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    Clinical Trial Results:
    A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Proof-of-Concept Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Subjects with Active Rheumatoid Arthritis and an Inadequate Response or Intolerance to Anti-TNF-α Therapy

    Summary
    EudraCT number
    		 2012-002181-12
    Trial protocol
    		 SE   GB   ES   DK   GR   IT   HU   AT  
    Global end of trial date
    08 Oct 2013

    Results information
    Results version number
    		 v1
    This version publication date
    16 Feb 2016
    First version publication date
    13 Jun 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-8457-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01651936
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials 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
    08 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    08 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 in participants with active rheumatoid arthritis (RA) and an inadequate response or intolerance to anti-tumor necrosis factor α (anti-TNF-α) therapy. The primary hypothesis of this study was that among participants with active RA, MK-8457 100 mg twice daily (BID) was superior to placebo as measured by the change in Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) after 12 weeks of treatment. On September 12, 2013, upon the planned review of the interim data, the standing internal Data Monitoring Committee made the decision to discontinue this Phase II study because of safety reviews. The results of this study need to be interpreted with caution given the small sample size (56 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 the base study were eligible for early escape at Week 12 or Week 18, only if they demonstrated a <20% improvement in both tender and swollen joint counts. If participants met the early escape criteria, participants could choose to either withdraw from the study or to continue into the safety extension portion of the study and receive MK-8457 100 mg twice daily (BID) for up to a total of 100 weeks of treatment.
    Background therapy
    		 Participants were required to be on background methotrexate (MTX) therapy at stable doses prior to and during the base study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Aug 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: 8
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Colombia: 11
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    56
    EEA total number of subjects
    20
    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)
    41
    From 65 to 84 years
    14
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This trial was conducted at 53 clinical centers in the United States, Australia, Columbia, Denmark, France, Greece, Hungary, Italy, New Zealand, Poland, South Africa, Spain, and in the United Kingdom.

    Pre-assignment
    Screening details
    		 Sixty-four of 120 participants screened for the study were not randomized; 56 were excluded for not meeting at least one of the inclusion or exclusion criteria. Eight participants were being screened but were 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-8456 100mg, BID, oral daily for 24 weeks

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

    Number of subjects in period 1 [1]
    		MK-8457 100mg BID Placebo
    Started
    30
    26
    Completed
    3
    1
    Not completed
    27
    25
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    3
    -
         Study Terminated By Sponsor
    21
    16
         Transferred to other arm/group
    2
    8
    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: Participants in the Base Study were eligible for early escape at Week 12 or Week 18 if they demonstrated a <20% improvement in both tender and swollen joint counts. Participants who met this criterion could withdraw from the base study and continued onto the Safety Extension Study (MK-8457 100 BID + MTX) for up to 76 weeks.
    Period 2
    Period 2 title
    Safety Extensions
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

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

    Investigational medicinal product name
    MK-8457 100mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-8456 100mg, BID, oral daily for up to 76 weeks

    Number of subjects in period 2 [2]
    		MK-8457 100 mg
    Started
    4
    Completed
    0
    Not completed
    14
         Study Terminated By Sponsor
    13
         Lack of efficacy
    1
    Joined
    10
         Transferred in from other group/arm
    10
    Notes
    [2] - 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: Participants in the Base Study were eligible for early escape at Week 12 or Week 18 if they demonstrated a <20% improvement in both tender and swollen joint counts. Participants who met this criterion could withdraw from the base study and continued onto the Safety Extension Study (MK-8457 100 BID + MTX) for up to 76 weeks. Four participants completed the Base Study and started the Safety Extension. Ten participants joined the Safety Extension after early escape from the Base 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 twice daily (BID) for 24 weeks

    Reporting group values
    		 MK-8457 100mg BID Placebo Total
    Number of subjects
    		 30 26 56
    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)
    		 21 20 41
        From 65-84 years
    		 8 6 14
        85 years and over
    		 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 22 21 43
        Male
    		 8 5 13

    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 twice daily (BID) for 24 weeks
    Reporting group title
    MK-8457 100 mg
    Reporting group description
    		 MK-8457 (100mg) BID, oral, for up to 76 weeks.

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

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    End point title
    		 Change From Baseline in the Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) 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
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 100mg BID Placebo
    Number of subjects analysed
    13 [1]
    18 [2]
    Units: DAS28-CRP score
        least squares mean (confidence interval 95%)
    -1.83 (-2.58 to -1.09)
    -1.31 (-2.01 to -0.62)
    Notes
    [1] - Number of participants with data at both Baseline and Week 12.
    [2] - 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
    Placebo v MK-8457 100mg BID
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.308
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.54
         upper limit
    		 0.5
    Notes
    [3] - 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: Percentage of Participants Achieving American College of Rheumatology 20 (ACR20) Response at Week 12

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    End point title
    		 Percentage of Participants Achieving American College of Rheumatology 20 (ACR20) Response at Week 12
    End point description
    ACR responses are 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 particpant’s overall assessment of pain on a visual analog scale (VAS, 100 mm, no pain to extreme pain); b. Participant’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
    30 [4]
    26 [5]
    Units: Percentage of participants
        number (not applicable)
    26.67
    26.92
    Notes
    [4] - Number of participants who completed Week 12 or discontinued before Week 12.
    [5] - Number of participants who has either completed Week 12 or has 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
    MK-8457 100mg BID v Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.91
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.52
         upper limit
    		 23.01
    Notes
    [6] - Based on Cochran-Mantel-Haenszel test stratified by region and screening inflammatory marker level.

