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    Clinical Trial Results:
    A Phase II, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Dose-Ranging Clinical Trial with a Proof-of-Concept Lead Cohort to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 + MTX in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy

    Summary
    EudraCT number
    		 2012-000439-17
    Trial protocol
    		 LT   DE   GB   DK   PL   HU   LV  
    Global end of trial date
    22 Oct 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Mar 2016
    First version publication date
    24 Jun 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    P08683
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01569152
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Protocol number: P08683, Merck Registration: MK-8457-008
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trial Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study assessed the safety and efficacy of MK-8457 + methotrexate (MTX) in participants with active rheumatoid arthritis (RA) despite MTX therapy. The primary hypothesis was that at least 1 dose of MK-8457 + MTX was superior to placebo + MTX as measured by the proportion of participants who achieved American College of Rheumatology 20 (ACR 20) response after 12 weeks of treatment. Study was terminated early (12 September 2013) based on preliminary analysis of data. The results of this study need to be interpreted with caution given the small sample size (82 participants) resulting from the early termination of the study.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measure defined for this individual study was in place for the protection of trial participants. Participants in all treatment groups in the base study were eligible for early escape at any point after Week 12 if they demonstrated a < 20% improvement in both tender and swollen joint counts. Participants could withdraw from the study or early escape and receive MK-8457 100mg twice daily (BID) in the safety extension portion of the study.
    Background therapy
    		 Participants were treated with methotrexate (MTX) for at least 3 months immediately prior to screening and continued on a stable weekly dose during the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 May 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 76 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Japan: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Moldova, Republic of: 19
    Worldwide total number of subjects
    82
    EEA total number of subjects
    19
    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)
    66
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This trial was conducted at 58 trial centers in the United States, Canada, Chile, Denmark, South Africa, Germany, Hungary, Japan, Lithuania, Moldova, Poland, South Korea, Taiwan, and in the United Kingdom.

    Pre-assignment
    Screening details
    		 One hundred and thirty-one of 213 participants screened for study were not randomized; 124 participants were excluded for not meeting at least one of the inclusion or exclusion criteria. Six participants withdrew from the study and 1 participant was not randomized due to the early termination of the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MK-8457 (100mg BID)
    Arm description
    		 MK-8457 100mg twice daily (BID) for 24 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-8457
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-8457 100mg BID for 24 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo to MK-8457 100mg BID for 24 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to MK-8457 100mg BID for 24 weeks

    Number of subjects in period 1
    		MK-8457 (100mg BID) Placebo
    Started
    41
    41
    Completed
    20
    9
    Not completed
    21
    32
         Consent withdrawn by subject
    2
    1
         Study terminated by Sponsor
    9
    8
         Adverse event, non-fatal
    4
    -
         Early Escape into Extension
    5
    22
         Non-compliance with study drug
    -
    1
         Lost to follow-up
    1
    -
    Period 2
    Period 2 title
    Safety Extension
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 MK-8457
    Arm description
    		 MK-8457 (100mg BID) for up to 76 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-8457
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-8457 (100mg) BID for up to 76 weeks

    Number of subjects in period 2 [1]
    		MK-8457
    Started
    29
    Completed
    0
    Not completed
    55
         Consent withdrawn by subject
    2
         Physician decision
    2
         Study terminated by Sponsor
    47
         Adverse event, non-fatal
    4
    Joined
    26
         Transferred in from other group/arm
    26
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: The number of participants transferring in and out of the arms in the period are not the same because 27 participants had an early escape from the Base Study and joined the MK-8457 100 mg BID arm in the Safety Extension Study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MK-8457 (100mg BID)
    Reporting group description
    		 MK-8457 100mg twice daily (BID) for 24 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to MK-8457 100mg BID for 24 weeks

    Reporting group values
    		 MK-8457 (100mg BID) Placebo Total
    Number of subjects
    		 41 41 82
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 35 31 66
        From 65-84 years
    		 6 10 16
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 30 33 63
        Male
    		 11 8 19

    End points

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    End points reporting groups
    Reporting group title
    MK-8457 (100mg BID)
    Reporting group description
    		 MK-8457 100mg twice daily (BID) for 24 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to MK-8457 100mg BID for 24 weeks
    Reporting group title
    MK-8457
    Reporting group description
    		 MK-8457 (100mg BID) for up to 76 weeks

