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    Clinical Trial Results:
    A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLEBLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CC-220 IN SUBJECTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS

    Summary
    EudraCT number
    		 2016-004574-17
    Trial protocol
    		 ES   HU   DE   BE   FR  
    Global end of trial date
    03 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2022
    First version publication date
    18 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-220-SLE-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium,
    Public contact
    Bristol-Myers Squibb International, EU Study Start-Up Unit, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy of three doses of CC-220 (0.45 mg once per day [QD], 0.3 mg QD or 0.15 mg QD) compared to placebo, for the treatment of active systemic lupus erythematosus (SLE) using the SLE Responder Index at Week 24
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jul 2017
    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
    Poland: 30
    Country: Number of subjects enrolled
    Argentina: 23
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Colombia: 40
    Country: Number of subjects enrolled
    Mexico: 54
    Country: Number of subjects enrolled
    United States: 58
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Serbia: 24
    Worldwide total number of subjects
    288
    EEA total number of subjects
    63
    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)
    270
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Placebo-controlled phase: 289 participants were randomized and 288 treated

    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
    		 PBO QD
    Arm description
    		 Placebo-matching treatment once a day
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    size #4 matching placebo identical in appearance to CC-220 0.15 mg, and 0.3 mg, and size #3 matching placebo identical in appearance to CC-220 0.45 mg formulated capsules

    Arm title
    		 0.45 mg QD
    Arm description
    		 Participants dosed with CC-220 at 0.45 mg once a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-220
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.45 mg (size#3) formulated capsules

    Arm title
    		 0.15 mg QD
    Arm description
    		 Participants dosed with CC-220 at 0.15 mg once a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-220
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.15 mg (size #4) formulated capsules

    Arm title
    		 0.30 mg QD
    Arm description
    		 Participants dosed with CC-220 at 0.30 mg once a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-220
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.3 mg (size #4) formulated capsules

    Number of subjects in period 1
    		PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Started
    83
    81
    42
    82
    Going to 0.30mg after week 24
    36 [1]
    0 [2]
    0 [3]
    0 [4]
    going to 0.45mg after week 24
    36 [5]
    0 [6]
    0 [7]
    0 [8]
    Staying on Placebo after week 24
    11 [9]
    0 [10]
    0 [11]
    0 [12]
    Completed
    73
    73
    39
    62
    Not completed
    10
    8
    3
    20
         Adverse event, serious fatal
    1
    -
    -
    -
         Consent withdrawn by subject
    2
    5
    2
    6
         Adverse event, non-fatal
    5
    2
    1
    11
         Pregnancy
    1
    -
    -
    -
         Other reasons
    1
    1
    -
    -
         Lost to follow-up
    -
    -
    -
    1
         Lack of efficacy
    -
    -
    -
    1
         Protocol deviation
    -
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the .30mg dosing after week 24
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the 0.45mg dosing after week 24
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 0 Subjects entered the 0.15mg dosing after week 24
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the .30mg dosing after week 24
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the .30mg and 0.45mg dosing after week 24
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the 0.45mg dosing after week 24
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 0 Subjects entered the 0.15mg dosing after week 24
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the 0.30mg dosing after week 24
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the .30mg and 0.45mg dosing after week 24
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the 0.45mg dosing after week 24
    [11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 0 Subjects entered the 0.15mg dosing after week 24
    [12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 36 Subjects entered the .30mg dosing after week 24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PBO QD
    Reporting group description
    		 Placebo-matching treatment once a day

    Reporting group title
    0.45 mg QD
    Reporting group description
    		 Participants dosed with CC-220 at 0.45 mg once a day

    Reporting group title
    0.15 mg QD
    Reporting group description
    		 Participants dosed with CC-220 at 0.15 mg once a day

    Reporting group title
    0.30 mg QD
    Reporting group description
    		 Participants dosed with CC-220 at 0.30 mg once a day

    Reporting group values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD Total
    Number of subjects
    		 83 81 42 82 288
    Age Categorical
    Units: Participants
        < 40 years old
    		 33 24 15 31 103
        >= 40 to <= 50
    		 26 28 15 21 90
        > 50 to < 65
    		 19 24 10 24 77
        >= 65
    		 5 5 2 6 18
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 43.4 ( 13.3 ) 46.4 ( 11.2 ) 43.8 ( 13.0 ) 44.7 ( 13.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 81 79 41 77 278
        Male
    		 2 2 1 5 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 41 33 21 46 141
        Not Hispanic or Latino
    		 42 48 21 36 147
        Unknown or Not Reported
    		 0 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 2 5 5 1 13
        Asian
    		 0 0 0 1 1
        Black or African American
    		 7 5 3 6 21
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        White
    		 60 60 29 59 208
        Not collected or reported
    		 0 0 0 0 0
        Other
    		 14 11 5 15 45

    End points

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    End points reporting groups
    Reporting group title
    PBO QD
    Reporting group description
    		 Placebo-matching treatment once a day

    Reporting group title
    0.45 mg QD
    Reporting group description
    		 Participants dosed with CC-220 at 0.45 mg once a day

