    		 1 1 1 2 5
        >= 75 years
    		 2 0 0 0 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.2 ( 13.45 ) 46.1 ( 10.07 ) 49.0 ( 9.60 ) 51.3 ( 14.13 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 23 22 17 22 84
        Male
    		 4 6 8 6 24
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 2 1 0 4
        Not Hispanic or Latino
    		 22 22 21 23 88
        Unknown or Not Reported
    		 4 4 3 5 16
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 6 4 3 5 18
        White
    		 21 24 22 22 89
        Multiracial
    		 0 0 0 1 1
    BMI Categories
    Units: Subjects
        < 30 kg/m^2
    		 24 23 16 22 85
        >= 30 kg/m^2
    		 3 5 9 6 23
    Smoking classification
    Units: Subjects
        Participant has never smoked
    		 16 19 18 18 71
        Participant is a current smoker
    		 6 5 5 6 22
        Participant is an ex-smoker
    		 5 4 2 4 15
    Region of Enrollment
    Units: Subjects
        Bulgaria
    		 2 1 1 1 5
        Czech Republic
    		 7 9 9 10 35
        Japan
    		 4 4 3 5 16
        Poland
    		 1 6 4 2 13
        Russia
    		 7 4 6 9 26
        Spain
    		 1 2 1 0 4
        United Kingdom
    		 5 2 1 1 9
    Study Specific Characteristic | Height
    Units: cm
        arithmetic mean (standard deviation)
    		 164.3 ( 10.51 ) 167.7 ( 6.65 ) 167.4 ( 8.36 ) 166.5 ( 9.24 ) -
    Study Specific Characteristic | Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 63.89 ( 14.511 ) 70.28 ( 15.911 ) 76.56 ( 18.660 ) 72.23 ( 19.168 ) -
    Study Specific Characteristic | Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 23.75 ( 5.542 ) 24.91 ( 5.210 ) 27.16 ( 5.605 ) 25.92 ( 6.313 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Namilumab placebo-matching, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 20 mg/mL
    Reporting group description
    		 Namilumab 20 mg/mL, subcutaneous (SC) injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 80 mg/mL
    Reporting group description
    		 Namilumab 80 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 150 mg/mL
    Reporting group description
    		 Namilumab 150 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant was discontinued from the study. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Primary: Change From Baseline in Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) at Week 12

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    End point title
    		 Change From Baseline in Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) at Week 12
    End point description
    The DAS28-CRP score is a measure of the participant’s disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], general health: patient’s global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and acute phase response: C-Reactive Protein (CRP) for a total possible score of 0 (best) to approximately 10 (worst). Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicates improvement. A mixed model repeated measures (MMRM) model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment, visit and previously failed medication, and visit and baseline value as a covariate and participant as a random effect with an unstructured covariance structure was used for analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Number of subjects analysed
    24
    25
    22
    26
    Units: score on a scale
        least squares mean (standard error)
    -0.77 ( 0.294 )
    -1.38 ( 0.288 )
    -1.36 ( 0.302 )
    -1.69 ( 0.286 )
    Statistical analysis title
    		 Placebo vs Namilumab 20 mg/mL
    Comparison groups
    Namilumab 20 mg/mL v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.086 [1]
    Method
    		 ANOVA
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.351
    Notes
    [1] - MMRM model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment, visit and previously failed medication, and visit and baseline value.
    Statistical analysis title
    		 Placebo vs Namilumab 80 mg/mL
    Comparison groups
    Placebo v Namilumab 80 mg/mL
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.107 [2]
    Method
    		 ANOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.366
    Notes
    [2] - MMRM model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment, visit and previously failed medication, and visit and baseline value.
    Statistical analysis title
    		 Placebo vs Namilumab 150 mg/mL
    Comparison groups
    Placebo v Namilumab 150 mg/mL
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.01 [3]
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.347
    Notes
    [3] - MMRM model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment, visit and previously failed medication, and visit and baseline value.

    Secondary: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20), 50% (ACR 50) and 70% (ACR70) Response at Weeks 12 and 24

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    End point title
    		 Percentage of Participants Achieving American College of Rheumatology 20% (ACR20), 50% (ACR 50) and 70% (ACR70) Response at Weeks 12 and 24
    End point description
    ACR20/50/70 response is defined as a ≥20/50/70% reduction from Baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), and the following: • Patient’s Assessment of Pain over the previous 24 hours using a Visual Analog Scale (VAS); left end of the line 0=no pain to right end of the line 100=unbearable pain • Patient’s Global Assessment of Disease Activity • Physician’s Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity • Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do • Acute-phase reactant: C-reactive Protein (CRP).
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 12 and 24
    End point values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Number of subjects analysed
    26
    28
    24
    28
    Units: percentage of participants
    number (not applicable)
        ACR 20, Week 12 (n=24,25,23,26)
    37.5
    72.0
    52.2
    53.8
        ACR 50, Week 12 (n=24,25,23,26)
    16.7
    20.0
    30.4
    38.5
        ACR 70, Week 12 (n=24,25,23,26)
    8.3
    4.0
    21.7
    15.4
        ACR 20, Week 24 (n=21,23,23,25)
    33.3
    65.2
    47.8
    56.0
        ACR 50, Week 24 (n=21,23,23,25)
    23.8
    34.8
    47.8
    36.0
        ACR 70, Week 24 (n=21,23,23,25)
    19.0
    13.0
    30.4
    20.0
    No statistical analyses for this end point