    Primary: Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12

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    End point title
    		 Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12
    End point description
    ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR 20 response is defined as a ≥ 20% improvement in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2. ≥20% improvement in 3 of the following 5 assessments: a. A participant’s overall assessment of pain on a visual analog scale (VAS, 100 mm, no pain to extreme pain; b. Patient’s Global Assessment of Disease Activity (VAS) participant doing very well (0) to very poor (100); c. Physician’s Global Assessment of Disease Activity (VAS); d. Patient’s assessment of function as measured by Health Assessment Questionnaire (HAQ). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area.; e. C-Reactive Protein (an inflammatory marker with a normal reference range of less than 0.9 mg/dL.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [1]
    41 [2]
    Units: Percentage of subjects
        number (not applicable)
    68.29
    24.39
    Notes
    [1] - Number of participants who have either completed Week 12 or have discontinued before Week 12.
    [2] - Number of participants who have either completed Week 12 or have discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Percentage of ACR20 responders at Week 12 treated with MK-8457 minus percentage of ACR20 responders at Week 12 treated with placebo.
    Comparison groups
    Placebo v MK-8457 (100mg BID)
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of percentages
    Point estimate
    43.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.52
         upper limit
    		 63.28
    Notes
    [3] - The primary efficacy analysis was based on the Full Analysis Set (FAS) population using the Cochran-Mantel-Haenszel (CMH) method stratified by CRP strata. A last observation carried forward procedure was used to impute the missing ACR20 components if the participants had data for at least 1 component at Week 12. If participants did not have data for any of the ACR components at Week 12, the participant was considered not to have achieved an ACR20 response.

    Secondary: Change from Baseline in Disease Activity Score (DAS-28) as Measured by Erythrocyte Sedimentation Rate (ESR) At Week 12

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    End point title
    		 Change from Baseline in Disease Activity Score (DAS-28) as Measured by Erythrocyte Sedimentation Rate (ESR) At Week 12
    End point description
    The DAS28 based on ESR is a continuous parameter based upon a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), (ESR, an inflammatory marker), and Patient's Global Assessment of Disease Activity (GH, on a visual analog scale (VAS) of 100 mm). It is a continuous parameter and is defined as follows: DAS 28 (ESR) = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.70 × ln (ESR) + 0.014 × GH. SQRT = square root. TEN28 is 28 joint count for tenderness and SW28 is 28 joint count for swelling. The DAS28 is a scale ranging from 0 to 10 indicating current RA disease activity. Depending upon the DAS28 value, improvement from baseline is No Response (>= 0.6), No response to Moderate Response (>0.6 - 1.2), and Moderate to Good Reponse (>1.2).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    37 [4]
    39 [5]
    Units: DAS-28
        least squares mean (confidence interval 95%)
    -2 (-2.4 to -1.61)
    -1.02 (-1.41 to -0.64)
    Notes
    [4] - Number of participants with data at both baseline and Week 12.
    [5] - Number of participants with data at both baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Difference in the least squares means between change from baseline in DAS28-ESR for participants taking MK-8457 at Week 12 vs. change from baseline in DAS28-ESR for participants taking placebo at Week 12. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 -0.43
    Notes
    [6] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had at least one baseline observation or post-baseline observation to be included in the model.

    Secondary: Change from Baseline in DAS28 as Measured by C-Reactive Protein (CRP) at Week 12

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    End point title
    		 Change from Baseline in DAS28 as Measured by C-Reactive Protein (CRP) at Week 12
    End point description
    The DAS28 is a continuous parameter derived from the formula: 0.56 × the square root of the tender joint count (0-28) + 0.28 × the square root of the swelling joint count (0-28) + 0.36 × the C reactive protein value (in mg/L +1) + 0.014 × Patient’s Global Assessment of Disease Activity Visual Analog Score of 0-100 mm + 0.96 = a value ranging from 2.0 to 10.0 with higher values meaning higher disease activity. A value of 2.6 was interpreted as remission.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    37 [7]
    39 [8]
    Units: DAS28-CRP
        least squares mean (confidence interval 95%)
    -1.98 (-2.34 to -1.61)
    -0.87 (-1.23 to -0.51)
    Notes
    [7] - Number of participants with data at both baseline and Week 12.
    [8] - Number of participants with data at both baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Difference in least squares means between change from baseline in DAS-28-CRP for participants taking MK-8457 at Week 12 vs. change from baseline in DAS-28-CRP for participants taking placebo at Week 12. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference of percentages
    Point estimate
    -1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.62
         upper limit
    		 -0.6
    Notes
    [9] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had at least one baseline observation or post-baseline observation to be included in the model.

