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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects with Rheumatoid Arthritis: The RAjuvenate Study

    Summary
    EudraCT number
    		 2015-003289-97
    Trial protocol
    		 SK   AT   PL   DE   ES  
    Global end of trial date
    20 Aug 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    17 Oct 2019
    First version publication date
    25 Aug 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    I8K-MC-JPDA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02628028
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 16173
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    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
    20 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Aug 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the safety and effectiveness of LY3337641 in adults with rheumatoid arthritis (RA).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Puerto Rico: 14
    Country: Number of subjects enrolled
    Argentina: 57
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Japan: 25
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Mexico: 35
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Australia: 3
    Worldwide total number of subjects
    286
    EEA total number of subjects
    60
    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)
    278
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consist of 2-parts. Part A included participants with at least mildly active rheumatoid arthritis (RA) and Part B included participants with moderately to severely active RA. Long-term extension (LTE) period allowed eligible participants who completed Part B of study to receive LY3337641 up to an additional 52 weeks.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Placebo
    Arm description
    		 Participants received oral dose of placebo once daily (QD) for 4 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
    Participants received oral dose of placebo once daily (QD) for 4 weeks.

    Arm title
    		 Part A: 5 mg LY3337641
    Arm description
    		 Participants received oral dose of 5 mg LY3337641 QD for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral dose of 5 mg LY3337641 QD for 4 weeks.

    Arm title
    		 Part A: 10 mg LY3337641
    Arm description
    		 Participants received oral dose of 10 mg LY3337641 QD for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    10 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral dose of 10 mg LY3337641 QD for 4 weeks.

    Arm title
    		 Part A: 30 mg LY3337641
    Arm description
    		 Participants received oral dose of 30 mg LY3337641 QD for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    30 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral dose of 30 mg LY3337641 QD for 4 weeks.

    Arm title
    		 Part B: Placebo
    Arm description
    		 Participants received oral dose of placebo QD for 12 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
    Participants received oral dose of placebo QD for 12 weeks.

    Arm title
    		 Part B: 5 mg LY3337641
    Arm description
    		 Participants received oral dose of 5 mg LY3337641 QD for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral dose of 5 mg LY3337641 QD for 12 weeks.

    Arm title
    		 Part B: 10 mg LY3337641
    Arm description
    		 Participants received oral dose of 10 mg LY3337641 QD for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    10 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral dose of 10 mg LY3337641 QD for 12 weeks.

    Arm title
    		 Part B: 30 mg LY3337641
    Arm description
    		 Participants received oral dose of 30 mg LY3337641 QD for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    30 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral dose of 30 mg LY3337641 QD for 12 weeks.

    Number of subjects in period 1
    		Part A: Placebo Part A: 5 mg LY3337641 Part A: 10 mg LY3337641 Part A: 30 mg LY3337641 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641
    Started
    9
    9
    10
    8
    62
    63
    62
    63
    Received at Least 1dose of Study Drug
    9
    9
    10
    8
    62
    63
    62
    63
    Completed
    9
    9
    9
    8
    46
    49
    46
    48
    Not completed
    0
    0
    1
    0
    16
    14
    16
    15
         Adverse event, serious fatal
    -
    -
    -
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    1
    -
    2
    4
    1
    1
         Physician decision
    -
    -
    -
    -
    -
    1
    -
    -
         Missing information
    -
    -
    -
    -
    2
    1
    2
    4
         Adverse event, non-fatal
    -
    -
    -
    -
    2
    1
    3
    2
         Site Terminated by Sponsor
    -
    -
    -
    -
    -
    1
    1
    -
         Study Terminated by Sponsor
    -
    -
    -
    -
    7
    6
    7
    7
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    1
    -
         Lack of efficacy
    -
    -
    -
    -
    3
    -
    1
    -
    Period 2
    Period 2 title
    Long-term extension (LTE) period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Long Term Extension: LY3337641-5 mg
    Arm description
    		 Participants who completed Part B of study received oral dose of 5 mg LY3337641 QD for an additional 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who completed Part B of study received oral dose of 5 mg LY3337641 QD for an additional 52 weeks.

