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    Clinical Trial Results:
    Phase 2b, Randomized, Multicenter, Double-blind, Parallel Group, Placebo Controlled, Dose Ranging Study to Investigate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ATI-450 Plus Methotrexate (MTX) Versus Placebo Plus MTX in Patients with Moderate to Severe Active Rheumatoid Arthritis (RA) who have had an Inadequate Response to MTX Alone

    Summary
    EudraCT number
    		 2021-002860-31
    Trial protocol
    		 CZ   BG  
    Global end of trial date
    11 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Oct 2024
    First version publication date
    10 Oct 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ATI-450-RA-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aclaris Therapeutics, Inc.
    Sponsor organisation address
    701 Lee Road, Suite 103, Wayne/PA, United States, 19087
    Public contact
    Clinical Operations, Aclaris Therapeutics, Inc., 1 4843247933, clinicaloperations@aclaristx.com
    Scientific contact
    Clinical Operations, Aclaris Therapeutics, Inc., 1 4843247933, clinicaloperations@aclaristx.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
    22 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluates ATI-450 plus MTX versus placebo plus MTX in participants with moderate to severe active RA who have had an inadequate response to MTX alone.
    Protection of trial subjects
    This study was performed in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCP), including the archiving of essential documents as well as the ethical principles of the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Feb 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 39
    Country: Number of subjects enrolled
    Czechia: 17
    Country: Number of subjects enrolled
    Poland: 131
    Country: Number of subjects enrolled
    United States: 64
    Worldwide total number of subjects
    251
    EEA total number of subjects
    187
    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)
    187
    From 65 to 84 years
    64
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 One participant randomized to the placebo group was identified as not meeting inclusion criteria and therefore, was not dosed in the study. The participant was included in the Intent-to-Treat (ITT) Population but excluded from the Safety Population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ATI-450 20 mg plus MTX
    Arm description
    		 Participants randomized to receive ATI-450 20 milligrams (mg) oral tablet twice daily (BID) with a stable weekly dose of methotrexate (MTX) (15 mg to 25 mg weekly).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Stable weekly dose of methotrexate (15 mg to 25 mg) for 12 weeks

    Investigational medicinal product name
    ATI-450 20 mg
    Investigational medicinal product code
    Other name
    zunsemetinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ATI-450 20 mg oral tablet twice daily (BID) for 12 weeks

    Arm title
    		 ATI-450 50 mg plus MTX
    Arm description
    		 Participants randomized to receive ATI-450 50 mg oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Stable weekly dose of methotrexate (15 mg to 25 mg) for 12 weeks

    Investigational medicinal product name
    ATI-450 50 mg
    Investigational medicinal product code
    Other name
    zunsemetinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ATI-450 50 mg oral tablet twice daily (BID) for 12 weeks

    Arm title
    		 Placebo plus MTX
    Arm description
    		 Participants randomized to receive placebo oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Stable weekly dose of methotrexate (15 mg to 25 mg) for 12 weeks

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for 12 weeks

    Number of subjects in period 1
    		ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Started
    83
    84
    84
    ITT Population (Randomized)
    83
    84
    84
    Completed
    66
    63
    73
    Not completed
    17
    21
    11
         Consent withdrawn by subject
    9
    11
    4
         Adverse event, non-fatal
    3
    8
    -
         Lost to follow-up
    3
    2
    1
         Discontinued prior to dosing
    -
    -
    1
         Lack of efficacy
    1
    -
    5
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ATI-450 20 mg plus MTX
    Reporting group description
    		 Participants randomized to receive ATI-450 20 milligrams (mg) oral tablet twice daily (BID) with a stable weekly dose of methotrexate (MTX) (15 mg to 25 mg weekly).

    Reporting group title
    ATI-450 50 mg plus MTX
    Reporting group description
    		 Participants randomized to receive ATI-450 50 mg oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly)

    Reporting group title
    Placebo plus MTX
    Reporting group description
    		 Participants randomized to receive placebo oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly).