    Secondary: Percentage of Participants Achieving an ACR70 Response at Week 12

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    End point title
    		 Percentage of Participants Achieving an ACR70 Response at Week 12
    End point description
    ACR responses are presented as the numerical measurement of improvement in multiple disease assessment criteria. An ACR 70 response is defined as a ≥ 70% improvement in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2. ≥ 70% improvement in 3 of the following 5 assessments: a. A participant’s overall assessment of pain on a visual analog scale (VAS, 100 mm, no pain to extreme pain); b. Patient’s Global Assessment of Disease Activity (VAS); c. Physician’s Global Assessment of Disease Activity (VAS); d. Patient’s assessment of function as measured by Health Assessment Questionnaire (HAQ). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area.; e. C-Reactive Protein (an inflammatory marker with a normal reference range of less than 0.9 mg/dL).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [10]
    41 [11]
    Units: Percentage of Subjects
        number (not applicable)
    19.51
    4.88
    Notes
    [10] - Number of participants who have either completed Week 12 or have discontinued before Week 12.
    [11] - Number of participants who have either completed Week 12 or have discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Percentage of participants treated with MK-8457 that were an ACR70 responder at Week 12 minus percentage of participants treated with placebo that were an ACR70 responder at Week 12.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.044
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentages
    Point estimate
    14.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 28.44
    Notes
    [12] - Cochran-Mantel-Haenszel test stratified by screening CRP level.

    Secondary: Percentage of Participants Achieving Hybrid ACR Response at Week 12

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    End point title
    		 Percentage of Participants Achieving Hybrid ACR Response at Week 12
    End point description
    Hybrid ACR Response evaluates the improvement in active RA by combining elements of the ACR20/50/70 with a continuous score of the mean change in each of the core set measures. The percentage improvement from baseline was computed in each of the 7 core components of the ACR. The average percent improvement was calculated and used with the participant's ACR20, ACR50, and ACR70 status to compute the hybrid ACR response, with a positive change indicating improvement.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Percentage of Subjects
        number (not applicable)
    Notes
    [13] - Due to the early termination of the study, this endpoint was not evaluated.
    [14] - Due to the early termination of the study, this endpoint was not evaluated.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving an ACR-N Response at Week 12

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    End point title
    		 Percentage of Participants Achieving an ACR-N Response at Week 12
    End point description
    The ACR-N Index of Improvement is defined as the minimum of the following 3 criteria: 1. The percent improvement from baseline in tender joint counts 2. The percent improvement from baseline in swollen joint counts 3. The median percent improvement from baseline for the following 5 assessments: a. Participant’s assessment of pain (VAS) b. Participant’s global assessment of disease activity (VAS) c. Physician’s global assessment of disease activity (VAS) d. Participant’s assessment of physical function as measured by the HAQ e. CRP levels
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [15] - Due to the early termination of the study, this endpoint was not evaluated.
    [16] - Due to the early termination of the study, this endpoint was not evaluated.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a DAS-28 ESR Response at Week 12

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    End point title
    		 Percentage of Participants Achieving a DAS-28 ESR Response at Week 12
    End point description
    The DAS28 based on ESR is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), Erythrocyte Sedimentation Rate (ESR), and Patient's Global Assessment of Disease Activity (GH, on a VAS of 100 mm). It is a continuous parameter and is defined as follows: DAS 28 (ESR) = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.70 × ln (ESR) + 0.014 × GH. SQRT = square root. TEN28 is 28 joint count for tenderness and SW28 is 28 joint count for swelling. Depending upon the DAS28 value, improvement from baseline is No Response (>= 0.6), No response to Moderate Response (>0.6 - 1.2), and Moderate to Good Reponse (>1.2). DAS28 response was defined as “Good” or “Moderate” response categories at a visit.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [17]
    41 [18]
    Units: Percentage of Subjects
        number (not applicable)
    70.73
    39.02
    Notes
    [17] - Number of participants who completed Week 12 or discontinued before Week 12.
    [18] - Number of participants who completed Week 12 or discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Percentage of participants taking MK-8457 who achieved a DAS28-ESR response on Week 12 minus the percentage of participants taking placebo who achieved a DAS28-ESR response on Week 12.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentages
    Point estimate
    31.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.29
         upper limit
    		 52.13
    Notes
    [19] - Based on Cochran-Mantel-Haenszel test stratified by screening ESR level.

