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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Study of Baricitinib in Patients with Systemic Lupus Erythematosus

    Summary
    EudraCT number
    		 2017-005027-25
    Trial protocol
    		 ES   IT   RO  
    Global end of trial date
    20 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I4V-MC-JAIA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03616964
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 16677
    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 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The reason for this study is to see how effective and safe the study drug known as baricitinib is in participants with systemic lupus erythematosus (SLE).
    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
    02 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 92
    Country: Number of subjects enrolled
    Chile: 34
    Country: Number of subjects enrolled
    Colombia: 48
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    India: 94
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 38
    Country: Number of subjects enrolled
    Philippines: 38
    Country: Number of subjects enrolled
    Poland: 93
    Country: Number of subjects enrolled
    Romania: 30
    Country: Number of subjects enrolled
    Serbia: 53
    Country: Number of subjects enrolled
    South Africa: 41
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    United States: 149
    Worldwide total number of subjects
    775
    EEA total number of subjects
    169
    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)
    1
    Adults (18-64 years)
    733
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 As only year of birth was collected on case report form, for one participant, age at enrollment was calculated as 17 years old, using the imputed day and month of “01Jul ”. Therefore, not necessarily indicating the participant's actual age.

    Pre-assignment
    Screening details
    		 Pharmacokinetic (PK) Population: 2 milligram (mg) Baricitinib (n=277), 4 mg Baricitinib (n=241). Participants with estimated glomerular filtration rate less than (<) 60 milliliter/minute (mL/min)/1.73 square meter (m2) at screening randomized to the 4 mg dose received a dose of 2 mg QD.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received 2 placebo tablets: one placebo tablet matching 4 mg baricitinib and one placebo tablet matching 2 mg baricitinib administered orally once daily (QD) for 52 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 2 placebo tablets: one placebo tablet matching 4 mg baricitinib and one placebo tablet matching 2 mg baricitinib administered orally QD for 52 weeks.

    Arm title
    		 2 mg Baricitinib
    Arm description
    		 Participants received one 2 mg baricitinib tablet and one placebo tablet matching 4 mg baricitinib administered QD for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Baricitinib
    Investigational medicinal product code
    LY3009104
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one 2 mg baricitinib tablet and one placebo tablet matching 4 mg baricitinib administered orally QD for 52 weeks.

    Arm title
    		 4 mg Baricitinib
    Arm description
    		 Participants received one 4 mg baricitinib tablet and one placebo tablet matching 2 mg baricitinib administered orally QD for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Baricitinib
    Investigational medicinal product code
    LY3009104
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one 4 mg baricitinib tablet and one placebo tablet matching 2 mg baricitinib administered QD for 52 weeks.

    Number of subjects in period 1
    		Placebo 2 mg Baricitinib 4 mg Baricitinib
    Started
    256
    261
    258
    Received at Least One Dose of Study Drug
    256
    261
    258
    Completed
    212
    222
    205
    Not completed
    44
    39
    53
         Adverse event, serious fatal
    3
    -
    4
         Consent withdrawn by subject
    18
    14
    21
         Physician decision
    -
    2
    -
         Adverse event, non-fatal
    15
    10
    16
         Due to Epidemic/Pandemic
    -
    1
    -
         Sponsor’s Decision
    1
    -
    -
         Withdrawal by Principal Investigator (PI)
    1
    1
    1
         Decreased Neutrophils due to SLE
    -
    1
    -
         Lost to follow-up
    2
    1
    3
         Lack of efficacy
    4
    8
    8
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 2 placebo tablets: one placebo tablet matching 4 mg baricitinib and one placebo tablet matching 2 mg baricitinib administered orally once daily (QD) for 52 weeks.

    Reporting group title
    2 mg Baricitinib
    Reporting group description
    		 Participants received one 2 mg baricitinib tablet and one placebo tablet matching 4 mg baricitinib administered QD for 52 weeks.

    Reporting group title
    4 mg Baricitinib
    Reporting group description
    		 Participants received one 4 mg baricitinib tablet and one placebo tablet matching 2 mg baricitinib administered orally QD for 52 weeks.