    Arm title
    		 Long Term Extension: LY3337641-10 mg
    Arm description
    		 Participants who completed Part B of study received oral dose of 10 mg LY3337641 QD for an additional 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    10 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who completed Part B of study received oral dose of 10 mg LY3337641 QD for an additional 52 weeks.

    Arm title
    		 Long Term Extension: LY3337641-30 mg
    Arm description
    		 Participants who completed Part B of study received oral dose of 30 mg LY3337641 QD for an additional 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    30 mg LY3337641
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who completed Part B of study received oral dose of 30 mg LY3337641 QD for an additional 52 weeks.

    Number of subjects in period 2 [1]
    		Long Term Extension: LY3337641-5 mg Long Term Extension: LY3337641-10 mg Long Term Extension: LY3337641-30 mg
    Started
    61
    58
    61
    Placebo Re-randomized in LTE
    14
    14
    14
    Completed
    1
    0
    0
    Not completed
    60
    58
    61
         Consent withdrawn by subject
    2
    3
    3
         Missing information
    3
    4
    3
         Adverse event, non-fatal
    1
    -
    3
         Study Terminated by Sponsor
    52
    51
    51
         Lack of efficacy
    2
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Part B LTE was optional. 42 participants completed part B placebo period,re-randomized to LTE period of 5 mg LY3337641 (14 participants), 10 mg LY3337641 (14 participants) and 30 mg LY3337641 (14 participants).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    		 Participants received oral dose of placebo once daily (QD) for 4 weeks.

    Reporting group title
    Part A: 5 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 5 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part A: 10 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 10 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part A: 30 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 30 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Participants received oral dose of placebo QD for 12 weeks.

    Reporting group title
    Part B: 5 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 5 mg LY3337641 QD for 12 weeks.

    Reporting group title
    Part B: 10 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 10 mg LY3337641 QD for 12 weeks.

    Reporting group title
    Part B: 30 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 30 mg LY3337641 QD for 12 weeks.

    Reporting group values
    		 Part A: Placebo Part A: 5 mg LY3337641 Part A: 10 mg LY3337641 Part A: 30 mg LY3337641 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641 Total
    Number of subjects
    		 9 9 10 8 62 63 62 63 286
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 9 7 9 8 62 63 59 61 278
        From 65-84 years
    		 0 2 1 0 0 0 3 2 8
        85 years and over
    		 0 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.3 ( 11.43 ) 54.0 ( 11.75 ) 56.9 ( 6.44 ) 51.9 ( 5.72 ) 50.5 ( 8.75 ) 50.1 ( 9.20 ) 51.7 ( 9.36 ) 51.9 ( 8.91 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8 9 5 54 53 56 53 246
        Male
    		 1 1 1 3 8 10 6 10 40
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 1 1 0 1 1 0 0 6
        Asian
    		 0 0 0 0 7 14 9 10 40
        Black or African American
    		 1 1 0 1 1 2 2 2 10
        White
    		 6 7 9 7 53 46 50 51 229
        More than one race
    		 0 0 0 0 0 0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 3 3 2 34 26 23 21 116
        Not Hispanic or Latino
    		 5 6 7 6 24 29 26 23 126
        Unknown or Not Reported
    		 0 0 0 0 4 8 13 19 44
    Region of Enrollment
    Units: Subjects
        Puerto Rico
    		 0 0 0 0 4 2 3 5 14
        Argentina
    		 0 0 0 0 15 13 15 14 57
        United States
    		 6 6 6 7 12 13 15 6 71
        Japan
    		 0 0 0 0 6 6 6 7 25
        Spain
    		 0 0 0 0 1 3 3 6 13
        South Korea
    		 0 0 0 0 0 5 0 3 8
        Austria
    		 0 0 0 0 1 0 0 0 1
        Poland
    		 0 0 2 1 9 9 4 7 32
        Italy
    		 0 0 0 0 1 2 2 5 10
        Mexico
    		 3 3 2 0 10 6 7 4 35
        South Africa
    		 0 0 0 0 2 3 5 3 13
        Slovakia
    		 0 0 0 0 0 0 2 2 4
        Australia
    		 0 0 0 0 1 1 0 1 3

    End points

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    End points reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    		 Participants received oral dose of placebo once daily (QD) for 4 weeks.