    Reporting group title
    0.15 mg QD
    Reporting group description
    		 Participants dosed with CC-220 at 0.15 mg once a day

    Reporting group title
    0.30 mg QD
    Reporting group description
    		 Participants dosed with CC-220 at 0.30 mg once a day

    Primary: Number of participants who achieve SLE Responder Index (SRI) (4) response

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    End point title
    		 Number of participants who achieve SLE Responder Index (SRI) (4) response
    End point description
    The primary objective is to evaluate the clinical efficacy of three doses of CC-220 (0.45 mg once per day [QD], 0.3 mg QD or 0.15 mg QD) compared to placebo, for the treatment of active systemic lupus erythematosus (SLE) using the SLE Responder Index at Week 24 Composite endpoint SRI(4), defined by the following criteria: - Reduction from Baseline of ≥ 4 points in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2K score and - No new one or more British Isles Lupus Assessment Group (BILAG) A or new (excludes A to B) 2 or more BILAG B items compared to Baseline using BILAG 2004 Index and - No worsening from Baseline defined by an increase of < 0.30 points from Baseline on a Physician's Global Assessment (PGA) visual analog scale (VAS) from 0-3
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    83
    81
    42
    82
    Units: Number of participants
    29
    44
    20
    33
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.214
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.57
         upper limit
    		 29
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.011
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    19.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.12
         upper limit
    		 33.42
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.512
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.77
         upper limit
    		 19.48

    Secondary: Number of participants with SLEDAI 2K score improvement of ≥ 4 points from Baseline

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    End point title
    		 Number of participants with SLEDAI 2K score improvement of ≥ 4 points from Baseline
    End point description
    The SLEDAI 2K score measures disease activity through assessment of 24 lupus manifestations using a weighted score of 1 to 8 points. A manifestation is recorded if it is present over the previous 30 days regardless of severity or whether it has improved or worsened. A SLEDAI 2K score of 3 to 4 points is representative of active disease and a decrease of 1 to 2 points is considered clinically meaningful.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    83
    81
    42
    82
    Units: Number of participants
    30
    45
    20
    35
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.264
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    10.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.66
         upper limit
    		 27.97
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.012
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    19.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.01
         upper limit
    		 33.36
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.399
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.45
         upper limit
    		 21

    Secondary: Number of participants with a ≥ 50% reduction in Cutaneous Lupus Area and Severity Index (CLASI) activity score from Baseline, in participants with Baseline CLASI activity score ≥ 10

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    End point title
    		 Number of participants with a ≥ 50% reduction in Cutaneous Lupus Area and Severity Index (CLASI) activity score from Baseline, in participants with Baseline CLASI activity score ≥ 10
    End point description
    The CLASI Activity Score ranges from 0 to 70. To generate the activity score erythema is scored on a scale of 0 (absent) to 3 (dark red; purple/violaceous/crusted/hemorrhagic) and scale/hypertrophy are scored on a scale of 0 (absent) to 2 (verrucous/hypertrophic). Both the erythema and scale/hypertrophy scores are assessed in 13 different anatomical locations. In addition, the presence of mucous membrane lesions is scored on a scale of 0 (absent) to 1 (lesion or ulceration), the occurrence of recent hair loss is captured (1=yes; 0=no) and non-scarring alopecia is scored on a scale of 0 (absent) to 3 (focal or patchy in more than one quadrant). To calculate the activity score, all scores for erythema, scale/hypertrophy, mucous membrane lesions and alopecia are added together.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    16
    19
    11
    18
    Units: Number of participants
    8
    13
    8
    8
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.446
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.38
         upper limit
    		 53.11
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.488
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    14.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.54
         upper limit
    		 44.48
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 > 0.999
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.64
         upper limit
    		 39.38

    Secondary: Number of participants with no new organ system affected as defined by 1 or more BILAG A or new (excludes A to B) 2 or more BILAG B items compared to Baseline using BILAG 2004 Index

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    End point title
    		 Number of participants with no new organ system affected as defined by 1 or more BILAG A or new (excludes A to B) 2 or more BILAG B items compared to Baseline using BILAG 2004 Index
    End point description
    The BILAG 2004 is a composite index that is based on the Classic BILAG index. It is a clinical measure of lupus disease activity. This tool assesses the changing severity of clinical manifestations of SLE using an ordinal scale scoring system that contain 9 systems (constitutional, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmic, renal and hematological). Activity in each organ system is scored as: A=most active disease; B=intermediate activity; C=mild, stable disease; D=previous involvement, currently inactive; E=no previous activity.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    83
    81
    42
    82
    Units: Number of participants
    65
    70
    38
    59
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.092
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 24.07
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.182
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.88
         upper limit
    		 19.65
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.434
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    -5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.43
         upper limit
    		 8.06

    Secondary: Percentage of participants with no worsening (increase of < 0.30 points from Baseline) in PGA compared to Baseline