    Reporting group values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib Total
    Number of subjects
    		 256 261 258 775
    Age categorical
    Units: Subjects
    Age continuous
    Analysis population description (APD): All randomized participants who received at least one dose of study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 43.50 ( 13.47 ) 42.80 ( 12.99 ) 42.20 ( 12.11 ) -
    Gender categorical
    APD: All randomized participants who received at least one dose of study drug.
    Units: Subjects
        Female
    		 241 246 245 732
        Male
    		 15 15 13 43
    Ethnicity (NIH/OMB)
    APD: All randomized participants who received at least one dose of study drug.
    Units: Subjects
        Hispanic or Latino
    		 9 11 8 28
        Not Hispanic or Latino
    		 40 38 40 118
        Unknown or Not Reported
    		 207 212 210 629
    Race (NIH/OMB)
    APD: All randomized participants who received at least one dose of study drug.
    Units: Subjects
        American Indian or Alaska Native
    		 14 12 13 39
        Asian
    		 71 66 70 207
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 1
        Black or African American
    		 17 23 26 66
        White
    		 145 152 140 437
        More than one race
    		 5 4 4 13
        Unknown or Not Reported
    		 4 4 4 12
    Region of Enrollment
    APD: All randomized participants who received at least one dose of study drug.
    Units: Subjects
        Argentina
    		 34 29 29 92
        Chile
    		 8 14 12 34
        Colombia
    		 17 15 16 48
        France
    		 3 2 2 7
        India
    		 32 28 34 94
        Italy
    		 2 2 5 9
        Japan
    		 14 12 12 38
        Philippines
    		 13 14 11 38
        Poland
    		 26 36 31 93
        Romania
    		 12 11 7 30
        Serbia
    		 15 20 18 53
        South Africa
    		 14 15 12 41
        South Korea
    		 4 7 8 19
        Spain
    		 12 6 12 30
        United States
    		 50 50 49 149

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 2 placebo tablets: one placebo tablet matching 4 mg baricitinib and one placebo tablet matching 2 mg baricitinib administered orally once daily (QD) for 52 weeks.

    Reporting group title
    2 mg Baricitinib
    Reporting group description
    		 Participants received one 2 mg baricitinib tablet and one placebo tablet matching 4 mg baricitinib administered QD for 52 weeks.

    Reporting group title
    4 mg Baricitinib
    Reporting group description
    		 Participants received one 4 mg baricitinib tablet and one placebo tablet matching 2 mg baricitinib administered orally QD for 52 weeks.

    Subject analysis set title
    2 mg Baricitinib
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received one 2 mg baricitinib tablet and one placebo tablet matching 4 mg baricitinib administered QD for 52 weeks.

    Subject analysis set title
    4 mg Baricitinib
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received one 4 mg baricitinib tablet and one placebo tablet matching 2 mg baricitinib administered QD for 52 weeks.

    Primary: Percentage of Participants Achieving a Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response (4 mg Baricitinib)

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    End point title
    		 Percentage of Participants Achieving a Systemic Lupus Erythematosus Responder Index 4 (SRI-4) Response (4 mg Baricitinib) [1]
    End point description
    SRI-4 response defined as 1)greater than or equal to (>=) 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score 2)no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score and 3)no worsening in Physician Global Assessment (PGA) of Disease Activity (worsening defined as an increase of >=0.3 from baseline on a 0-3 visual analogue scale). SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms,or laboratory parameters related to Systemic Lupus Erythematosus (SLE),divided into 9 organ systems. For each organ system A=severe disease,B=moderate disease,C=mild stable disease,D=inactive,but previously active,E=inactive and never affected. PGA assess disease activity on a visual analogue scale from 0 to 3 (1=mild, 2=moderate, 3=severe).
    End point type
    Primary
    End point timeframe
    Week 52 APD: All randomized participants who received at least one dose of study drug (modified intent-to-treat (mITT) population). Missing data was imputed using the hybrid imputation method [nonresponder imputation (NRI) + multiple imputation (MI)].
    Notes
    [1] - 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: The endpoint is planned only for these reporting arms.
    End point values
    		 Placebo 4 mg Baricitinib
    Number of subjects analysed
    256
    258
    Units: percentage of participants
        number (not applicable)
    45.6
    47.1
    Statistical analysis title
    		 SRI-4 Response (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.711
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.53

    Secondary: Percentage of Participants Achieving SRI-4 Response (2 mg Baricitinib)