    Reporting group values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX Total
    Number of subjects
    		 83 84 84 251
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.9 ( 10.28 ) 55.8 ( 10.79 ) 55.5 ( 11.86 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 62 64 72 198
        Male
    		 21 20 12 53
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 14 12 33
        Not Hispanic or Latino
    		 72 61 67 200
        Unknown or Not Reported
    		 4 9 5 18
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    		 3 2 3 8
        White
    		 76 73 75 224
        Asian
    		 0 1 0 1
        Not reported
    		 4 8 6 18
    DAS28-CRP (Categorical)
    Units: Subjects
        ≥ 3.2 to ≤ 5.1 (Moderate Disease Activity)
    		 27 30 27 84
        > 5.1 (High/Severe Disease Activity)
    		 56 54 56 166
        Not Assessed
    		 0 0 1 1
    Disease Activity Score using 28 Joint Count-C-reactive Protein (DAS28-CRP)
    The DAS28-CRP consists of a composite score of the following variables: tender joint count out of 28 joint count (TJC28), swollen joint count out of 28 joint count (SJC28), C-reactive protein (CRP) (hsCRP is used for the purposes of this study), and Patient's Global Assessment of Disease Activity. Interpretation of the DAS28-CRP is on a scale of 0 to 9.4, where <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal disease activity, ≥3.2 to ≤5.1 is considered moderate disease activity, and >5.1 is considered high/severe disease activity.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 5.43 ( 0.769 ) 5.47 ( 0.866 ) 5.45 ( 0.806 ) -
    High-sensitivity C-reactive protein (hsCRP)
    Units: mg/L
        median (full range (min-max))
    		 5.58 (0.17 to 74.63) 6.22 (0.15 to 127.53) 4.40 (0.46 to 74.58) -

    End points

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    End points reporting groups
    Reporting group title
    ATI-450 20 mg plus MTX
    Reporting group description
    		 Participants randomized to receive ATI-450 20 milligrams (mg) oral tablet twice daily (BID) with a stable weekly dose of methotrexate (MTX) (15 mg to 25 mg weekly).

    Reporting group title
    ATI-450 50 mg plus MTX
    Reporting group description
    		 Participants randomized to receive ATI-450 50 mg oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly)

    Reporting group title
    Placebo plus MTX
    Reporting group description
    		 Participants randomized to receive placebo oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly).

    Primary: Percentage of Participants Achieving ACR20 at Week 12

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    End point title
    		 Percentage of Participants Achieving ACR20 at Week 12
    End point description
    Participants achieving American College of Rheumatology (ACR) 20 (responders) were defined as having ≥20% improvement in both the number of swollen and tender joints (66/68 joint counts) and ≥20% improvement in ≥3 of the following 5 measures: Patient's Global Assessment of Disease Activity (VAS), Patient's Assessment of Arthritis Pain (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), Physician's Global Assessment of Disease Activity (VAS), and acute phase reactant as measured by hsCRP. Model-based estimates and 95% confidence intervals (CIs) were produced.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    84
    Units: percentage of participants
        number (confidence interval 95%)
    42.2 (31.5 to 52.9)
    34.7 (24.2 to 44.9)
    46.5 (35.7 to 57.2)
    Statistical analysis title
    		 Participants Achieving ACR20
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -11.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.63
         upper limit
    		 3.07
    Notes
    [1] - Significance level = 0.05.
    Statistical analysis title
    		 Participants Achieving ACR20
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.585 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -4.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.38
         upper limit
    		 10.95
    Notes
    [2] - Significance level = 0.05.

    Secondary: Percentage of Participants Achieving ACR50 at Week 12

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    End point title
    		 Percentage of Participants Achieving ACR50 at Week 12
    End point description
    Participant achieving ACR50 (responders) were defined as having ≥50% improvement in both the number of swollen and tender joints (66/68 joint counts) and ≥50% improvement in ≥3 of the following 5 measures: Patient's Global Assessment of Disease Activity (VAS), Patient's Assessment of Arthritis Pain (VAS), HAQ-DI, Physician's Global Assessment of Disease Activity (VAS), Acute phase reactant as measured by hsCRP. Model-based estimates and 95% CIs were produced.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    84
    Units: percentage of participants
        number (confidence interval 95%)
    20.9 (12.1 to 29.7)
    20.7 (12.0 to 29.4)
    27.7 (18.1 to 37.3)
    Statistical analysis title
    		 Participants Achieving ACR50
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.305 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.84
         upper limit
    		 6.23
    Notes
    [3] - Significance level = 0.05.
    Statistical analysis title
    		 Participants Achieving ACR50
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.286 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -7.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.02
         upper limit
    		 5.93
    Notes
    [4] - Significance level = 0.05.

