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    Clinical Trial Results:
    A randomised, double blind, placebo-controlled, multiple dose, phase 2b, 24 week trial followed by an open label extension of NNC0109-0012, an anti-IL-20 biologic, in patients with active rheumatoid arthritis who are inadequate responders to Methotrexate

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2012-000610-11
    Trial protocol
    BE   HU   CZ   DE   ES   IT  
    Global end of trial date
    10 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    20 May 2016
    First version publication date
    20 May 2016
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    NN8226-3613
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01636843
    WHO universal trial number (UTN)
    U1111-1127-9324
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the clinical efficacy of NNC0109-0012 compared to placebo when administered as weekly repeat subcutaneous (s.c., under the skin) injections in patients with active rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX) while on a stable background of MTX therapy.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, October 2000, Amended 2002, 2004 and 2008, International Conference on Harmonisation (ICH) Good Clinical Practice, May 1996. Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 312.120, and 21 CFR, parts 312, 50, and 56 were followed for United States (US) trial sites.
    Background therapy
    All subjects were on a stable background treatment with methotrexate (MTX); MTX treatment for at least 16 weeks at a dose of ≥15.0 mg/week to ≤25 mg/week and at a stable dose for at least 8 weeks prior to the screening visit. Subjects could be on MTX as low as 10 mg/week only if due to documented MTX intolerance, stable dose for at least 8 weeks prior to the screening visit. Additional background treatments could have included hydroxychloroquine/chloroquine, non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal medication.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    30 Oct 2012
    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
    Poland: 12
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Argentina: 51
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Mexico: 37
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    Ukraine: 73
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    298
    EEA total number of subjects
    52
    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)
    252
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 80 sites in 14 countries; Argentina: 6 sites; Belgium: 1 site; Brazil: 8 sites; Czech Republic: 6 sites; France: 1 site; Germany: 1 site; Hungary: 1 site; Italy: 1 site; Mexico: 8 sites; Poland: 6 sites; Russian Federation: 9 sites; Spain: 5 sites; Ukraine: 15 sites; United States: 12 sites.

    Pre-assignment
    Screening details
    Of 739 subjects screened, 441 were screen failures, with 298 randomized to either placebo or one of the 3 doses of NNC0109-0012 (i.e., 60 mg/120 mg/240 mg).

    Period 1
    Period 1 title
    Main Trial Period (week 0-24)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The trial period consisted of a 24-week double-blinded and a 28-week open label extension in which investigators and subjects were still blinded. Blinding was kept for all staff involved in trial-related activities at the site and at the sponsor. After all subjects had completed the week 24 assessment, a planned week 24 partial Database Lock (DBL) was performed, and the treatment codes for all subjects released to selected individuals at the sponsor for statistical analyses.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Main-Placebo
    Arm description
    Subjects received NNC0109-0012 placebo once weekly for a duration of 24-week (double-blinded main treatment period).
    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
    NNC0109-0012 placebo was administered once weekly with NovoPen®4 by subcutaneous (s.c., under the skin) injection.

    Arm title
    Main-60 mg
    Arm description
    Subjects received 60 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0109-0012
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NNC0109-0012, 60 mg was administered once weekly with NovoPen®4 by s.c. injection.

    Arm title
    Main-120 mg
    Arm description
    Subjects received 120 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0109-0012
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NNC0109-0012, 120 mg was administered once weekly with NovoPen®4 by s.c. injection.

    Arm title
    Main-240 mg
    Arm description
    Subjects received 240 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0109-0012
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NNC0109-0012, 240 mg was administered once weekly with NovoPen®4 by s.c. injection.

    Number of subjects in period 1
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Started
    75
    74
    74
    75
    Completed
    55
    53
    48
    52
    Not completed
    20
    21
    26
    23
         Adverse event, non-fatal
    3
    3
    1
    -
         Withdrawal criteria
    13
    18
    25
    21
         Unclassified
    1
    -
    -
    -
         Lost to follow-up
    2
    -
    -
    -
         Protocol deviation
    1
    -
    -
    -
         Lack of efficacy
    -
    -
    -
    2
    Period 2
    Period 2 title
    Extension Trial Period (Week 25-52)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The trial period consisted of a 24-week double-blinded and a 28-week open label extension in which investigators and subjects were still blinded. After week 24 partial DBL analysis, the decision was made to discontinue the trial because of failure to reach the primary efficacy endpoint.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Extension-Placebo-240 mg
    Arm description
    Subjects, who demonstrated at least a 20% improvement over baseline in tender joint count (TJC) and swollen joint count (SJC) at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to placebo in the main treatment period (week 0-24), were to be switched to NNC0109-0012, 240 mg, in the 28-week open-label extension treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0109-0012
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NNC0109-0012, 240 mg was administered once weekly with NovoPen®4 by s.c. injection.