    Reporting group title
    Part A: 5 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 5 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part A: 10 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 10 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part A: 30 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 30 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Participants received oral dose of placebo QD for 12 weeks.

    Reporting group title
    Part B: 5 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 5 mg LY3337641 QD for 12 weeks.

    Reporting group title
    Part B: 10 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 10 mg LY3337641 QD for 12 weeks.

    Reporting group title
    Part B: 30 mg LY3337641
    Reporting group description
    		 Participants received oral dose of 30 mg LY3337641 QD for 12 weeks.
    Reporting group title
    Long Term Extension: LY3337641-5 mg
    Reporting group description
    		 Participants who completed Part B of study received oral dose of 5 mg LY3337641 QD for an additional 52 weeks.

    Reporting group title
    Long Term Extension: LY3337641-10 mg
    Reporting group description
    		 Participants who completed Part B of study received oral dose of 10 mg LY3337641 QD for an additional 52 weeks.

    Reporting group title
    Long Term Extension: LY3337641-30 mg
    Reporting group description
    		 Participants who completed Part B of study received oral dose of 30 mg LY3337641 QD for an additional 52 weeks.

    Subject analysis set title
    LY3337641
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received single oral dose of 5 mg, 10 mg and 30 mg LY3337641 tablet QD for 4 weeks in Part A and 12 weeks in Part B.

    Primary: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs) or Adverse Events of Special Interest (AESIs) or Any Serious AEs (SAEs) in Part A

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    End point title
    		 Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs) or Adverse Events of Special Interest (AESIs) or Any Serious AEs (SAEs) in Part A [1] [2]
    End point description
    TEAEs are any untoward medical occurrence that either occurs or worsens at any time after treatment baseline, and in the opinion of the investigators is possibly related to study drug. Skin Rash was the only event that was considered an AESI. A serious AE is defined as an event that results in death, initial or prolonged hospitalization, is life-threatening, leads to persistent or significant disability/incapacity, is associated with congenital anomaly/birth defect, or is considered significant by the investigator for any other reason. A summary of SAEs and other non-serious AEs, regardless of whether or not they were possibly related to study drug, is located in the Reported Adverse Event section. Analysis population description (APD) included all randomized participants who received at least 1 dose of the study drug in Part A.
    End point type
    Primary
    End point timeframe
    Up to 6 Weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics were planned or conducted for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No inferential statistics were planned or conducted for this endpoint.
    End point values
    		 Part A: Placebo Part A: 5 mg LY3337641 Part A: 10 mg LY3337641 Part A: 30 mg LY3337641
    Number of subjects analysed
    9
    9
    10
    8
    Units: subjects
        TEAEs
    3
    1
    6
    2
        AESIs
    0
    0
    0
    0
        SAEs
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B

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    End point title
    		 Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B [3]
    End point description
    ACR20 Responder Index is composite of clinical,laboratory,and functional measures in rheumatoid arthritis (RA). "ACR20 Responder" is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria:Physician's Global Assessment of Disease Activity,Patient's Global Assessment of Disease Activity,Patient's Global Assessment of Arthritis Pain using visual analog scale (VAS),Health Assessment Questionnaire-Disability Index (HAQ-DI) and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and/or participants who discontinue study or drug before analysis timepoint are deemed non-responders. APD included all randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using NRI.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is planned only for Part B.
    End point values
    		 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641
    Number of subjects analysed
    54
    56
    52
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    48.1 (34.8 to 61.5)
    55.4 (42.3 to 68.4)
    44.2 (30.7 to 57.7)
    50.9 (37.7 to 64.1)
    Statistical analysis title
    		 ACR20 Response
    Comparison groups
    Part B: Placebo v Part B: 5 mg LY3337641
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.473
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 ACR20 Response
    Comparison groups
    Part B: Placebo v Part B: 10 mg LY3337641
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 ACR20 Response
    Comparison groups
    Part B: Placebo v Part B: 30 mg LY3337641
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.823
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B