    Secondary: ACR Numeric (N) Index (ACRn) at Week 12

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    End point title
    		 ACR Numeric (N) Index (ACRn) at Week 12
    End point description
    ACRn is defined as the lowest % improvement for TJC68, SJC66 and the median of 5 ACR components. These are • Patient’s Assessment of Pain over previous 24 hours using a VAS; left end of line 0=no pain to right end of line 100=unbearable pain • Patient’s Global Assessment of Disease Activity • Physician’s Global Assessment of Disease Activity over previous 24 hours using a VAS where left end of line 0=no disease activity to right end of line 100=maximum disease activity • Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do • Acute-phase reactant: CRP. A positive % change indicates improvement. MMRM model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment and visit and previously failed medication and participant used as a random effect with an unstructured covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Number of subjects analysed
    24
    25
    23
    26
    Units: percentage change
        least squares mean (standard error)
    -17.25 ( 16.469 )
    3.97 ( 16.372 )
    19.68 ( 16.875 )
    17.14 ( 16.098 )
    No statistical analyses for this end point

    Secondary: ACR Numeric (N) Index (ACRn) at Week 24

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    End point title
    		 ACR Numeric (N) Index (ACRn) at Week 24
    End point description
    ACRn is defined as the lowest % improvement for TJC68, SJC66 and the median of 5 ACR components. These are • Patient’s Assessment of Pain over previous 24 hours using a VAS; left end of line 0=no pain to right end of line 100=unbearable pain • Patient’s Global Assessment of Disease Activity • Physician’s Global Assessment of Disease Activity over previous 24 hours using a VAS where left end of line 0=no disease activity to right end of line 100=maximum disease activity • Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do • Acute-phase reactant: CRP. A positive % change indicates improvement. MMRM model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment and visit and previously failed medication and participant used as a random effect with an unstructured covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Number of subjects analysed
    26
    28
    24
    28
    Units: percentage change
        arithmetic mean (standard deviation)
    34.04 ( 40.248 )
    35.35 ( 50.191 )
    44.66 ( 38.203 )
    36.57 ( 38.709 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in DAS28-CRP at Weeks 2, 6, and 10

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    End point title
    		 Change From Baseline in DAS28-CRP at Weeks 2, 6, and 10
    End point description
    The DAS28-CRP score is a measure of the participant’s disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], general health: patient’s global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and acute phase response: C-Reactive Protein (CRP) for a total possible score of 0 (best) to approximately 10 (worst). Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicates improvement. A MMRM model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment, visit and previously failed medication, and visit and baseline value as a covariate and participant as a random effect with an unstructured covariance structure was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 6 and 10
    End point values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Number of subjects analysed
    26
    28
    24
    28
    Units: score on a scale
    least squares mean (standard error)
        Change at Week 2 (n=26,28,23,28)
    -0.33 ( 0.236 )
    -0.58 ( 0.222 )
    -0.84 ( 0.245 )
    -0.95 ( 0.224 )
        Change at Week 6 (n=25,26,23,27)
    -0.70 ( 0.268 )
    -1.13 ( 0.256 )
    -1.37 ( 0.275 )
    -1.42 ( 0.257 )
        Change at Week 10 (n=25,25,22,27)
    -0.75 ( 0.280 )
    -1.19 ( 0.273 )
    -1.39 ( 0.289 )
    -1.51 ( 0.269 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in DAS28-CRP at Week 24

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    End point title
    		 Change From Baseline in DAS28-CRP at Week 24
    End point description
    The DAS28-CRP score is a measure of the participant’s disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], general health: patient’s global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and acute phase response: C-Reactive Protein (CRP) for a total possible score of 0 (best) to approximately 10 (worst). Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Number of subjects analysed
    12
    18
    16
    17
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.75 ( 1.401 )
    -2.37 ( 1.083 )
    -2.20 ( 1.219 )
    -2.26 ( 0.962 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Reduction of Pain as Measured Using a Visual Analog Scale (VAS) at Weeks 2, 12 and 24