    Arm title
    Extension-60-60 mg
    Arm description
    Subjects, who demonstrated at least a 20% improvement over baseline in TJC and SJC at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 60 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0109-0012
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NNC0109-0012, 60 mg was administered once weekly with NovoPen®4 by s.c. injection.

    Arm title
    Extension-120-120 mg
    Arm description
    Subjects, who demonstrated at least a 20% improvement over baseline in TJC and SJC at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 120 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0109-0012
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NNC0109-0012, 120 mg was administered once weekly with NovoPen®4 by s.c. injection.

    Arm title
    Extension-240-240 mg
    Arm description
    Subjects, who demonstrated at least a 20% improvement over baseline in TJC and SJC at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 240 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0109-0012
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NNC0109-0012, 240 mg was administered once weekly with NovoPen®4 by s.c. injection.

    Number of subjects in period 2 [1]
    Extension-Placebo-240 mg Extension-60-60 mg Extension-120-120 mg Extension-240-240 mg
    Started
    53
    50
    45
    51
    Completed
    20
    24
    20
    19
    Not completed
    33
    26
    25
    32
         Adverse event, serious fatal
    1
    -
    -
    -
         Adverse event, non-fatal
    2
    1
    4
    1
         Withdrawal criteria
    30
    24
    21
    31
         Protocol deviation
    -
    1
    -
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Number of subjects completed the main trial period = 208. Number of subjects started the extension trial period = 199. Number of subjects completed main trial period, but did not enter extension trial period = 9 (2 in placebo [1 due to protocol deviation and 1 met withdrawal criteria]; 3 [all met withdrawal criteria] in main-60 mg; 3 [1 due to AE-non fatal and 2 met withdrawal criteria] in main-120 mg; and 1 [due to AE-non fatal] in main-240 mg.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main-Placebo
    Reporting group description
    Subjects received NNC0109-0012 placebo once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-60 mg
    Reporting group description
    Subjects received 60 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-120 mg
    Reporting group description
    Subjects received 120 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-240 mg
    Reporting group description
    Subjects received 240 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg Total
    Number of subjects
    75 74 74 75 298
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.3 ( 12.5 ) 51.7 ( 11.7 ) 52.4 ( 12 ) 50.4 ( 11 ) -
    Gender categorical
    Units: Subjects
        Female
    63 59 55 60 237
        Male
    12 15 19 15 61
    Duration of Rheumatoid Arthritis
    Units: Years
        arithmetic mean (standard deviation)
    5.8 ( 5.6 ) 8.3 ( 10.1 ) 8.3 ( 7.9 ) 6.5 ( 5.3 ) -
    C-reactive protein (CRP)
    Units: mg/L
        geometric mean (full range (min-max))
    14.3 (0.5 to 96) 20.1 (0.7 to 214.9) 15.3 (0.7 to 123.1) 16.7 (0.8 to 137.8) -
    Disease activity score in 28 joints (DAS28)
    Units: CRP
        arithmetic mean (standard deviation)
    6.3 ( 0.8 ) 6.3 ( 0.7 ) 6.3 ( 0.9 ) 6.3 ( 0.7 ) -
    Tender joint count (TJC)28
    Units: Number
        arithmetic mean (standard deviation)
    18.5 ( 6.4 ) 17.2 ( 6.3 ) 18.2 ( 6.4 ) 17.7 ( 6.2 ) -
    Swollen joint count (SJC)28
    Units: Number
        arithmetic mean (standard deviation)
    15.3 ( 5.4 ) 13.5 ( 5.3 ) 13.8 ( 5.6 ) 13.9 ( 4.7 ) -
    Tender joint count (TJC)68
    Units: Number
        arithmetic mean (standard deviation)
    33.2 ( 14 ) 28.1 ( 14 ) 30.7 ( 15.3 ) 30.4 ( 13.3 ) -
    Swollen joint count (SJC)66
    Units: Number
        arithmetic mean (standard deviation)
    21.8 ( 9.8 ) 17.7 ( 8.1 ) 18.5 ( 9.1 ) 18.8 ( 7.6 ) -
    Pain (visual analogue scale [VAS])
    Units: Centimeter
        arithmetic mean (standard deviation)
    6.5 ( 2.3 ) 6.8 ( 1.7 ) 6.8 ( 1.9 ) 6.7 ( 2.1 ) -
    Patient’s Global Assessment of disease activity (PtGA) (VAS)
    Units: Centimeter
        arithmetic mean (standard deviation)
    6.7 ( 2.2 ) 6.8 ( 1.7 ) 6.7 ( 2 ) 7 ( 1.9 ) -
    Physician’s Global Assessment of disease activity (PhGA) (VAS)
    Units: Centimeter
        arithmetic mean (standard deviation)
    7 ( 1.5 ) 6.9 ( 1.7 ) 6.9 ( 1.4 ) 6.9 ( 1.4 ) -
    Health Assessment Questionnaire-Disability Index (HAQ-DI)
    Units: Points
        arithmetic mean (standard deviation)
    1.8 ( 0.5 ) 1.8 ( 0.6 ) 1.7 ( 0.6 ) 1.7 ( 0.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Main-Placebo
    Reporting group description
    Subjects received NNC0109-0012 placebo once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-60 mg
    Reporting group description
    Subjects received 60 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-120 mg
    Reporting group description
    Subjects received 120 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-240 mg
    Reporting group description
    Subjects received 240 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).
    Reporting group title
    Extension-Placebo-240 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in tender joint count (TJC) and swollen joint count (SJC) at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to placebo in the main treatment period (week 0-24), were to be switched to NNC0109-0012, 240 mg, in the 28-week open-label extension treatment period.