    Secondary: Percentage of Participants Achieving a DAS-28 CRP Response at Week 12

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    End point title
    		 Percentage of Participants Achieving a DAS-28 CRP Response at Week 12
    End point description
    The DAS28-CRP is a continuous parameter derived from the formula: 0.56 × the square root of the tender joint count (0-28) + 0.28 × the square root of the swelling joint count (0-28) + 0.36 × the C reactive protein value (in mg/L +1) + 0.014 × Patient’s Global Assessment of Disease Activity Visual Analog Score of 0-100 mm + 0.96 = a value ranging from 2.0 to 10.0 with higher values meaning higher disease activity. A value of 2.6 was interpreted as remission.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [20]
    41 [21]
    Units: Percentage of subjects
        number (not applicable)
    73.17
    43.9
    Notes
    [20] - Number of participants who have either completed Week 12 or have discontinued before Week 12.
    [21] - Number of participants who have either completed Week 12 or have discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Percentage of subjects treated with MK-8457 who achieved a DAS28-CRP response score at Week 12 minus percentage of subjects treated with placebo who achieved a DAS28-CRP response score at Week 12.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.007
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentages
    Point estimate
    29.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.9
         upper limit
    		 49.63
    Notes
    [22] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time.

    Secondary: Percentage of Participants Achieving DAS28-ESR Remission at Week 12

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    End point title
    		 Percentage of Participants Achieving DAS28-ESR Remission at Week 12
    End point description
    The DAS28 based on ESR is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), Erythrocyte Sedimentation Rate (ESR), and Patient's Global Assessment of Disease Activity (GH, on a VAS of 100 mm). It is a continuous parameter and is defined as follows: DAS 28 (ESR) = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.70 × ln (ESR) + 0.014 × GH. SQRT = square root. TEN28 is 28 joint count for tenderness and SW28 is 28 joint count for swelling. Depending upon the DAS28 value, improvement from baseline is No Response (>= 0.6), No response to Moderate Response (>0.6 - 1.2), and Moderate to Good Response (>1.2). DAS28 remission was defined as a DAS28 value of < 2.6 at a visit.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [23]
    41 [24]
    Units: Percentage of participants
        number (not applicable)
    9.76
    0
    Notes
    [23] - Number of participants who completed Week 12 or discontinued before Week 12.
    [24] - Number of participants who completed Week 12 or discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Percentage of participants treated with MK-8457 who have achieved DAS28-ESR remission at Week 12 minus percentage of participants treated with placebo who have achieved DAS28-ESR remission at Week 12.
    Comparison groups
    Placebo v MK-8457 (100mg BID)
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.039
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentages
    Point estimate
    9.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 18.84
    Notes
    [25] - Based on Cochran-Mantel-Haenszel test stratified by screening CRP level.

    Secondary: Percentage of Participants Achieving DAS-28 CRP Remission at Week 12

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    End point title
    		 Percentage of Participants Achieving DAS-28 CRP Remission at Week 12
    End point description
    The DAS28 based on CRP is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP, and GH. The DAS28 is a continuous parameter and is defined as follows: DAS28 (CRP) = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.36 × ln (CRP+1) + 0.014 × GH + 0.96 where: TEN28 is 28 joint count for tenderness; SW28 is 28 joint count for swelling. SQRT is the square root. DAS28 remission is defined as a DAS28 value of < 2.6 at a visit.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [26]
    41 [27]
    Units: Percentage of participants
        number (not applicable)
    12.2
    0
    Notes
    [26] - Number of participants who completed Week 12 or discontinued before Week 12.
    [27] - Number of participants who completed Week 12 or discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Percentage of participants treated with MK-8457 who have achieved DAS28-CRP remission at Week 12 minus percentage of participants treated with placebo who have achieved DAS28-CRP remission at Week 12.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018 [28]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentages
    Point estimate
    12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.18
         upper limit
    		 22.21
    Notes
    [28] - Based on Cochran-Mantel-Haenszel test stratified by screening CRP level.

    Secondary: DAS-28 Area Under the Curve (AUC)

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    End point title
    		 DAS-28 Area Under the Curve (AUC)
    End point description
    DAS28 area under the disease activity curve (AUC) was calculated from the DAS28 score versus time curve, which provided an assessment of changes in disease activity over time. AUC DAS28 was averaged over study days. The DAS28 AUC was calculated using the trapezoidal rule as the DAS28 multiplied by the duration of the assessment period (in weeks) and was presented as %-weeks. Higher calculated AUC values indicate higher disease activity (worse).
    End point type
    Secondary
    End point timeframe
    Up to 12 Weeks
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    0 [29]
    0 [30]
    Units: DAS-28 AUC
        number (not applicable)
    Notes
    [29] - Due to the early study termination, this endpoint was not evaluated.
    [30] - Due to the early study termination, this endpoint was not evaluated.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Tender Joint Count at Week 12