    Secondary: Percentage of Participants Achieving ACR70 at Week 12

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    End point title
    		 Percentage of Participants Achieving ACR70 at Week 12
    End point description
    Participants achieving ACR70 (responders) were defined as having ≥70% improvement in both the number of swollen and tender joints (66/68 joint counts) and ≥70% improvement in ≥3 of the following 5 measures: Patient's Global Assessment of Disease Activity (VAS), Patient's Assessment of Arthritis Pain (VAS), HAQ-DI, Physician's Global Assessment of Disease Activity (VAS), Acute phase reactant as measured by hsCRP. Model-based estimates and 95% CIs were produced.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    84
    Units: percentage of participants
        number (confidence interval 95%)
    8.9 (2.8 to 15.1)
    7.6 (1.9 to 13.3)
    14.7 (7.1 to 22.3)
    Statistical analysis title
    		 Participants Achieving ACR70
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.144 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -7.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.53
         upper limit
    		 2.43
    Notes
    [5] - Significance level = 0.05.
    Statistical analysis title
    		 Participants Achieving ACR70
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.246 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -5.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.53
         upper limit
    		 3.99
    Notes
    [6] - Significance level = 0.05.

    Secondary: Change from baseline in DAS28-CRP at Week 12

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    End point title
    		 Change from baseline in DAS28-CRP at Week 12
    End point description
    The DAS28-CRP consists of a composite score of the following variables: TJC28, SJC28, CRP (hsCRP was used for the purposes of this study), and Patient's Global Assessment of Disease Activity. Interpretation of the DAS28-CRP is on a scale of 0 to 9.4, where <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal disease activity, ≥3.2 to ≤5.1 is considered moderate disease activity, and >5.1 is considered high/severe disease activity. The least square (LS) mean change from baseline in DAS28-CRP at Week 12 was estimated from the Mixed Model Repeated Measures (MMRM) model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    84
    Units: units on a scale
        least squares mean (standard error)
    -1.66 ( 0.170 )
    -1.64 ( 0.167 )
    -1.60 ( 0.162 )
    Statistical analysis title
    		 Change from baseline in DAS28-CRP
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87 [7]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.41
    Notes
    [7] - Significance level = 0.05.
    Statistical analysis title
    		 Change from baseline in DAS28-CRP
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.797 [8]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.4
    Notes
    [8] - Significance level = 0.05.

    Secondary: Percentage of Participants Achieving DAS28-CRP Remission (Score <2.6) at Week 12

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    End point title
    		 Percentage of Participants Achieving DAS28-CRP Remission (Score <2.6) at Week 12
    End point description
    The Disease Activity Score using 28 Joint Count-C-reactive protein (DAS28-CRP) consists of a composite score of the following variables: TJC28, SJC28, CRP (hsCRP is used for the purposes of this study), and Patient's Global Assessment of Disease Activity. Interpretation of the DAS28-CRP is on a scale of 0 to 9.4, where <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal disease activity, ≥3.2 to ≤5.1 is considered moderate disease activity, and >5.1 is considered high/severe disease activity. Model-based estimates and 95% CIs were produced.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    84
    Units: percentage of participants
        number (confidence interval 95%)
    19.8 (11.1 to 28.4)
    14.8 (7.2 to 22.4)
    21.9 (13.0 to 30.8)
    Statistical analysis title
    		 Participants Achieving DAS28-CRP Remission
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.236 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -7.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.77
         upper limit
    		 4.65
    Notes
    [9] - Significance level = 0.05.
    Statistical analysis title
    		 Participants Achieving DAS28-CRP Remission
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.736 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -2.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.49
         upper limit
    		 10.25
    Notes
    [10] - Significance level = 0.05.