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    End point title
    		 Percentage of Participants Achieving SRI-4 Response (2 mg Baricitinib) [2]
    End point description
    SRI-4 response defined as 1)greater than or equal to (>=) 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score 2)no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score and 3)no worsening in Physician Global Assessment (PGA) of Disease Activity (worsening defined as an increase of >=0.3 from baseline on a 0-3 visual analogue scale). SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms,or laboratory parameters related to Systemic Lupus Erythematosus (SLE),divided into 9 organ systems. For each organ system A=severe disease,B=moderate disease,C=mild stable disease,D=inactive,but previously active,E=inactive and never affected. PGA assess disease activity on a visual analogue scale from 0 to 3 (1=mild, 2=moderate, 3=severe).
    End point type
    Secondary
    End point timeframe
    Week 52 APD: All randomized participants who received at least 1 dose of study drug (mITT population). Missing data was imputed using the hybrid imputation method [nonresponder imputation (NRI) + multiple imputation (MI)].
    Notes
    [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: The endpoint is planned only for these reporting arms.
    End point values
    		 Placebo 2 mg Baricitinib
    Number of subjects analysed
    256
    261
    Units: percentage of participants
        number (not applicable)
    45.6
    46.3
    Statistical analysis title
    		 SRI-4 Response (2 mg)
    Comparison groups
    Placebo v 2 mg Baricitinib
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.789
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.5

    Secondary: Percentage of Participants Achieving a Lupus Low Disease Activity State (LLDAS)

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    End point title
    		 Percentage of Participants Achieving a Lupus Low Disease Activity State (LLDAS)
    End point description
    The LLDAS is a composite measure designed to identify patients achieving a state of low disease activity. The LLDAS response criteria were: (1) SLEDAI-2K <=4, with no activity in major organ systems (CNS, vascular, renal, cardiorespiratory and constitutional); where “no activity” is defined as all items of SLEDAI-2K within these major organ systems equal to 0. (2) no new features of lupus disease activity compared to previous occurred visit, where the “new feature” is defined as any of the SLEDAI-2K 24 items changed from 0 to greater than 0; (3) PGA (scale 0-3), <=1; (4) current prednisolone (or equivalent) dose <=7.5 mg daily. APD: All randomized participants who received at least 1 dose of study drug (mITT population). Missing data was imputed using the hybrid imputation method [nonresponder imputation (NRI) + multiple imputation (MI)].
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    256
    261
    258
    Units: percentage of participants
        number (not applicable)
    23.2
    24.0
    25.4
    Statistical analysis title
    		 Lupus Low Disease Activity State (2 mg)
    Comparison groups
    Placebo v 2 mg Baricitinib
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.673
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.68
    Statistical analysis title
    		 Lupus Low Disease Activity State (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.528
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.75

    Secondary: Time to First Severe Flare

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    End point title
    		 Time to First Severe Flare
    End point description
    Time to first severe flare analyzed using a Cox proportional hazards model with treatment group, baseline disease activity [Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) <10; SLEDAI-2K ≥10], baseline corticosteroid dose (<10 mg/day; ≥10 mg/day prednisone or equivalent), and region fitted as explanatory variables. Participants who did not have severe flare during the flare exposure time period were censored at the end of the flare exposure time. APD: All randomized participants who received at least 1 dose of study drug (mITT population). 9999=Data Not Available (N/A) as < 50% of participants experienced first flare, median was not reached, and 95% confidence interval could not be calculated.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    256
    251
    258
    Units: weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 in Participants Receiving Greater Than 7.5 mg/Day at Baseline

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    End point title
    		 Percentage of Participants Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 in Participants Receiving Greater Than 7.5 mg/Day at Baseline
    End point description
    For the analysis of steroid use, steroid dosages were converted to a prednisone equivalent in mg. A responder was defined as having a prednisone reduction by >=25% from Baseline to <=7.5 mg/day during Weeks 40 through 52. APD: All randomized participants who received at least 1 dose of study drug (mITT population) and had received >7.5 mg prednisone at baseline. Missing data was imputed using the hybrid imputation method [NRI + mLOCF (modified last observation carried forward)].
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40 through Week 52
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    104
    114
    105
    Units: percentage of participants
        number (not applicable)
    31.7
    29.8
    34.3
    Statistical analysis title
    		 Prednisone Dose Reduction (2 mg)
    Comparison groups
    Placebo v 2 mg Baricitinib
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.761
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.64
    Statistical analysis title
    		 Prednisone Dose Reduction (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.611
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 2.1

    Secondary: Change from Baseline in Worst Pain Numeric Rating Scale (NRS)