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    End point title
    		 Change from Baseline in Tender Joint Count at Week 12
    End point description
    Tender Joint Count was examined on 68 joints of the fingers, elbows, hips, knees, ankles, and toes distal for pain in response to pressure or passive motion at the study time points. Joint pain was scored as 0 = Absent; 1 = Present for each joint. Change from baseline in tender joint count was calculated as Tender Joint Count at Week 12 minus Tender Joint Count at Baseline. The overall Tender Joint Count count ranged from 0 to 68. A higher score indicated greater disease severity.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    38 [31]
    39 [32]
    Units: Tender Joint Count
        least squares mean (confidence interval 95%)
    -13.53 (-16.73 to -10.34)
    -8.78 (-11.96 to -5.6)
    Notes
    [31] - Number of participants with data at both baseline and Week 12.
    [32] - Number of participants with data at both baseline and Week 12.
    Statistical analysis title
    		 Difference in the Least Squares Mean
    Statistical analysis description
    Change from baseline in the least squares mean of tender joint count at Week 12 for participants treated with MK-8457 minus change from baseline in the least squares mean of Tender Joint Count at Week 12 for participants treated with placebo. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    Placebo v MK-8457 (100mg BID)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.028
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.99
         upper limit
    		 -0.52
    Notes
    [33] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had to have at least one baseline observation or post-baseline observation to be included in the model.

    Secondary: Change from Baseline in Swollen Joint Count at Week 12

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    End point title
    		 Change from Baseline in Swollen Joint Count at Week 12
    End point description
    Swollen joint count included 66 joints (same joints as for tender joint count except this excluded evaluation of hips) that were assessed for the presence of swelling. Soft tissue swelling was considered to be present if there was palpable or visible evidence of capsular distention considered to be due to either synovial thickening and/or a joint effusion. Bony swelling, nodule formation, and joint deformity were excluded from consideration. A swollen joint was scored as 0 = Absent; 1 = Present for each joint. The overall swollen joint count ranged from 0 to 66. A higher score indicated greater disease severity.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    38 [34]
    39 [35]
    Units: Swollen Joint Count
        least squares mean (confidence interval 95%)
    -10.29 (-13.01 to -7.58)
    -7.65 (-10.34 to -4.95)
    Notes
    [34] - Number of participants with data at both Baseline and Week 12.
    [35] - Number of participants with data at both Baseline and Week 12.
    Statistical analysis title
    		 Difference in Least Squares Mean
    Statistical analysis description
    Change from baseline in least squares mean at Week 12 for participants treated with MK-8457 minus change from baseline in least squares mean for participants at Week 12 for participants treated with placebo. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 0.11
    Method
    		 Constrained Longitudinal Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.91
         upper limit
    		 0.62
    Notes
    [36] - Constrained longitudinal data analysis model included terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had to have at least one baseline observation or post-baseline observation to be included in the model.

    Secondary: Change from Baseline in Simplified Disease Activity Index (SDAI) at Week 12

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    End point title
    		 Change from Baseline in Simplified Disease Activity Index (SDAI) at Week 12
    End point description
    SDAI is the simple linear sum of the outcome parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint assessment, patient global assessment of disease activity [PGA visual analogue scale (VAS) 0 to 10cm], physician global assessment of disease activity (MDGA VAS 0–10cm) and C-reactive protein levels (CRP in mg/dL). SDAI =TJC + SJC + PGA + MDGA + CRP. Overall scores can range from 0.1 to 86.0. A higher score indicated greater disease severity.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    37 [37]
    39 [38]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -23.73 (-28.5 to -18.96)
    -13.17 (-17.9 to -8.45)
    Notes
    [37] - Number of Participants with data at both Baseline and Week 12.
    [38] - Number of Participants with data at both Baseline and Week 12.
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Change from baseline in least squares means of SDAI at Week 12 for participants treated with MK-8457 minus change from baseline in least squares means of SDAI at Week 12 for participants treated with placebo. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.002
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.97
         upper limit
    		 -4.15
    Notes
    [39] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had to have at least one baseline observation or post-baseline observation to be included in the model. Negative differences are in favor of the MK-8457 treatment group in the comparison.