    Secondary: Percentage of Participants Achieving DAS28-CRP Low Disease Activity (Score ≤ 3.2) at Week 12

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    End point title
    		 Percentage of Participants Achieving DAS28-CRP Low Disease Activity (Score ≤ 3.2) at Week 12
    End point description
    The DAS28-CRP consists of a composite score of the following variables: TJC28, SJC28, CRP (hsCRP is used for the purposes of this study), and Patient's Global Assessment of Disease Activity. Interpretation of the DAS28-CRP is on a scale of 0 to 9.4, where <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal disease activity, ≥3.2 to ≤5.1 is considered moderate disease activity, and >5.1 is considered high/severe disease activity. Model-based estimates and 95% CIs were produced.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    84
    Units: percentage of participants
        number (confidence interval 95%)
    24.1 (14.8 to 33.4)
    19.1 (10.7 to 27.6)
    29.8 (19.9 to 39.7)
    Statistical analysis title
    		 Achieving DAS28-CRP Low Disease Activity
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.108 [11]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -10.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.65
         upper limit
    		 2.37
    Notes
    [11] - Significance level = 0.05.
    Statistical analysis title
    		 Achieving DAS28-CRP Low Disease Activity
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.414 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -5.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.19
         upper limit
    		 7.93
    Notes
    [12] - Significance level = 0.05.

    Secondary: Change from Baseline in HAQ-DI Score at Week12

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    End point title
    		 Change from Baseline in HAQ-DI Score at Week12
    End point description
    The HAQ-DI (standard disability method calculation) was utilized to assess the participant's physical function or disability according to the participant. The HAQ-DI is a 20-item, validated questionnaire used to assess the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities [errands and chores]). Responses in each functional area are scored from 0 (no difficulty) to 3 (inability to perform a ask in that area). Overall score was computed as the sum of category scores and divided by the number of categories answered, ranging from 0 to 3. A lower score demonstrated less disability. LS mean change from baseline in HAQ-DI score at Week 12 was estimated from the MMRM model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    76
    79
    81
    Units: units on a scale
        least squares mean (standard error)
    -0.24 ( 0.072 )
    -0.33 ( 0.067 )
    -0.37 ( 0.063 )
    Statistical analysis title
    		 Change from Baseline in HAQ-DI Score
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.622 [13]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.21
    Notes
    [13] - Significance level = 0.05.
    Statistical analysis title
    		 Change from Baseline in HAQ-DI Score
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.136
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.31

    Secondary: Change from Baseline in CDAI Score at Week 12

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    End point title
    		 Change from Baseline in CDAI Score at Week 12
    End point description
    The Clinical Disease Activity Index (CDAI) was the sum of 4 outcome parameters: • Tender joint count out of 28 joints (TJC28) • Swollen joint count out of 28 joints (SJC28) • Patient’s Global Assessment of Disease Activity; and • Physician’s Global Assessment of Disease Activity. Interpretation of the CDAI disease activity was measured on a scale of 0 to 76, where ≤2.8 was considered remission, >2.8 to ≤10 was considered low/minimal disease activity, >10 to ≤22 was considered moderate disease activity, and >22.0 was considered high/severe disease activity. LS mean change from baseline in CDAI score at Week 12 was estimated from the MMRM model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    83
    Units: units on a scale
        least squares mean (standard error)
    -18.39 ( 1.595 )
    -17.79 ( 1.669 )
    -17.89 ( 1.524 )
    Statistical analysis title
    		 Change from Baseline in CDAI Score
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.963 [14]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 4.3
    Notes
    [14] - Significance level = 0.05.
    Statistical analysis title
    		 Change from Baseline in CDAI Score
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.812 [15]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.66
         upper limit
    		 3.65
    Notes
    [15] - Significance level = 0.05.