    Reporting group title
    Extension-60-60 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in TJC and SJC at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 60 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.

    Reporting group title
    Extension-120-120 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in TJC and SJC at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 120 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.

    Reporting group title
    Extension-240-240 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in TJC and SJC at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 240 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.

    Primary: ACR20 (defined as 20% improvement in American College of Rheumatology criteria measures) (i.e., responder or non-responder)

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    End point title
    ACR20 (defined as 20% improvement in American College of Rheumatology criteria measures) (i.e., responder or non-responder)
    End point description
    American College of Rheumatology (ACR)20 response was achieved at week 12, if there was an improvement equal to or greater than 20% from baseline in the following assessment: 1) Improvement in the swollen joint count (66 out of 68 joints; excludes hips) 2) Improvement in the tender joint count (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments: i) Patient’s assessment of pain (visual analogue scale [VAS]) ii) Patient’s Global Assessment of disease activity (PtGA) (VAS) iii) Physician’s Global Assessment of disease activity (PhGA) (VAS) iv) Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI; patient reported outcomes [PRO]) v) C-reactive protein (CRP) Analysis population: The full analysis set (FAS) included all randomised subjects. Missing data were imputed using last observation carried forward (LOCF).
    End point type
    Primary
    End point timeframe
    At Week 12
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: Percentage of subjects
    number (not applicable)
        Responder
    54.7
    59.5
    50
    53.3
        Non-responder
    45.3
    40.5
    50
    46.7
    Statistical analysis title
    Main-240 mg versus main-placebo
    Statistical analysis description
    This binary endpoint was analysed using a logistic regression model; the model included stratum (positive or negative rheumatoid factor [RF]/anti-cyclic citrullinated protein antibodies [anti-CCP] at screening) and treatment as fixed factors and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP) at baseline and duration of RA at baseline as continuous covariates. Comparison groups: main-240 mg versus main-placebo.
    Comparison groups
    Main-Placebo v Main-240 mg
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.9572 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.88
    Notes
    [1] - The statistical analyses sought to determine which doses of NNC0109-0012 were effective, and to describe the dose-response relationship for NNC0109-0012. The dose levels of NNC0109-0012 were compared to placebo in a hierarchical manner, starting by comparing the highest dose level of NNC0109-0012 to placebo.
    [2] - p-values below 5% were regarded as statistically significant.
    Statistical analysis title
    Main-120 mg versus main-placebo
    Statistical analysis description
    This binary endpoint was analysed using a logistic regression model; the model included stratum (positive or negative rheumatoid factor [RF]/anti-cyclic citrullinated protein antibodies [anti-CCP] at screening) and treatment as fixed factors and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP) at baseline and duration of RA at baseline as continuous covariates. Comparison groups: main-120 mg versus main-placebo.
    Comparison groups
    Main-Placebo v Main-120 mg
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.8453 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.81
    Notes
    [3] - The statistical analyses sought to determine which doses of NNC0109-0012 were effective, and to describe the dose-response relationship for NNC0109-0012. The dose levels of NNC0109-0012 were compared to placebo in a hierarchical manner, starting by comparing the highest dose level of NNC0109-0012 to placebo.
    [4] - p-values below 5% were regarded as statistically significant.
    Statistical analysis title
    Main-60 mg versus main-placebo
    Statistical analysis description
    This binary endpoint was analysed using a logistic regression model; the model included stratum (positive or negative rheumatoid factor [RF]/anti-cyclic citrullinated protein antibodies [anti-CCP] at screening) and treatment as fixed factors and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP) at baseline and duration of RA at baseline as continuous covariates. Comparison groups: main-60 mg versus main-placebo.
    Comparison groups
    Main-Placebo v Main-60 mg
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.353 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    2.67
    Notes
    [5] - The statistical analyses sought to determine which doses of NNC0109-0012 were effective, and to describe the dose-response relationship for NNC0109-0012. The dose levels of NNC0109-0012 were compared to placebo in a hierarchical manner, starting by comparing the highest dose level of NNC0109-0012 to placebo.
    [6] - p-values below 5% were regarded as statistically significant.