    Secondary: Change from Baseline in Short Form Health Survey (SF-36) at Week 12

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    End point title
    		 Change from Baseline in Short Form Health Survey (SF-36) at Week 12
    End point description
    The SF-36 is a health-related quality of life instrument that consists of 8 multi-item scales: limitations in physical functioning due to health problems, limitations in usual role activities due to physical health problems, bodily pain, general mental health (psychological distress and well-being), limitations in usual role activities due to personal or emotional problems, limitations in social functioning due to physical or mental health problems, vitality (energy and fatigue), and general health perception. The concepts measured by the SF-36 are not specific to any age, disease, or treatment group, allowing the comparison of relative burden of disease and relative benefit of different treatments. Each scale is directly transformed into a 0 to 100 scale on the assumption that each question carries equal weight. The lower the score the greater the disability i.e., a score of 0 is equivalent to maximum disability and a score of 100 is equivalent to no disability.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    0 [40]
    0 [41]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [40] - Due to the early termination of the study, this endpoint was not evaluated.
    [41] - Due to the early termination of the study, this endpoint was not evaluated.
    No statistical analyses for this end point

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

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    End point title
    		 Change from Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 12
    End point description
    The Functional Assessment of Chronic Illness Therapy (FACIT-F) is a questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). The larger the participant's response to the questions, the greater the participants fatigue.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    0 [42]
    0 [43]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [42] - Due to the early termination of the study, this endpoint was not evaluated.
    [43] - Due to the early termination of the study, this endpoint was not evaluated.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Patient's Global Assessment of Disease Status/Activity (GADSA) at Week 12

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    End point title
    		 Change from Baseline in the Patient's Global Assessment of Disease Status/Activity (GADSA) at Week 12
    End point description
    Patient's Global Assessment of Disease Status/Activity (PGDSA) are measured using a visual analog scale with scores ranging from 0 to 100mm (VAS; 0mm [best] to 100mm [worst]) with increasing scores indicating increased level of disease. A negative value in change from baseline indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    37 [44]
    39 [45]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -29.06 (-35.93 to -22.19)
    -8.21 (-15 to -1.43)
    Notes
    [44] - Number of participants with data at both Baseline and Week 12.
    [45] - Number of participants with data at both Baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Change from baseline in Patient Global Assessment of Disease Activity at Week 12 for participants treated with MK-8457 minus change from baseline in Patient Global Assessment of Disease Activity at Week 12 for participants treated with placebo. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.98
         upper limit
    		 -11.71
    Notes
    [46] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had to have at least one baseline observation or post-baseline observation to be included in the model. Negative differences are in favor of the MK-8457 treatment group in the comparison.

    Secondary: Change from Baseline in the Patient's Global Assessment of Pain (PGAP) at Week 12

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    End point title
    		 Change from Baseline in the Patient's Global Assessment of Pain (PGAP) at Week 12
    End point description
    A participant’s overall assessment of pain was assessed from the amount of pain due to arthritis experienced during the past 48 hours on a visual analog scale (VAS, 100mm VAS scale—0mm “no pain,” 100mm “extreme pain.”).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    37 [47]
    39 [48]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -28.85 (-37.17 to -20.54)
    -8.17 (-16.42 to 0.09)
    Notes
    [47] - Number of participants with data at both Baseline and Week 12.
    [48] - Number of participants with data at both Baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Change from baseline in Patient Global Assessment of Pain at Week 12 for participants treated with MK-8457 minus change from baseline in Patient Global Assessment of Pain at Week 12 for participants treated with placebo.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [49]
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.29
         upper limit
    		 -10.09
    Notes
    [49] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had to have at least one baseline observation or post-baseline observation to be included in the model. Negative differences are in favor of the MK-8457 treatment group in the comparison.

    Secondary: Change from Baseline in the Health Assessment Questionnaire Disability (HAQ) Subscales at Week 12

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    End point title
    		 Change from Baseline in the Health Assessment Questionnaire Disability (HAQ) Subscales at Week 12
    End point description
    The functional status of the participant was assessed using the Disability Index of the HAQ. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. The overall score for the Disability Index is the mean of the 8 functional area scores and also ranges from 0 to 3, with a lower score indicating less disability.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    38 [50]
    39 [51]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -0.67 (-0.83 to -0.51)
    -0.05 (-0.21 to 0.11)
    Notes
    [50] - Number of participants with data at both Baseline and Week 12.
    [51] - Number of participants with data at both Baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Change from baseline in HAQ at Week 12 for participants treated with MK-8457 minus change from baseline in HAQ at Week 12 for participants treated with placebo. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [52]
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 -0.4
    Notes
    [52] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had to have at least one baseline observation or post-baseline observation to be included in the model. Negative differences are in favor of the MK-8457 treatment group in the comparison.