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    End point title
    		 Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B [4]
    End point description
    ACR50 Responder Index is composite of clinical, laboratory, and functional measures in RA. "ACR50 Responder" is a participant who has at least 50% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Patient's Global Assessment of Arthritis Pain using VAS, HAQ-DI and hsCRP. Participants with missing responses and/or participants who discontinue study or drug before analysis timepoint are deemed non-responders. Analysis population description included all randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is planned only for Part B.
    End point values
    		 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641
    Number of subjects analysed
    54
    56
    52
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    27.8 (15.8 to 39.7)
    25.0 (13.7 to 36.3)
    15.4 (5.6 to 25.2)
    29.1 (17.1 to 41.1)
    Statistical analysis title
    		 ACR50 Response
    Comparison groups
    Part B: Placebo v Part B: 5 mg LY3337641
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.743
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 ACR50 Response
    Comparison groups
    Part B: Placebo v Part B: 10 mg LY3337641
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.124
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 ACR50 Response
    Comparison groups
    Part B: Placebo v Part B: 30 mg LY3337641
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.858
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B

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    End point title
    		 Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B [5]
    End point description
    ACR70 Responder Index is composite of clinical, laboratory, and functional measures in RA. "ACR70 Responder" is a participant who has at least 70% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Patient's Global Assessment of Arthritis Pain using VAS, HAQ-DI and hsCRP. Participants with missing responses and/or participants who discontinue study or drug before analysis timepoint are deemed non-responders. Analysis population description included all randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is planned only for Part B.
    End point values
    		 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641
    Number of subjects analysed
    54
    56
    52
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    16.7 (6.7 to 26.6)
    8.9 (1.5 to 16.4)
    1.9 (0.0 to 5.7)
    16.4 (6.6 to 26.1)
    Statistical analysis title
    		 ACR70 Response
    Comparison groups
    Part B: Placebo v Part B: 5 mg LY3337641
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.199
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 ACR70 Response
    Comparison groups
    Part B: Placebo v Part B: 10 mg LY3337641
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028
    Method
    		 Regression, Logistic
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
    Statistical analysis title
    		 ACR70 Response
    Comparison groups
    Part B: Placebo v Part B: 30 mg LY3337641
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.863
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B

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    End point title
    		 Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B [6]
    End point description
    Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity using VAS. DAS28 was calculated using following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Analysis population description included all randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is planned only for Part B.
    End point values
    		 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641
    Number of subjects analysed
    62
    63
    62
    63
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.62 ( 1.447 )
    -1.55 ( 1.182 )
    -1.24 ( 1.146 )
    -1.80 ( 1.453 )
    Statistical analysis title
    		 DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 5 mg LY3337641
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.863
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Statistical analysis title
    		 DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 10 mg LY3337641
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.503
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Statistical analysis title
    		 DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 30 mg LY3337641
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.289
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 0.23

    Secondary: Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B

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    End point title
    		 Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B [7]
    End point description
    Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity using VAS. DAS28 was calculated using following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Analysis population description included all randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is planned only for Part B.
    End point values
    		 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641
    Number of subjects analysed
    45
    49
    47
    46
    Units: Percentage of Participants
        number (confidence interval 95%)
    24.2 (13.5 to 34.9)
    28.6 (17.4 to 39.7)
    17.7 (8.2 to 27.3)
    25.4 (14.6 to 36.1)
    Statistical analysis title
    		 Low Disease Activity Using DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 5 mg LY3337641
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.626
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Low Disease Activity Using DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 10 mg LY3337641
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.418
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Low Disease Activity Using DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 30 mg LY3337641
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.951
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B