    Secondary: ACR20

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    End point title
    ACR20
    End point description
    ACR20 response was achieved at week 24, if there was an improvement equal to or greater than 20% from baseline in the following assessment: 1) Improvement in the swollen joint count (66 out of 68 joints; excludes hips) 2) Improvement in the tender joint count (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments i) Patient’s assessment of pain (VAS) ii) Patient’s Global Assessment of disease activity (PtGA) (VAS) iii) Physician’s Global Assessment of disease activity (PhGA) (VAS) iv) Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI; PRO) v) C-reactive protein (CRP) Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF. Due to the premature termination of this study, this endpoint was analysed only at the pre-planned week 24 time point, but could not be analysed at the pre-planned week 52 time point.
    End point type
    Secondary
    End point timeframe
    At week 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: Percentage of subjects
    number (not applicable)
        Responder
    60
    58.1
    47.3
    52
        Non-responder
    40
    41.9
    52.7
    48
    No statistical analyses for this end point

    Secondary: ACR50

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    End point title
    ACR50
    End point description
    ACR50 response was achieved at week 24, if there was an improvement equal to or greater than 50% from baseline in the following assessment: 1) Improvement in the swollen joint count (66 out of 68 joints; excludes hips) 2) Improvement in the tender joint count (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments i) Patient’s assessment of pain (VAS) ii) Patient’s Global Assessment of disease activity (PtGA) (VAS) iii) Physician’s Global Assessment of disease activity (PhGA) (VAS) iv) Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI; PRO) v) C-reactive protein (CRP) Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF. Due to the premature termination of this study, this endpoint was analysed only at the pre-planned week 24 time point, but could not be analysed at the pre-planned week 52 time point.
    End point type
    Secondary
    End point timeframe
    At week 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: Percentage of subjects
    number (not applicable)
        Responder
    40
    31.1
    27
    25.3
        Non-responder
    60
    68.9
    73
    74.7
    No statistical analyses for this end point

    Secondary: ACR70

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    End point title
    ACR70
    End point description
    ACR70 response was achieved at week 24, if there was an improvement equal to or greater than 70% from baseline in the following assessment: 1) Improvement in the swollen joint count (66 out of 68 joints; excludes hips) 2) Improvement in the tender joint count (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments i) Patient’s assessment of pain (VAS) ii) Patient’s Global Assessment of disease activity (PtGA) (VAS) iii) Physician’s Global Assessment of disease activity (PhGA) (VAS) iv) Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI; PRO) v) C-reactive protein (CRP) Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF. Due to the premature termination of this study, this endpoint was analysed only at the pre-planned week 24 time point, but could not be analysed at the pre-planned week 52 time point.
    End point type
    Secondary
    End point timeframe
    At week 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: Percentage of subjects
    number (not applicable)
        Responder
    14.7
    10.8
    10.8
    12
        Non-responder
    85.3
    89.2
    89.2
    88
    No statistical analyses for this end point

    Secondary: Change in DAS28-CRP (defined as Disease Activity Score for 28 joints with C-reactive protein measure) from baseline

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    End point title
    Change in DAS28-CRP (defined as Disease Activity Score for 28 joints with C-reactive protein measure) from baseline
    End point description
    The 28 joints assessed for this measurement are the proximal interphalangeal (PIP) joints of the fingers, the interphalangeal (IP) joints of the thumbs, the 10 metacarpophalangeal (MCP) joints plus the wrists, elbows, shoulders and knees. In order to calculate the DAS28, each of the 28 joints was to be evaluated for tenderness and swelling. Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At weeks 12 and 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    73
    75
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    -1.6 ( 1.2 )
    -1.6 ( 1.2 )
    -1.5 ( 1.2 )
    -1.6 ( 1.1 )
        Week 24
    -2 ( 1.5 )
    -1.9 ( 1.1 )
    -1.8 ( 1.3 )
    -2 ( 1.4 )
    No statistical analyses for this end point

    Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) (At week 12)

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    End point title
    Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) (At week 12)
    End point description
    Simplified Disease Activity Index (SDAI) remission was achieved when the SDAI was below or equal to 3.3. The SDAI is the simple sum of the TJC (using 28 joints), SJC (using 28 joints), patient global assessment (PtGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), physician global assessment (PhGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), and CRP level (mg/dL). Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    71
    71
    74
    Units: Percentage of subjects
    number (not applicable)
        Responder
    0
    4.1
    1.4
    1.3
        Non-responder
    100
    95.9
    98.6
    98.7
    No statistical analyses for this end point

    Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) (At week 24)

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    End point title
    Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) (At week 24)
    End point description
    SDAI remission was achieved when the SDAI was below or equal to 3.3. The SDAI is the simple sum of the TJC (using 28 joints), SJC (using 28 joints), patient global assessment (PtGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), physician global assessment (PhGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), and CRP level (mg/dL). Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At week 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    71
    73
    69
    72
    Units: Percentage of subjects
    number (not applicable)
        Responder
    5.3
    1.4
    4.2
    4
        Non-responder
    94.7
    98.6
    95.8
    96
    No statistical analyses for this end point

    Secondary: European League Against Rheumatism (EULAR) criteria response (At week 12)

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    End point title
    European League Against Rheumatism (EULAR) criteria response (At week 12)
    End point description
    The EULAR response criteria (no response, moderate response and good response) were calculated using the present and observed changes in DAS28-CRP. Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At week 12
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    73
    75
    Units: Percentage of subjects
    number (not applicable)
        No response
    32
    28.4
    31.5
    28
        Moderate response
    61.3
    58.1
    60.3
    60
        Good response
    6.7
    13.5
    8.2
    12
    No statistical analyses for this end point

    Secondary: European League Against Rheumatism (EULAR) criteria response (At week 24)

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    End point title
    European League Against Rheumatism (EULAR) criteria response (At week 24)
    End point description
    The EULAR response criteria (no response, moderate response and good response) were calculated using the present and observed changes in DAS28-CRP. Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At week 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    73
    75
    Units: Percentage of subjects
    number (not applicable)
        No response
    30.7
    29.7
    38.4
    36
        Moderate response
    46.7
    52.7
    42.5
    44
        Good response
    22.7
    17.6
    19.2
    20
    No statistical analyses for this end point

    Secondary: Change from baseline in the overall scores of Health Assessment Questionnaire – Disability Index (HAQ-DI)

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    End point title
    Change from baseline in the overall scores of Health Assessment Questionnaire – Disability Index (HAQ-DI)
    End point description
    The HAQ-DI assesses the functional status for performing activities of daily living and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning which represent dressing, rising, eating walking, hygiene, reach, grip, and usual activities. For each of these categories, the subjects reported the amount of difficulty in performing two or three specific activities. The HAQ-DI score ranges from 0-3 (3=worst functioning) and was calculated according to the HAQ manual based on the 8-category scores and the use of aids/devices and/or help from another person when indicated. Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At weeks 12 and 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    73
    75
    Units: Score
    arithmetic mean (standard deviation)
        At week 12
    -0.48 ( 0.63 )
    -0.47 ( 0.54 )
    -0.42 ( 0.47 )
    -0.46 ( 0.67 )
        At week 24
    -0.57 ( 0.66 )
    -0.5 ( 0.61 )
    -0.47 ( 0.5 )
    -0.52 ( 0.74 )
    No statistical analyses for this end point

    Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Physical Component

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    End point title
    Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Physical Component
    End point description
    The SF-36v2 Health Survey is a survey which assesses the functional status and well-being of the subject utilising 36 questions covering selected concepts. The concepts cover physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health over the prior 4 weeks. Scores for each concept and overall scores for the physical and the mental components were calculated according to the SF-36 manual. The scores were transformed to a 100-point scale with higher scores indicating a better health state. Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At weeks 12 and 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    74
    73
    73
    75
    Units: Score
    arithmetic mean (standard deviation)
        At week 12
    7.7 ( 8.3 )
    6.2 ( 6.4 )
    6 ( 7.4 )
    5.8 ( 7.2 )
        At week 24
    8.7 ( 7.5 )
    7 ( 7.7 )
    7.7 ( 8 )
    6.9 ( 9.5 )
    No statistical analyses for this end point

    Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Mental Component

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    End point title
    Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Mental Component
    End point description
    The SF-36v2 Health Survey is a survey which assesses the functional status and well-being of the patient utilising 36 questions covering selected concepts. The concepts cover physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health over the prior 4 weeks. Scores for each concept and overall scores for the physical and the mental components were calculated according to the SF-36 manual. The scores were transformed to a 100-point scale with higher scores indicating a better health state. Analysis population: The FAS included all randomised subjects. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    At weeks 12 and 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    74
    73
    73
    75
    Units: Score
    arithmetic mean (standard deviation)
        At week 12
    3.4 ( 11 )
    4.5 ( 9.7 )
    4.7 ( 10.7 )
    5.7 ( 11.8 )
        At week 24
    5.5 ( 13.1 )
    6 ( 9.6 )
    3.7 ( 10.9 )
    6.5 ( 11.8 )
    No statistical analyses for this end point

    Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Upto week 24

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    End point title
    Safety endpoint: Incidence and type of adverse events (AEs) - Upto week 24
    End point description
    All AEs presented in this report are treatment-emergent AEs (TEAEs). A TEAE was defined as an event that has onset date on or after the first day of dose administration, and no later than the end of the entire trial. Analysis population: The safety analysis set (SAS) consisted of all subjects randomised and exposed to at least one dose of trial product. For the SAS, AE data are presented for the main treatment period (week 0-24) plus follow-up period (12-week) for subjects who withdrew during the main treatment period.
    End point type
    Secondary
    End point timeframe
    Upto week 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: Number of events
        All AEs
    115
    164
    122
    160
        Serious AEs (SAEs)
    4
    4
    3
    1
        Non-serious AEs (nSAEs)
    111
    160
    119
    159
    No statistical analyses for this end point

    Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Upto week 52

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    End point title
    Safety endpoint: Incidence and type of adverse events (AEs) - Upto week 52
    End point description
    Analysis population: The extension trial set (ETS) consisted of subjects who entered the open-label extension treatment period (week 25-52). For the ETS, the data analyses included measurements starting at week 0 through week 52 plus the 12-week follow-up, and could therefore overlap with AE data reported for the SAS (i.e., for the main treatment period [week 0-24]).
    End point type
    Secondary
    End point timeframe
    Upto week 52
    End point values
    Extension-Placebo-240 mg Extension-60-60 mg Extension-120-120 mg Extension-240-240 mg
    Number of subjects analysed
    53
    50
    45
    51
    Units: Number of events
        All AEs
    170
    169
    97
    161
        Serious AEs (SAEs)
    8
    5
    6
    4
        Non-serious AEs (nSAEs)
    162
    164
    91
    157
    No statistical analyses for this end point

    Secondary: Radiographic assessments - Change from baseline in van der Heijde sharp score.

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    End point title
    Radiographic assessments - Change from baseline in van der Heijde sharp score.
    End point description
    Change from baseline at week 24 in the van der Heijde modified Total Sharp Score (mTSS) and 2 subdomains of the van der Heijde Sharp score (i.e., erosion score and joint-space narrowing score [JSN]) was ranked for the subjects. The van der Heijde modified Sharp scoring system assesses changes in structural damage, assigning scores for erosions of 0–5.0 from 16 areas in the hands and wrists, and from the feet, each side of the 10 metatarsophalangeals (MTPs) and two intraphalangeal joints of the big toe. For Joint Space Narrowing (JSN) scores of 0–5 were assigned to 15 areas from the hands and wrists and six areas from the feet. The total van der Heijde radiographic score ranged from 0-448. Analysis population: The FAS included all randomised subjects. Missing data were imputed using LOCF. Change from baseline in van der Heijde sharp score was planned to be analysed only at the pre-planned week 24; hence, no data for week 12 are available.
    End point type
    Secondary
    End point timeframe
    At week 24
    End point values
    Main-Placebo Main-60 mg Main-120 mg Main-240 mg
    Number of subjects analysed
    61
    60
    63
    65
    Units: Score
    arithmetic mean (standard deviation)
        Total Erosion Score
    0.8 ( 1.9 )
    0.6 ( 1.7 )
    0.8 ( 2.5 )
    0.3 ( 1.8 )
        Joint space narrowing (JSN)
    0.3 ( 0.6 )
    0.3 ( 1.2 )
    0.1 ( 0.8 )
    0.1 ( 0.8 )
        modified Total Sharp Score (mTSS)
    1.1 ( 2.2 )
    0.8 ( 2.6 )
    0.9 ( 2.9 )
    0.4 ( 2.2 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For main trial period: treatment period (week 0-24) + follow-up period (12-week) for subjects who withdrew during the main treatment period. Extension trial period: treatment period (week 25-52) + follow-up period (12-week).
    Adverse event reporting additional description
    AEs are reported for the SAS and for the ETS. For the ETS, the data analyses included measurements starting at week 0 through week 52 plus the 12-week follow-up, and could therefore overlap with AE data reported for the SAS (i.e., for the main treatment period [week 0-24]).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Main-placebo
    Reporting group description
    Subjects received NNC0109-0012 placebo once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-120 mg
    Reporting group description
    Subjects received 120 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-240 mg
    Reporting group description
    Subjects received 240 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-60 mg
    Reporting group description
    Subjects received 60 mg of NNC0109-0012, once weekly for a duration of 24-week (double-blinded main treatment period).