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    End point title
    		 Percentage of Participants with a Reduction of Pain as Measured Using a Visual Analog Scale (VAS) at Weeks 2, 12 and 24
    End point description
    Reduction of Pain, defined as a ≥40% change from Baseline as measured using a 100 mm Visual Analog Scale (VAS); left end of the line 0=no pain to right end of the line 100=unbearable pain at weeks 2, 12 and 24.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2, 12 and 24
    End point values
    		 Placebo Namilumab 20 mg/mL Namilumab 80 mg/mL Namilumab 150 mg/mL
    Number of subjects analysed
    26
    28
    24
    28
    Units: percentage of participants
    number (not applicable)
        Week 2 (n=26,28,23,28)
    7.7
    14.3
    8.7
    3.6
        Week 12 (n=24,25,23,26)
    20.8
    44.0
    39.1
    30.8
        Week 24 (n=22,23,23,25)
    22.7
    43.5
    47.8
    24.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to 30 days after last dose of study drug (Up to 46.4 Weeks)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Namilumab 20 mg/mL
    Reporting group description
    		 Namilumab 20 mg/mL, subcutaneous (SC) injection, once on Days 1, 15, 43, 71 and every 4 weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Placebo
    Reporting group description
    		 Namilumab placebo-matching, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 150 mg/mL
    Reporting group description
    		 Namilumab 150 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Placebo to Namilumab 150 mg/mL
    Reporting group description
    		 Namilumab placebo-matching, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks up to Week 12; followed by Namilumab 150 mg/mL, SC injection, every 4 weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab 80 mg/mL
    Reporting group description
    		 Namilumab 80 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Reporting group title
    Namilumab to Namilumab 150 mg/mL
    Reporting group description
    		 Namilumab 20 or 80 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks up to Week 12; followed by namilumab 150 mg/mL, SC injection, every 4 weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

    Serious adverse events
    		 Namilumab 20 mg/mL Placebo Namilumab 150 mg/mL Placebo to Namilumab 150 mg/mL Namilumab 80 mg/mL Namilumab to Namilumab 150 mg/mL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    1 / 28 (3.57%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
    4 / 24 (16.67%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    1 / 28 (3.57%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Namilumab 20 mg/mL Placebo Namilumab 150 mg/mL Placebo to Namilumab 150 mg/mL Namilumab 80 mg/mL Namilumab to Namilumab 150 mg/mL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 28 (46.43%)
    9 / 27 (33.33%)
    12 / 28 (42.86%)
    5 / 12 (41.67%)
    12 / 25 (48.00%)
    6 / 24 (25.00%)
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    2 / 28 (7.14%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 27 (3.70%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    3 / 25 (12.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    0
    0
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
    0 / 28 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
    3 / 28 (10.71%)
    1 / 12 (8.33%)
    2 / 25 (8.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    3
    1
    2
    0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    2 / 25 (8.00%)
    1 / 24 (4.17%)
         occurrences all number
    3
    0
    0
    0
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 28 (25.00%)
    5 / 27 (18.52%)
    5 / 28 (17.86%)
    0 / 12 (0.00%)
    2 / 25 (8.00%)
    1 / 24 (4.17%)
         occurrences all number
    8
    6
    5
    0
    2
    1
    Bronchitis
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 27 (7.41%)
    1 / 28 (3.57%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    1
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    2 / 28 (7.14%)
    0 / 12 (0.00%)
    2 / 25 (8.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    3
    0
    2
    1
    Laryngitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    0 / 12 (0.00%)
    2 / 25 (8.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
    0 / 28 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2014
    The protocol was amended to clarify the study populations, secondary and exploratory endpoints, statistical analysis, biomarker analyses, and blood sample collection time points. The following summarizes the significant changes made in the amendment: 1) Updated the nonclinical and clinical background sections; 2) Updated the objectives and endpoints sections; 3) Clarified the study design and description sections; 4) Updated the TNF-IR and MTX population balance 5) Addition of language for screening subjects in Asia; 6) Changed the inclusion and exclusion criteria; 7) Clarified the excluded medications and treatments sections; 8) Amended the blood sample collection, laboratory test and lung function test parameters to exclusion criteria; 9) Changed the statistical analysis section; 10) Addition of information regarding management of AEs.
    02 Apr 2015
    The protocol was amended to include Japan in the study. The following summarizes the significant changes made in the amendment: 1) Updated the sponsorship for the study; 2) Changed the Takeda representative’s approval; 3) Updated the MTX-IR population; 4) Clarified regarding statistical considerations, especially in regard to modeling and Stratification; 5) Addition of Japan; 6) Japan specific visit, and procedures and processes; 7) Updated the biomarker sampling; 8) Revised contraception and pregnancy avoidance counselling; 9) Updated sponsor supplied companion medication.
    21 Jan 2016
    The primary purpose of this amendment was to remove the extension period of the study and reduce the overall sample size to approximately 100 subjects. The following summarizes the significant changes made in the amendment: 1) Reduced the minimum number of subjects assigned to each treatment group; 2) Removed the minimum number requirement for TNF-IR subjects; 3) Included a primary analysis once all subjects had completed 12 weeks of treatment; 4) Revised the section for sample size justification; 5) Updated timing of the PGx analysis; 6) Allowed prior treatment with 1 immunomodulatory biological agent or kinase inhibitor; 7) Updated exclusion criteria around lung function and management of associated AEs; 8) Clarified excluded medications and treatments.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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