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    End point title
    		 Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B [8]
    End point description
    Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity using visual analog scale (VAS) (participant global VAS). DAS28 was calculated using following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Clinical remission is defined as DAS28-hsCRP <2.6. Analysis population description included all randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is planned only for Part B.
    End point values
    		 Part B: Placebo Part B: 5 mg LY3337641 Part B: 10 mg LY3337641 Part B: 30 mg LY3337641
    Number of subjects analysed
    45
    49
    47
    46
    Units: Percentage of Participants
        number (confidence interval 95%)
    17.7 (8.2 to 27.3)
    17.5 (8.1 to 26.8)
    6.5 (0.3 to 12.6)
    22.2 (12.0 to 32.5)
    Statistical analysis title
    		 Clinical Remission Using DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 5 mg LY3337641
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.905
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Clinical Remission Using DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 10 mg LY3337641
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.069
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Clinical Remission Using DAS28-hsCRP
    Comparison groups
    Part B: Placebo v Part B: 30 mg LY3337641
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.547
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Pharmacokinetics (PK): Clearance Parameter of LY3337641

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    End point title
    		 Pharmacokinetics (PK): Clearance Parameter of LY3337641
    End point description
    Apparent total body clearance of drug after oral administration based on population PK analysis was evaluated. As prespecified per protocol, an overall population estimate of clearance is generated and data from Part A and B were combined for the analysis. The sparse data was then analyzed using population PK methods in Non linear Mixed Effects Model (NONMEM) to generate an overall population estimate of clearance. Analysis population description included all randomized participants who received at least 1 dose of the study drug and have evaluable PK data in in Part A and Part B.
    End point type
    Secondary
    End point timeframe
    Part A: Weeks 1, 2, and 4, Day 1 (0.5 to 2 hours postdose); Part B: Weeks 2, 4, 8, and 12, Day 1 (0.5 to 2 hours postdose)
    End point values
    		 LY3337641
    Number of subjects analysed
    209
    Units: Liter per hour (L/hr)
        arithmetic mean (standard error)
    29.1 ( 5.9 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 88 Weeks
    Adverse event reporting additional description
    All randomized participants who received at least 1 dose of the study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    		 Participants received oral dose of placebo once daily (QD) for 4 weeks.

    Reporting group title
    Part A: LY3337641-5mg
    Reporting group description
    		 Participants received oral dose of 5 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part A: LY3337641-10mg
    Reporting group description
    		 Participants received oral dose of 10 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part A: LY3337641-30mg
    Reporting group description
    		 Participants received oral dose of 30 mg LY3337641 QD for 4 weeks.

    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Participants received oral dose of placebo QD for 12 weeks.

    Reporting group title
    Part B: LY3337641-5mg
    Reporting group description
    		 Participants received oral dose of 5 mg LY3337641 QD for 12 weeks.

    Reporting group title
    Part B: LY3337641-10mg
    Reporting group description
    		 Participants received oral dose of 10 mg LY3337641 QD for 12 weeks.

    Reporting group title
    Part B: LY3337641-30mg
    Reporting group description
    		 Participants received oral dose of 30 mg LY3337641 QD for 12 weeks.

    Reporting group title
    Long Term Extension: LY3337641-5 mg
    Reporting group description
    		 Participants who completed Part B of study received oral dose of 5 mg LY3337641 QD for an additional 52 weeks.

    Reporting group title
    Long Term Extension: LY3337641-10 mg
    Reporting group description
    		 Participants who completed Part B of study received oral dose of 10 mg LY3337641 QD for an additional 52 weeks.

    Reporting group title
    Long Term Extension: LY3337641-30 mg
    Reporting group description
    		 Participants who completed Part B of study received oral dose of 30 mg LY3337641 QD for an additional 52 weeks.