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    End point title
    		 Change from Baseline in Worst Pain Numeric Rating Scale (NRS)
    End point description
    Participants assessed the worst pain in the last 24 hours on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The average worst daily pain score was calculated as the mean of the scores over the last 7 days prior to each assessment time point. Higher score indicated severe pain. Least Squares (LS) mean was calculated using MMRM analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >= 10 mg/day prednisone or equivalent), region (North America, Central/South, America/Mexico, Europe, Asia Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction. APD: All randomized participants who received at least one dose of study drug (mITT population) and had baseline and post-baseline values at the specified time point. Missing data was imputed using the hybrid imputation method (NRI + MMRM).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    183
    182
    179
    Units: score on a scale
        least squares mean (standard error)
    -1.37 ( 0.14 )
    -1.45 ( 0.14 )
    -1.44 ( 0.14 )
    Statistical analysis title
    		 Change from Baseline in Worst Pain NRS (2 mg)
    Comparison groups
    Placebo v 2 mg Baricitinib
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.698
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    		 Change from Baseline in Worst Pain NRS (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.744
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2

    Secondary: Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Total Score

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    End point title
    		 Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Total Score
    End point description
    FACIT-Fatigue score calculated according to a 13-item questionnaire that assess self reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse possible score) to 52 (best score). A higher score reflected an improvement in the participant's health status. Least Squares (LS) mean was calculated using Mixed Model Repeated Measures (MMRM) analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >= 10 mg/day prednisone or equivalent), region (North America, Central/South, America/Mexico, Europe, Asia Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52 APD:All randomized participants who received at least one dose of study drug (mITT population) and had baseline and post-baseline values at the specified time point.Missing data was imputed using the hybrid imputation method (NRI+MMRM).
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    200
    203
    193
    Units: score on a scale
        least squares mean (standard error)
    7.26 ( 0.60 )
    6.90 ( 0.60 )
    6.96 ( 0.61 )
    Statistical analysis title
    		 Change from Baseline in FACIT-Fatigue (2 mg)
    Comparison groups
    Placebo v 2 mg Baricitinib
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.665
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 1.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Statistical analysis title
    		 Change from Baseline in FACIT-Fatigue (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.723
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.95
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84

    Secondary: Percentage of Participants with Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Total Activity Score ≥10 at Baseline with ≥50% Reduction in CLASI Total Activity Score

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    End point title
    		 Percentage of Participants with Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Total Activity Score ≥10 at Baseline with ≥50% Reduction in CLASI Total Activity Score
    End point description
    The CLASI is a single-page tool that separately quantifies disease activity and damage. For the activity score, points are given for the presence of erythema, scale, mucous membrane lesions, recent hair loss, and inflammatory alopecia. The total score represents the sum of the individual scores and ranges from 0 to 70. Higher scores are awarded for more severe manifestations. Analysis population description included all randomized participants who received at least one dose of study drug (mITT population) and had baseline CLASI score >=10. Missing data was imputed using NRI method. APD: All randomized participants who received at least one dose of study drug (mITT population) and had baseline CLASI score >=10. Missing data was imputed using NRI method.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    59
    51
    50
    Units: percentage of participants
        number (not applicable)
    66.1
    56.9
    58.0
    Statistical analysis title
    		 50% Reduction in CLASI (2 mg)
    Comparison groups
    Placebo v 2 mg Baricitinib
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.372
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 1.55
    Statistical analysis title
    		 50% Reduction in CLASI (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.555
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.78

    Secondary: Change from Baseline in Tender Joint Count

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    End point title
    		 Change from Baseline in Tender Joint Count
    End point description
    The number of tender and painful joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as tender or not tender. LS mean was calculated using Mixed Model Repeated Measures (MMRM) analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >=10 mg/day prednisone or equivalent), region (North America, Central/South America/Mexico, Europe, Asia and Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction. APD: All randomized participants who received at least one dose of study drug (mITT population) and had baseline and post-baseline values at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    200
    201
    190
    Units: tender joint count
        least squares mean (standard error)
    -6.92 ( 0.301 )
    -7.40 ( 0.300 )
    -7.83 ( 0.306 )
    Statistical analysis title
    		 Change from Baseline Tender joint Count (2 mg)
    Comparison groups
    Placebo v 2 mg Baricitinib
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.251
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.422
    Statistical analysis title
    		 Change from Baseline Tender joint Count (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.333
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.74
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.425