    Secondary: Change from Baseline in Serum CRP at Week 12

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    End point title
    		 Change from Baseline in Serum CRP at Week 12
    End point description
    C-Reactive Protein is an inflammatory marker with a normal reference range of less than 0.9 mg/dL. Change from Baseline in CRP at Week 12 (Week 12 score minus Baseline score).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    38 [53]
    39 [54]
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -0.76 (-1.66 to 0.14)
    0.83 (-0.07 to 1.73)
    Notes
    [53] - Number of participants with data at both Baseline and Week 12.
    [54] - Number of participants with data at both Baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Change from baseline in CRP at Week 12 for participants treated with MK-8457 minus change from baseline in CRP at Week 12 for participants treated with placebo. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 = 0.007
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.73
         upper limit
    		 -0.45
    Notes
    [55] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had to have at least one baseline observation or post-baseline observation to be included in the model.

    Secondary: Change from Baseline in ESR at Week 12

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    End point title
    		 Change from Baseline in ESR at Week 12
    End point description
    The ESR is the rate at which red blood cells sediment in a period of one hour, and is a non-specific measure of inflammation. Change from Baseline in ESR equals score at Week 12 minus score at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    38 [56]
    39 [57]
    Units: mm/h
        least squares mean (confidence interval 95%)
    -6.8 (-13.98 to 0.38)
    -1.9 (-9.03 to 5.23)
    Notes
    [56] - Number of participants with data at both Baseline and Week 12.
    [57] - Number of participants with data at both Baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Change from Baseline in ESR at Week 12 (score for participants treated with MK-8457 minus score for participants treated with placebo). Number of participants with data at both baseline and Week 12. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [58]
    P-value
    		 = 0.315
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.54
         upper limit
    		 4.74
    Notes
    [58] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant needs to have at least one baseline observation or post-baseline observation to be included in the model.

    Secondary: Change from Baseline in Hemoglobin at Week 12

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    End point title
    		 Change from Baseline in Hemoglobin at Week 12
    End point description
    Change from Baseline in hemoglobin equals Week 12 values minus baseline values for participants treated with MK-8457 or placebo. Hemoglobin is the iron-containing oxygen-transport metalloprotein in red blood cells.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    39 [59]
    39 [60]
    Units: gm/dL
        arithmetic mean (standard deviation)
    0.11 ± 0.83
    -0.07 ± 0.86
    Notes
    [59] - The number of participants in each treatment group with non-missing Baseline and Week 12 values.
    [60] - The number of participants in each treatment group with non-missing Baseline and Week 12 values.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving an ACR50 Response at Week 12

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    End point title
    		 Percentage of Participants Achieving an ACR50 Response at Week 12
    End point description
    Percentage of participants who were ACR50 responders at Week 12 with ACR responses presented as the numerical measurement of improvement in multiple disease assessment criteria. An ACR 50 response is defined as a ≥ 50% improvement in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2. ≥ 50% improvement in 3 of the following 5 assessments: a. A participant’s overall assessment of pain on a visual analog scale (VAS, 100 mm, no pain to extreme pain); b. Patient’s Global Assessment of Disease Activity (VAS); c. Physician’s Global Assessment of Disease Activity (VAS); d. Patient’s assessment of function as measured by Health Assessment Questionnaire (HAQ). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area.; e. C-Reactive Protein (an inflammatory marker with a normal reference range of less than 0.9 mg/dL).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [61]
    41 [62]
    Units: Percentage of participants
        number (not applicable)
    36.59
    4.88
    Notes
    [61] - Number of participants who completed Week 12 or discontinued before Week 12.
    [62] - Number of participants who completed Week 12 or discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    ACR50 response rate at Week 12 for participants treated with MK-8457 minus ACR50 response rate at Week 12 for participants treated with placebo.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other [63]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    31.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.56
         upper limit
    		 47.86
    Notes
    [63] - Based on Cochran-Mantel-Haenszel test stratified by screening CRP level.