    Secondary: Percentage of Participants Achieving an ACR20 Response at Week 24

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    End point title
    		 Percentage of Participants Achieving an ACR20 Response at Week 24
    End point description
    Percentage of participants who were ACR20 responders at Week 24. ACR responses were presented as the numerise assessment criteria. An ACR 20 response was 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 particpant’s overall assessment of pain on a visual analog scale (VAS, 100 mm, no pain to extreme pain); b. Participant’s Global Assessment of Disease Activity (VAS); c. Physician’s Global Assessment of Disease Activity (VAS); d. Participant’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 24
    End point values
    		 MK-8457 100mg BID Placebo
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [7] - Due to the early termination of the study, this endpoint was not evaluated.
    [8] - 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 ACR50 Response at Week 12

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    End point title
    		 Percentage of Participants Achieving ACR50 Response at Week 12
    End point description
    Percentage of participants who were ACR50 responders at Week 12. ACR responses are presented as the numerical measurement of improvement in multiple disease assessment criteria. An ACR50 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. Participant’s Global Assessment of Disease Activity (VAS); c. Physician’s Global Assessment of Disease Activity (VAS); d. Participant’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
    30 [9]
    26 [10]
    Units: Percentage of participants
        number (not applicable)
    20
    11.54
    Notes
    [9] - Number of participants who completed Week 12 or discontinued before Week 12.
    [10] - Number of participants who completed Week 12 or discontinued before Week 12.
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Percentage of ACR50 responders at Week 12 treated with MK-8457 minus percentage of ACR50 responders at Week 12 treated with placebo.
    Comparison groups
    Placebo v MK-8457 100mg BID
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.468
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.4
         upper limit
    		 27.32
    Notes
    [11] - Based on Cochran-Mantel-Haenszel test stratified by region and screening inflammatory marker level.

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

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    End point title
    		 Change From Baseline in DAS28-CRP at Week 24
    End point description
    DAS28 (CRP) is a continuous response validated measure which includes tender and swollen joint count, inflammatory marker, and patient global assessment. 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 MK-8457 100mg BID Placebo
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: DAS28-CRP score
        number (not applicable)
    Notes
    [12] - Due to the early terminaton of the study, this endpoint was not evaluated.
    [13] - Due to the early terminaton of the study, this endpoint was not evaluated.
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Health Assessment Questionnaire (HAQ) at Week 12

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    End point title
    		 Change From Baseline in the Health Assessment Questionnaire (HAQ) 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 assessed the degree of difficulty a person had 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8457 100mg BID Placebo
    Number of subjects analysed
    13 [14]
    18 [15]
    Units: HAQ score
        least squares mean (confidence interval 95%)
    -0.67 (-0.95 to -0.39)
    -0.26 (-0.52 to -0.01)
    Notes
    [14] - Number of participants with data at both Baseline and Week 12.
    [15] - 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
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.038
    Method
    		 Difference in LS Means
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 -0.02
    Notes
    [16] - Constrained longitudinal data analysis model includes terms for region, screening inflammatory marker level, time in weeks, and treatment by time. A participant needed to have at least one baseline observation or post-baseline observation to be included in the model.

    Secondary: Percentage of Participants Achieving ACR50 Response at Week 24

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    End point title
    		 Percentage of Participants Achieving ACR50 Response at Week 24
    End point description
    Percentage of participants who were ACR50 responders at Week 24. ACR responses are presented as the numerical measurement of improvement in multiple disease assessment criteria. An ACR50 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. Participant’s Global Assessment of Disease Activity (VAS); c. Physician’s Global Assessment of Disease Activity (VAS); d. Participant’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 24
    End point values
    		 MK-8457 100mg BID Placebo
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: Percentage of Participants
        number (not applicable)
    Notes
    [17] - Due to the early termination of the study, this endpoint was not evaluated.
    [18] - 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 HAQ at Week 24

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    End point title
    		 Change From Baseline in the HAQ at Week 24
    End point description
    The functional status of the participant was assessed using the Disability Index of the HAQ. This 20-question instrument assessed the degree of difficulty a person had 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 MK-8457 100mg BID Placebo
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: HAQ score
        number (not applicable)
    Notes
    [19] - Due to the early terminaton of the study, this endpoint was not evaluated.
    [20] - Due to the early terminaton of the study, this endpoint was not evaluated.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 102 weeks
    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
    		 -

    Reporting group title
    Placebo (Base study)
    Reporting group description
    		 -

    Reporting group title
    MK-8457 100 mg (Safety Extension)
    Reporting group description
    		 -

    Serious adverse events
    		 MK-8457 100 mg (Base Study) Placebo (Base study) MK-8457 100 mg (Safety Extension)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 30 (16.67%)
    0 / 26 (0.00%)
    2 / 14 (14.29%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
    0 / 14 (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
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
    0 / 14 (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
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
    0 / 14 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
    0 / 14 (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
    Lung infection
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         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) Placebo (Base study) MK-8457 100 mg (Safety Extension)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 30 (33.33%)
    2 / 26 (7.69%)
    6 / 14 (42.86%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Mouth injury
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    5 / 30 (16.67%)
    1 / 26 (3.85%)
    2 / 14 (14.29%)
         occurrences all number
    5
    1
    3
    Dyspepsia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2013
    This amendment was a global amendment and included changes to the primary and secondary objectives, reduction in the sample size, and removal of the second planned interim analysis. No participants were enrolled under this amendment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Sep 2013
    On September 12, 2013, upon the planned review of the interim data, the standing internal Data Monitoring Committee made the decision to discontinue this Phase II study because of safety reviews.
    -

    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 (56 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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