    Secondary: Percentage of Participants Achieving CDAI Remission (score ≤ 2.8)

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    End point title
    		 Percentage of Participants Achieving CDAI Remission (score ≤ 2.8)
    End point description
    The CDAI was the sum of 4 outcome parameters: • Tender joint count out of 28 joints (TJC28) • Swollen joint count out of 28 joints (SJC28) • Patient’s Global Assessment of Disease Activity; and • Physician’s Global Assessment of Disease Activity. Interpretation of the CDAI disease activity was measured on a scale of 0 to 76, where ≤2.8 was considered remission, >2.8 to ≤10 was considered low/minimal disease activity, >10 to ≤22 was considered moderate disease activity, and >22.0 was considered high/severe disease activity. Model-based estimates and 95% CIs were produced.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    83
    84
    84
    Units: percentage of participants
        number (confidence interval 95%)
    6.6 (1.3 to 12.0)
    6.6 (1.2 to 11.9)
    7.7 (2.0 to 13.5)
    Statistical analysis title
    		 Participants Achieving CDAI Remission
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.765
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.97
         upper limit
    		 6.6
    Statistical analysis title
    		 Participants Achieving CDAI Remission
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Model Estimate
    Point estimate
    -1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.94
         upper limit
    		 6.72
    Notes
    [16] - Significance level = 0.05.

    Secondary: Percent Change from Baseline in hsCRP Level at Week 12

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    End point title
    		 Percent Change from Baseline in hsCRP Level at Week 12
    End point description
    Blood samples were evaluated to measure levels of hsCRP.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    67
    59
    76
    Units: percent change
        median (full range (min-max))
    -28.274 (-89.766 to 1121.0533)
    -22.779 (-86.392 to 528.571)
    1.546 (-93.280 to 838.047)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Short Form Health Survey SF-36 Physical Component Summary (PCS) Score at Week 12

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    End point title
    		 Change from Baseline in Short Form Health Survey SF-36 Physical Component Summary (PCS) Score at Week 12
    End point description
    The PCS is composed of 4 scales of the Short Form-36 Health Status Survey Questionnaire (SF-36) version 2 assessing physical function, role limitations caused by physical problems, bodily pain, and general health. The range of the SF-36 PCS is between 0 and 100, where higher scores represent better physical functioning. A 2.5 to 5-point change from baseline is established as the minimum clinically-important difference for the PCS in RA participants. LS mean change from baseline in SF-36 PCS score at Week 12 was estimated from the MMRM model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    78
    80
    81
    Units: units on a scale
        least squares mean (standard error)
    6.48 ( 1.025 )
    7.08 ( 1.057 )
    7.01 ( 0.935 )
    Statistical analysis title
    		 Change from Baseline in SF-36 PCS Score
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.958 [17]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.52
         upper limit
    		 2.66
    Notes
    [17] - Significance level = 0.05.
    Statistical analysis title
    		 Change from Baseline in SF-36 PCS Score
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.687 [18]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.14
         upper limit
    		 2.07
    Notes
    [18] - Significance level = 0.05.

    Secondary: Change from Baseline in Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue) Score at Week 12

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    End point title
    		 Change from Baseline in Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue) Score at Week 12
    End point description
    The FACIT-Fatigue is a 13-item questionnaire that measures an individual’s level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a 4 point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The total score range is from 0 to 52. The higher the score, the lower the fatigue level. LS mean change from baseline in FACIT-Fatigue score at Week 12 was estimated from the MMRM model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo plus MTX
    Number of subjects analysed
    76
    78
    81
    Units: units on a scale
        least squares mean (standard error)
    4.21 ( 1.296 )
    6.93 ( 1.313 )
    6.53 ( 1.168 )
    Statistical analysis title
    		 Change from Baseline in FACIT-Fatigue Score
    Comparison groups
    ATI-450 50 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.816 [19]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.01
         upper limit
    		 3.81
    Notes
    [19] - Significance level = 0.05.
    Statistical analysis title
    		 Change from Baseline in FACIT-Fatigue Score
    Comparison groups
    ATI-450 20 mg plus MTX v Placebo plus MTX
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.174 [20]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.66
         upper limit
    		 1.03
    Notes
    [20] - Significance level = 0.05.