    Reporting group title
    Main-total NNC0109-0012
    Reporting group description
    This reporting group is the combination of 3 reporting groups, i.e., main-60 mg + main-120 mg + main-240 mg.

    Reporting group title
    Extension-Placebo-240 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in tender joint count (TJC) and swollen joint count (SJC) at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to placebo in the main treatment period (week 0-24), were to be switched to NNC0109-0012, 240 mg, in the 28-week open-label extension treatment period.

    Reporting group title
    Extension-60-60 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in tender joint count (TJC) and swollen joint count (SJC) at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 60 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extentsion treatment period.

    Reporting group title
    Extension-120-120 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in tender joint count (TJC) and swollen joint count (SJC) at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 120 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.

    Reporting group title
    Extension-240-240 mg
    Reporting group description
    Subjects, who demonstrated at least a 20% improvement over baseline in tender joint count (TJC) and swollen joint count (SJC) at week 24 (i.e., after main treatment period), were allowed to enter the 28-week open-label extension period. Subjects randomised to active product, “NNC0109-0012, 240 mg” in the main treatment period (week 0-24), were to maintain their same dose regimen in the 28-week open-label extension treatment period.

    Serious adverse events
    Main-placebo Main-120 mg Main-240 mg Main-60 mg Main-total NNC0109-0012 Extension-Placebo-240 mg Extension-60-60 mg Extension-120-120 mg Extension-240-240 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 74 (4.05%)
    1 / 75 (1.33%)
    4 / 74 (5.41%)
    8 / 223 (3.59%)
    5 / 53 (9.43%)
    4 / 50 (8.00%)
    5 / 45 (11.11%)
    3 / 51 (5.88%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    1 / 223 (0.45%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Embolic stroke
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Mononeuropathy multiplex
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 223 (0.45%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    1 / 223 (0.45%)
    0 / 53 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 223 (0.45%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    1 / 223 (0.45%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    1 / 223 (0.45%)
    0 / 53 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    1 / 223 (0.45%)
    0 / 53 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis chronic
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    1 / 50 (2.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 223 (0.45%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    1 / 53 (1.89%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Visceral leishmaniasis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 223 (0.00%)
    0 / 53 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    Main-placebo Main-120 mg Main-240 mg Main-60 mg Main-total NNC0109-0012 Extension-Placebo-240 mg Extension-60-60 mg Extension-120-120 mg Extension-240-240 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 75 (37.33%)
    19 / 74 (25.68%)
    32 / 75 (42.67%)
    34 / 74 (45.95%)
    85 / 223 (38.12%)
    33 / 53 (62.26%)
    23 / 50 (46.00%)
    15 / 45 (33.33%)
    29 / 51 (56.86%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 74 (2.70%)
    2 / 75 (2.67%)
    4 / 74 (5.41%)
    8 / 223 (3.59%)
    2 / 53 (3.77%)
    3 / 50 (6.00%)
    2 / 45 (4.44%)
    2 / 51 (3.92%)
         occurrences all number
    3
    2
    2
    4
    8
    2
    4
    3
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 74 (1.35%)
    1 / 75 (1.33%)
    2 / 74 (2.70%)
    4 / 223 (1.79%)
    3 / 53 (5.66%)
    2 / 50 (4.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
         occurrences all number
    2
    1
    1
    2
    4
    3
    2
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 74 (2.70%)
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    3 / 223 (1.35%)
    3 / 53 (5.66%)
    3 / 50 (6.00%)
    1 / 45 (2.22%)
    2 / 51 (3.92%)
         occurrences all number
    3
    2
    0
    1
    3
    3
    3
    1
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    2 / 74 (2.70%)
    2 / 223 (0.90%)
    1 / 53 (1.89%)
    3 / 50 (6.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    2
    2
    1
    3
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    4 / 74 (5.41%)
    5 / 223 (2.24%)
    4 / 53 (7.55%)
    3 / 50 (6.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    0
    1
    4
    5
    4
    3
    0
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 75 (1.33%)
    3 / 74 (4.05%)
    4 / 75 (5.33%)
    2 / 74 (2.70%)
    9 / 223 (4.04%)
    2 / 53 (3.77%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    6
    2
    11
    16
    2
    0
    12