    Secondary: Change from Baseline in Swollen Joint Count

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    End point title
    		 Change from Baseline in Swollen Joint Count
    End point description
    The number of swollen joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as swollen or not swollen. LS mean was calculated using MMRM analysis with treatment, baseline disease activity (total SLEDAI-2K <10; >=10), baseline corticosteroid dose (<10 mg/day; >=10 mg/day prednisone or equivalent), region (North America, Central/South America/Mexico, Europe, Asia and Rest of World), visit (as categorical variable), baseline value, treatment-by-visit interaction, and baseline value-by-visit interaction. Analysis population description included all randomized participants who received at least one dose of study drug (mITT population) and had baseline and post-baseline values at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    200
    201
    190
    Units: swollen joint count
        least squares mean (standard error)
    -4.79 ( 0.202 )
    -5.10 ( 0.201 )
    -5.31 ( 0.205 )
    Statistical analysis title
    		 Change from Baseline Swollen joint Count (2 mg)
    Comparison groups
    2 mg Baricitinib v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.284
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.282
    Statistical analysis title
    		 Change from Baseline Swollen joint Count (4 mg)
    Comparison groups
    Placebo v 4 mg Baricitinib
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.069
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean difference (Final Values)
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.08
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.284

    Secondary: Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve for Dosing Interval of Baricitinib at Steady State (AUCtau,ss)

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    End point title
    		 Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve for Dosing Interval of Baricitinib at Steady State (AUCtau,ss)
    End point description
    AUCtau,ss reported for participants who received multiple doses of mg baricitinib was derived by a population pharmacokinetics approach. APD: All randomized participants who received at least one dose of study drug with evaluable PK data. Analysis population description included all randomized participants who received at least one dose of study drug with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Week 0 (Baseline): 15 minutes (min) and 60 min postdose; Week 4: 2 to 4 hours (hr) postdose; Week 8: 4 to 6 hr postdose; Week 12 and Week 16 predose
    End point values
    		 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    277
    241
    Units: nanogram*hour/milliliter (ng*h/mL)
        geometric mean (geometric coefficient of variation)
    257 ( 48 )
    505 ( 50 )
    No statistical analyses for this end point

    Secondary: Population PK: Maximum Observed Drug Concentration at Steady State (Cmax,ss)

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    End point title
    		 Population PK: Maximum Observed Drug Concentration at Steady State (Cmax,ss)
    End point description
    PK: Maximum Concentration of Baricitinib at steady-state (Cmax,ss) was derived by a population pharmacokinetics approach. APD: All randomized participants who received at least one dose of study drug with evaluable PK data. Analysis population description included all randomized participants who received at least one dose of study drug with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Week 0 (Baseline): 15 minutes (min) and 60 min postdose; Week 4: 2 to 4 hours (hr) postdose; Week 8: 4 to 6 hr postdose; Week 12 and Week 16 predose
    End point values
    		 2 mg Baricitinib 4 mg Baricitinib
    Number of subjects analysed
    277
    241
    Units: nanograms per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    27.0 ( 23 )
    54.1 ( 24 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through Follow-up (Up to 56 Weeks)
    Adverse event reporting additional description
    All randomized participants who received at least one dose of study drug and who did not discontinue from the study for the reason 'Lost to Follow-up' at the first postbaseline visit. Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 2 placebo tablets: one placebo tablet matching 4 mg baricitinib and one placebo tablet matching 2 mg baricitinib administered orally QD for 52 weeks.

    Reporting group title
    2 mg Baricitinib
    Reporting group description
    		 Participants received one 2 mg baricitinib tablet and one placebo tablet matching 4 mg baricitinib administered QD for 52 weeks.

    Reporting group title
    4 mg Baricitinib
    Reporting group description
    		 Participants received one 4 mg baricitinib tablet and one placebo tablet matching 2 mg baricitinib administered QD for 52 weeks.