    Serious adverse events
    		 Part A: Placebo Part A: LY3337641-5mg Part A: LY3337641-10mg Part A: LY3337641-30mg Part B: Placebo Part B: LY3337641-5mg Part B: LY3337641-10mg Part B: LY3337641-30mg Long Term Extension: LY3337641-5 mg Long Term Extension: LY3337641-10 mg Long Term Extension: LY3337641-30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    2 / 62 (3.23%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    3 / 63 (4.76%)
    1 / 61 (1.64%)
    3 / 58 (5.17%)
    1 / 61 (1.64%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 61 (1.64%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ankle fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    foot fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hand fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    joint dislocation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    multiple injuries
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    patella fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pubis fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    wrist fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    venous thrombosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystitis acute
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    nephrolithiasis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    pneumonia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Placebo Part A: LY3337641-5mg Part A: LY3337641-10mg Part A: LY3337641-30mg Part B: Placebo Part B: LY3337641-5mg Part B: LY3337641-10mg Part B: LY3337641-30mg Long Term Extension: LY3337641-5 mg Long Term Extension: LY3337641-10 mg Long Term Extension: LY3337641-30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    6 / 10 (60.00%)
    2 / 8 (25.00%)
    7 / 62 (11.29%)
    10 / 63 (15.87%)
    12 / 62 (19.35%)
    19 / 63 (30.16%)
    11 / 61 (18.03%)
    12 / 58 (20.69%)
    10 / 61 (16.39%)
    Nervous system disorders
    carotid artery aneurysm
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    dizziness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    1 / 61 (1.64%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    headache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 10 (20.00%)
    1 / 8 (12.50%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    1 / 63 (1.59%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    1
    1
    0
    0
    0
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    4 / 63 (6.35%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    0
    0
    0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    benign prostatic hyperplasia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [1]
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    erectile dysfunction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [2]
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    constipation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    diarrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    2 / 63 (3.17%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    3
    0
    0
    0
    dry mouth
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    nausea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    1 / 63 (1.59%)
    1 / 61 (1.64%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    1
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    1 / 63 (1.59%)
    2 / 61 (3.28%)
    1 / 58 (1.72%)
    2 / 61 (3.28%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    1
    2
    1
    2
    Musculoskeletal and connective tissue disorders
    osteopenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 61 (0.00%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    rheumatoid arthritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    1 / 62 (1.61%)
    3 / 63 (4.76%)
    4 / 62 (6.45%)
    2 / 63 (3.17%)
    1 / 61 (1.64%)
    1 / 58 (1.72%)
    2 / 61 (3.28%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    4
    2
    1
    2
    2
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    2 / 63 (3.17%)
    1 / 61 (1.64%)
    3 / 58 (5.17%)
    1 / 61 (1.64%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    2
    1
    4
    1
    laryngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 61 (1.64%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    2 / 62 (3.23%)
    3 / 63 (4.76%)
    1 / 62 (1.61%)
    5 / 63 (7.94%)
    1 / 61 (1.64%)
    0 / 58 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    0
    0
    0
    2
    3
    2
    5
    1
    0
    2
    pharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    2 / 62 (3.23%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    3 / 63 (4.76%)
    0 / 61 (0.00%)
    2 / 58 (3.45%)
    1 / 61 (1.64%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    1
    4
    0
    2
    1
    sinusitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    1 / 63 (1.59%)
    0 / 61 (0.00%)
    2 / 58 (3.45%)
    2 / 61 (3.28%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    1
    0
    2
    2
    urinary tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    1 / 63 (1.59%)
    2 / 61 (3.28%)
    3 / 58 (5.17%)
    4 / 61 (6.56%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    1
    1
    2
    4
    4
    Metabolism and nutrition disorders
    hypertriglyceridaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    1 / 61 (1.64%)
    0 / 58 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    hypokalaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    2 / 63 (3.17%)
    0 / 61 (0.00%)
    1 / 58 (1.72%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    0
    2
    0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2016
    The main changes include the addition of a 4 week lead in safety study, and a lowering of the top dose from 40mg to 30mg. In the European Union (EU), the ongoing initial Clinical Trial Application (CTA)s were withdrawn prior to approval. Therefore the submission of the amended JPDA(a) will be the re-submission of the initial CTA for the study, rather than an amendment of an approved protocol in the EU countries.
    31 Oct 2016
    The main changes include (1) expanding Part B from 3 arms to 4 arms by addition of a 5-mg QD dose group, (2) the sample size was increased from 150 subjects to 244 subjects in Part B, and (3) for Part B, region (Japan vs non-Japan) was added as a stratification factor due to regulatory requirements in Japan for evaluating the consistency of results between Japanese subjects and the overall population. In addition, region (Japan vs non-Japan) was added as an independent variable in the primary analysis.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination leading to fewer number of subjects included in primary analysis than planned.
    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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