    Injection site reaction
         subjects affected / exposed
    1 / 75 (1.33%)
    6 / 74 (8.11%)
    12 / 75 (16.00%)
    4 / 74 (5.41%)
    22 / 223 (9.87%)
    7 / 53 (13.21%)
    3 / 50 (6.00%)
    5 / 45 (11.11%)
    7 / 51 (13.73%)
         occurrences all number
    1
    7
    21
    6
    34
    12
    22
    5
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
    0 / 75 (0.00%)
    2 / 74 (2.70%)
    3 / 223 (1.35%)
    2 / 53 (3.77%)
    3 / 50 (6.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    1
    0
    2
    3
    3
    3
    0
    0
    Gastritis
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    3 / 74 (4.05%)
    4 / 223 (1.79%)
    4 / 53 (7.55%)
    2 / 50 (4.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    0
    1
    3
    4
    4
    2
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 74 (2.70%)
    3 / 75 (4.00%)
    3 / 74 (4.05%)
    8 / 223 (3.59%)
    0 / 53 (0.00%)
    3 / 50 (6.00%)
    1 / 45 (2.22%)
    3 / 51 (5.88%)
         occurrences all number
    0
    2
    4
    3
    9
    0
    3
    1
    4
    Rheumatoid arthritis
         subjects affected / exposed
    4 / 75 (5.33%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    4 / 74 (5.41%)
    5 / 223 (2.24%)
    3 / 53 (5.66%)
    2 / 50 (4.00%)
    1 / 45 (2.22%)
    1 / 51 (1.96%)
         occurrences all number
    4
    0
    1
    6
    7
    3
    2
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    2 / 74 (2.70%)
    3 / 223 (1.35%)
    3 / 53 (5.66%)
    1 / 50 (2.00%)
    2 / 45 (4.44%)
    3 / 51 (5.88%)
         occurrences all number
    1
    0
    1
    3
    4
    3
    1
    2
    3
    Gastroenteritis
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 74 (2.70%)
    2 / 75 (2.67%)
    1 / 74 (1.35%)
    5 / 223 (2.24%)
    2 / 53 (3.77%)
    1 / 50 (2.00%)
    3 / 45 (6.67%)
    4 / 51 (7.84%)
         occurrences all number
    1
    2
    2
    1
    5
    2
    1
    3
    4
    Influenza
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 74 (0.00%)
    3 / 75 (4.00%)
    4 / 74 (5.41%)
    7 / 223 (3.14%)
    5 / 53 (9.43%)
    3 / 50 (6.00%)
    1 / 45 (2.22%)
    2 / 51 (3.92%)
         occurrences all number
    3
    0
    3
    4
    7
    5
    3
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 74 (2.70%)
    3 / 75 (4.00%)
    1 / 74 (1.35%)
    6 / 223 (2.69%)
    2 / 53 (3.77%)
    3 / 50 (6.00%)
    0 / 45 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    2
    3
    1
    6
    3
    3
    0
    3
    Pharyngitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    3 / 75 (4.00%)
    1 / 74 (1.35%)
    5 / 223 (2.24%)
    4 / 53 (7.55%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    4
    2
    7
    4
    0
    0
    4
    Respiratory tract infection
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    1 / 223 (0.45%)
    4 / 53 (7.55%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    4
    0
    0
    1
    1
    6
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 75 (4.00%)
    1 / 74 (1.35%)
    4 / 75 (5.33%)
    4 / 74 (5.41%)
    9 / 223 (4.04%)
    2 / 53 (3.77%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    3
    1
    5
    7
    13
    3
    3
    0
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 74 (1.35%)
    3 / 75 (4.00%)
    3 / 74 (4.05%)
    7 / 223 (3.14%)
    1 / 53 (1.89%)
    4 / 50 (8.00%)
    2 / 45 (4.44%)
    4 / 51 (7.84%)
         occurrences all number
    2
    1
    3
    3
    7
    1
    5
    2
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2012
    Added deviation of highly effective contraception methods; added joint count assessments at Visit (V)32, V38, V44, V50; Added pregnancy test at V16 and V20 and the correction of other inconsistencies.
    10 Nov 2012
    Added 1 and 2 hours post dose Vital Signs to week 24; Added Biochemistry, Haematology, Urinalysis and Vital Signs to week 30; reduced frequency of antinuclear antibodies (ANA) testing to Screening visit, week 24 and end of trial; increased intra-articular (IA) injection dose from 40 mg/week to 80 mg/week and the correction of other inconsistencies.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Aug 2014
    On 07-Aug-2014, Novo Nordisk A/S announced the decision to terminate the phase 2a Trial NN8226-3613 for the development of NNC0109-0012 for rheumatoid arthritis (RA). This occurred as a consequence of the planned partial database lock (pDBL) and analysis (01-July-2014) which showed no significant differences in primary endpoint achievement (ACR20 at week 12) comparing NNC0109-0012 treatment with placebo. This analysis included all randomised subjects in Trial NN8226-3613. The decision by Novo Nordisk to discontinue dosing in the trial as of 07-Aug 2014 was based on the finding of no statistically significant differences in changes in disease activity after treatment with NNC0109-0012 compared with placebo.
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    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was terminated prematurely.
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