    Secondary: ACR20 Response Rate Over Time

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    End point title
    		 ACR20 Response Rate Over Time
    End point description
    Percentage of participants who were ACR20 responders at Week 1, 2, 4, 6, 12, 18, and 24 with ACR responses presented as the numerical measurement of improvement in multiple disease assessment criteria. An ACR 20 response is defined as a ≥ 20% improvement in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2. ≥ 20% improvement in 3 of the following 5 assessments: a. A participant’s overall assessment of pain on a visual analog scale (VAS, 100 mm, no pain to extreme pain); b. Patient’s Global Assessment of Disease Activity (VAS); c. Physician’s Global Assessment of Disease Activity (VAS); d. Patient’s assessment of function as measured by Health Assessment Questionnaire (HAQ). Responses in each functional area are scored from 0, no difficulty, to 3, inability to perform a task in that area; e. C-Reactive Protein (an inflammatory marker with a normal reference range of less than 0.9 mg/dL).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 4, Week 6, Week 12, Week 18, Week 24
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    41 [64]
    41 [65]
    Units: Percentage of Participants
    number (not applicable)
        Week 1
    12.2
    9.8
        Week 2
    51.2
    14.6
        Week 4
    61
    22
        Week 6
    63.4
    14.6
        Week 12
    68.3
    24.4
        Week 18
    53.7
    12.2
        Week 24
    48.8
    22
    Notes
    [64] - The number of participants in each treatment group at particular weeks.
    [65] - The number of participants in each treatment group at particular weeks.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Investigator's Global Assessment of Disease Status/Activity (IGADSA) at Week 12

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    End point title
    		 Change from Baseline in the Investigator's Global Assessment of Disease Status/Activity (IGADSA) at Week 12
    End point description
    Investigator's Global Assessment of Disease Status/Activity (IGADSA) is measured using a visual analog scale with scores ranging from 0 to 100mm (VAS; 0mm [best] to 100mm [worst]) with increasing scores indicating how well the participant was doing. A negative value in change from baseline indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 (100mg BID) Placebo
    Number of subjects analysed
    38 [66]
    39 [67]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -34.21 (-41.8 to -26.63)
    -14.73 (-22.23 to -7.23)
    Notes
    [66] - Number of participants with data at both baseline and Week 12.
    [67] - Number of participants with data at both baseline and Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Change from baseline in IGADA at Week 12 for participants treated with MK-8457 minus change from baseline in IGADA at Week 12 for participants treated with placebo. Negative differences are in favor of the MK-8457 treatment group in the comparison.
    Comparison groups
    MK-8457 (100mg BID) v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [68]
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.69
         upper limit
    		 -9.28
    Notes
    [68] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant had at least one baseline observation or post-baseline observation to be included in the model.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 104 weeks
    Adverse event reporting additional description
    Adverse events were reported for participants treated with MK-8457 100 mg for up to 76 weeks in the Safety Extension.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    MK-8457 100 mg (Base Study)
    Reporting group description
    		 Participants who received at least one dose of MK-8457 100 mg during the Base Study.

    Reporting group title
    MK-8457 100 mg (Safety Extension)
    Reporting group description
    		 Participants who received at least one dose of MK-8457 100 mg during the Safety Extension.

    Reporting group title
    Placebo (Base Study)
    Reporting group description
    		 Participants who received at least one dose of placebo to MK-8457 during the Base Study.

    Serious adverse events
    		 MK-8457 100 mg (Base Study) MK-8457 100 mg (Safety Extension) Placebo (Base Study)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 55 (5.45%)
    0 / 41 (0.00%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 55 (1.82%)
    0 / 41 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 55 (3.64%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 55 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 55 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MK-8457 100 mg (Base Study) MK-8457 100 mg (Safety Extension) Placebo (Base Study)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 41 (36.59%)
    11 / 55 (20.00%)
    9 / 41 (21.95%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 55 (5.45%)
    1 / 41 (2.44%)
         occurrences all number
    2
    5
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 55 (5.45%)
    0 / 41 (0.00%)
         occurrences all number
    1
    4
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 55 (1.82%)
    0 / 41 (0.00%)
         occurrences all number
    3
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 55 (1.82%)
    0 / 41 (0.00%)
         occurrences all number
    3
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 55 (1.82%)
    0 / 41 (0.00%)
         occurrences all number
    4
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 55 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    1
    0
    3
    Nausea
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 55 (1.82%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 55 (5.45%)
    3 / 41 (7.32%)
         occurrences all number
    1
    3
    3
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 55 (3.64%)
    1 / 41 (2.44%)
         occurrences all number
    5
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2012
    Additional blood pressure assessment time points were added to the study; in order to better characterize the effects of MK-8457 on blood pressure in participants with rheumatoid arthritis. Pharmacokinetic sampling time points shifted to coincide with additional blood pressure monitoring timepoints for simplicity.
    08 Aug 2013
    The doses of study drug was changed to 100mg BID, 150mg QD, 75mg QD, 25mg QD, and placebo. The time point for the primary endpoint was changed to 12 weeks.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Sep 2013
    Study was terminated early (12 September 2013) based on preliminary analysis of data.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The results of this study need to be interpreted with caution given the small sample size (82 participants) resulting from the early termination of the study.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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