    Serious adverse events
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 256 (10.16%)
    35 / 261 (13.41%)
    32 / 258 (12.40%)
         number of deaths (all causes)
    3
    0
    4
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    basal cell carcinoma
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    cervix carcinoma
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [1]
    0 / 241 (0.00%)
    1 / 246 (0.41%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastric cancer
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    squamous cell carcinoma
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 256 (0.78%)
    0 / 261 (0.00%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    peripheral ischaemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    hip arthroplasty
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    2 / 261 (0.77%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    knee arthroplasty
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    rehabilitation therapy
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    thyroidectomy
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    abortion spontaneous
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [2]
    1 / 241 (0.41%)
    1 / 246 (0.41%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    chest pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    oedema peripheral
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    Reproductive system and breast disorders
    genital prolapse
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ovarian cyst
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [3]
    0 / 241 (0.00%)
    1 / 246 (0.41%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pelvic pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    postmenopausal haemorrhage
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [4]
    1 / 241 (0.41%)
    0 / 246 (0.00%)
    0 / 245 (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
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    haemoptysis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    hyperventilation
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    pulmonary embolism
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    psychotic disorder
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    blood creatine phosphokinase increased
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    electrocardiogram t wave inversion
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    fall
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    humerus fracture
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    joint dislocation
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    lumbar vertebral fracture
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    post procedural haemorrhage
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    soft tissue injury
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tendon rupture
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    acute myocardial infarction
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    atrial fibrillation
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cardiac arrest
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    myocardial infarction
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    post herpetic neuralgia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    transient ischaemic attack
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    autoimmune haemolytic anaemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pancytopenia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    vertigo positional
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    abdominal pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    food poisoning
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    gastritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intestinal pseudo-obstruction
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pancreatitis acute
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    vomiting
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    Hepatobiliary disorders
    cholelithiasis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    lupus nephritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    nephrotic syndrome
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pelvi-ureteric obstruction
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ureterolithiasis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    costochondritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    foot deformity
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    osteoarthritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    osteonecrosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    spinal stenosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    systemic lupus erythematosus
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    6 / 261 (2.30%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    abscess jaw
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    appendicitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    covid-19
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    2 / 261 (0.77%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    covid-19 pneumonia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 261 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    coronavirus infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cytomegalovirus colitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    disseminated varicella zoster virus infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    erysipelas
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    gastroenteritis salmonella
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    herpes zoster meningomyelitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    nasopharyngitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 256 (1.17%)
    1 / 261 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    pneumonia bacterial
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 256 (0.78%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pyelonephritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    0 / 258 (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
    salmonellosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    sinusitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tubo-ovarian abscess
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [5]
    0 / 241 (0.00%)
    1 / 246 (0.41%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    typhoid fever
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urosepsis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    0 / 261 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    hyponatraemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 261 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. 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 to this adverse event. 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.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. 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.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. 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.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. 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.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 2 mg Baricitinib 4 mg Baricitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 256 (37.50%)
    100 / 261 (38.31%)
    96 / 258 (37.21%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    9 / 256 (3.52%)
    12 / 261 (4.60%)
    13 / 258 (5.04%)
         occurrences all number
    9
    13
    14
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    23 / 256 (8.98%)
    25 / 261 (9.58%)
    19 / 258 (7.36%)
         occurrences all number
    26
    28
    21
    Blood and lymphatic system disorders
    neutropenia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    7 / 256 (2.73%)
    5 / 261 (1.92%)
    13 / 258 (5.04%)
         occurrences all number
    9
    6
    19
    Gastrointestinal disorders
    diarrhoea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    13 / 256 (5.08%)
    20 / 261 (7.66%)
    10 / 258 (3.88%)
         occurrences all number
    14
    25
    11
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    6 / 256 (2.34%)
    8 / 261 (3.07%)
    15 / 258 (5.81%)
         occurrences all number
    6
    8
    20
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    23 / 256 (8.98%)
    18 / 261 (6.90%)
    21 / 258 (8.14%)
         occurrences all number
    28
    20
    27
    upper respiratory tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    13 / 256 (5.08%)
    17 / 261 (6.51%)
    19 / 258 (7.36%)
         occurrences all number
    16
    18
    22
    urinary tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    26 / 256 (10.16%)
    29 / 261 (11.11%)
    19 / 258 (7.36%)
         occurrences all number
    32
    36
    26

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2018
    - Modified logistic regression analyses; - Clarified the definition of post-menopausal; - Data from types of chest imaging other than x-ray can be accepted for tuberculosis screening; - Arterial thromboembolic events (ATEs) adjudicated by a blinded clinical event committee; - Analysis Methods were revised; - Language was revised for missing data imputation; - Subgroup analysis has been removed from the protocol.
    20 Apr 2020
    - Participant number and statistical analysis was revised to account for COVID-19 affected participants; - Protocol updated to include provisions put into place in order to assure the safety of trial participants and minimizing risks to trial integrity during the COVID-19 pandemic; - Schedule of activities was clarified; - Analysis of British Isles Lupus Assessment Group Based Composite Lupus Assessment (BICLA) endpoint was included in the protocol to supplement efficacy analyses; - Updated to clarify that while most concomitant medications should remain stable during the trial, reductions in dose for safety are permitted; - Updated to clarify that prohibited use of corticosteroids for SLE requires discontinuation from study drug, while use of prohibited doses of corticosteroids for other reasons may not require discontinuation of study drug; - An interim analysis has been added to assess the likelihood of trial failure time prior to trial conclusion in order to minimize participant exposure to an ineffective drug.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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