    Secondary: ATI-450 and Metabolite (CDD-2164) Concentrations

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    End point title
    		 ATI-450 and Metabolite (CDD-2164) Concentrations [21]
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours postdose on Days 1, 8, and 85
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified by the protocol and SAP, pharmacokinetic data are presented for ATI-450 and Metabolite (CDD-2164) only.
    End point values
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX
    Number of subjects analysed
    81
    84
    Units: ng/milliliters (mL)
    arithmetic mean (standard deviation)
        ATI-450 Day 1
    79.289 ( 46.0493 )
    177.627 ( 120.9491 )
        ATI-450 Day 8
    104.032 ( 41.8903 )
    245.377 ( 113.5619 )
        ATI-450 Day 85
    94.615 ( 58.6913 )
    244.670 ( 127.9654 )
        CDD-2164 Day 1
    30.609 ( 18.8977 )
    66.602 ( 47.0467 )
        CDD-2164 Day 8
    36.375 ( 15.6280 )
    89.692 ( 48.0216 )
        CDD-2164 Day 85
    33.219 ( 21.5870 )
    89.196 ( 50.6267 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) through Week 16
    Adverse event reporting additional description
    Serious adverse events (AEs) and non-serious AEs were assessed using Safety Population (dosed) and analyzed by treatment received. 1 participant in ATI-450 20 mg received 50 mg and was included in ATI-450 50 mg Plus MTX arm. 1 participant in placebo was not dosed and excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    ATI-450 20 mg plus MTX
    Reporting group description
    		 Participants received ATI-450 20 mg oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly).

    Reporting group title
    ATI-450 50 mg plus MTX
    Reporting group description
    		 Participants received ATI-450 50 mg oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly)

    Reporting group title
    Placebo Plus MTX
    Reporting group description
    		 Participants received placebo oral tablet BID with a stable weekly dose of MTX (15 mg to 25 mg weekly).

    Serious adverse events
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo Plus MTX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 82 (0.00%)
    3 / 85 (3.53%)
    1 / 83 (1.20%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Ultrasound ovary abnormal
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 85 (1.18%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastrointestinal bacterial infection
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 ATI-450 20 mg plus MTX ATI-450 50 mg plus MTX Placebo Plus MTX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 82 (24.39%)
    31 / 85 (36.47%)
    12 / 83 (14.46%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    1 / 83 (1.20%)
         occurrences all number
    0
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    1 / 83 (1.20%)
         occurrences all number
    0
    2
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 85 (3.53%)
    1 / 83 (1.20%)
         occurrences all number
    2
    3
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 82 (2.44%)
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences all number
    2
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    0
    2
    0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 85 (0.00%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 82 (2.44%)
    1 / 85 (1.18%)
    1 / 83 (1.20%)
         occurrences all number
    2
    1
    1
    Tremor
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    0
    2
    0
    Pregnancy, puerperium and perinatal conditions
    Headache
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    1 / 83 (1.20%)
         occurrences all number
    0
    2
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 85 (0.00%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    2
    2
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    0
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 82 (1.22%)
    3 / 85 (3.53%)
    1 / 83 (1.20%)
         occurrences all number
    1
    3
    1
    Nausea
         subjects affected / exposed
    2 / 82 (2.44%)
    4 / 85 (4.71%)
    1 / 83 (1.20%)
         occurrences all number
    2
    4
    1
    Vomiting
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    0
    2
    0
    Rash
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    1
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 85 (2.35%)
    1 / 83 (1.20%)
         occurrences all number
    1
    2
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 85 (2.35%)
    0 / 83 (0.00%)
         occurrences all number
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 85 (3.53%)
    3 / 83 (3.61%)
         occurrences all number
    2
    3
    3
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 85 (2.35%)
    1 / 83 (1.20%)
         occurrences all number
    5
    2
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 85 (2.35%)
    1 / 83 (1.20%)
         occurrences all number
    2
    2
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 85 (1.18%)
    2 / 83 (2.41%)
         occurrences all number
    1
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2001
    - Additional ECGs and PKs to allow for cardiac safety monitoring. - Added Exclusion Criteria for cardiac safety.
    12 Aug 2021
    - Safety guidelines for SARS-CoV-2 pandemic.
    22 Nov 2021
    - One ATI-450 dose arm removed.
    04 Feb 2022
    - Updated concomitant medication allowed - Oral contraceptives allowed. - For Inclusion, Prior Hepatitis B, C, latent tuberculosis exposures, and marijuana use clarified.
    13 May 2022
    - Details added regarding rescreening guidelines. - COVID-19 treatment guidance added. Guidance added for temporary discontinuation due to COVID-19 or unrelated AEs. Maximum allowed number of days of a temporary discontinuation updated. - Sample size calculations updated.

    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
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