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    End point title
    		 Percentage of participants with no worsening (increase of < 0.30 points from Baseline) in PGA compared to Baseline
    End point description
    The PGA uses a visual analog scale with scores between 0 and 3 to indicate worsening of disease. The scoring is as follows: 0 = none, 1 = mild disease, 2 = moderate disease, and 3 = severe disease.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    83
    81
    42
    82
    Units: Percentage of participants
        number (not applicable)
    78.3
    85.2
    90.5
    73.2
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.098
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.98
         upper limit
    		 23.78
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.521
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    -4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.36
         upper limit
    		 8.92
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.267
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Stratified difference
    Point estimate
    6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.24
         upper limit
    		 18.55

    Secondary: Mean change from Baseline in swollen joint count in participants with ≥ 2 swollen joints at Baseline

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    End point title
    		 Mean change from Baseline in swollen joint count in participants with ≥ 2 swollen joints at Baseline
    End point description
    Joint tenderness and swelling will be noted as “present” or “absent,” with no quantitation of severity using a 28- joint count. Note: Data presented is Adjusted mean data.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    62
    56
    33
    54
    Units: swollen joints
        arithmetic mean (confidence interval 95%)
    -6.7 (-7.2 to -6.2)
    -6.6 (-7.1 to -6.1)
    -6.0 (-6.7 to -5.3)
    -6.0 (-6.7 to -5.2)
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.116
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 1.5
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.094
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 1.6
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.881
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.8

    Secondary: Mean change from Baseline in tender joint count in participants with ≥ 2 tender joints at Baseline

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    End point title
    		 Mean change from Baseline in tender joint count in participants with ≥ 2 tender joints at Baseline
    End point description
    Joint tenderness and swelling will be noted as “present” or “absent,” with no quantitation of severity using a 28- joint count. Note: Data presented is Adjusted mean data.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    62
    56
    33
    54
    Units: tender joints
        arithmetic mean (confidence interval 95%)
    -7.9 (-8.8 to -7.0)
    -7.6 (-8.5 to -6.7)
    -6.8 (-8.1 to -5.6)
    -6.7 (-7.7 to -5.6)
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.16
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 2.6
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.621
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.6
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.056
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 2.6

    Secondary: Mean change from Baseline in PGA score

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    End point title
    		 Mean change from Baseline in PGA score
    End point description
    The PGA uses a visual analog scale with scores between 0 and 3 to indicate worsening of disease. The scoring is as follows: 0 = none, 1 = mild disease, 2 = moderate disease, and 3 = severe disease.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    66
    70
    38
    63
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.803 ( 0.605 )
    -0.883 ( 0.546 )
    -0.805 ( 0.528 )
    -0.819 ( 0.629 )
    No statistical analyses for this end point

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

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    End point title
    		 Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score
    End point description
    The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means “not at all,” and 4 means “very much.” The total FACIT-Fatigue score ranges from 0 to 52. Note: Data presented is Adjusted mean data.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    67
    69
    38
    60
    Units: scores on a scale
        arithmetic mean (confidence interval 95%)
    3.8 (1.6 to 6.0)
    5.2 (3.0 to 7.4)
    2.7 (-0.3 to 5.6)
    3.1 (0.9 to 5.4)
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.546
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 2.5
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.35
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 4.4
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.681
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 2.4

    Secondary: Percentage of participants with Corticosteroid Reduction

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    End point title
    		 Percentage of participants with Corticosteroid Reduction
    End point description
    - The percentage of participants with a prednisone or equivalent dose of ≥ 10 mg/day at Baseline whose prednisone or equivalent dose has been reduced to ≤ 7.5 mg/day by Week 16 and maintained through Week 24 with no flares between Week 16 and Week 24 - The percentage of participants with a prednisone or equivalent dose of ≥ 10 mg/day at Baseline whose prednisone or equivalent dose has been reduced to < 10 mg/day by Week 16 and maintained through Week 24 with no flares between Week 16 and Week 24
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    31
    32
    17
    30
    Units: Percentage of participants
    number (not applicable)
        Week 24, <= 7.5 mg/day
    3.2
    0.0
    0.0
    3.3
        Week 24, < 10 mg/day
    6.5
    0.0
    0.0
    3.3
    Statistical analysis title
    		 Placebo vs 0.30mg in < 10 mg/day
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 > 0.999
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Stratified difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.74
         upper limit
    		 13
    Notes
    [1] - < 10 mg/day
    Statistical analysis title
    		 Placebo vs 0.30mg in <= 7.5 mg/day
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 > 0.999
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Stratified difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.13
         upper limit
    		 15.91
    Notes
    [2] - <= 7.5 mg/day

    Secondary: Percent change from Baseline in Corticosteroid Reduction

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    End point title
    		 Percent change from Baseline in Corticosteroid Reduction
    End point description
    Percent change from Baseline in oral corticosteroid (OCS) dose in subjects with prednisone or equivalent ≥ 10 mg/day at Baseline Note: Data presented is Adjusted mean data.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    26
    30
    17
    25
    Units: percent change from baseline
        arithmetic mean (confidence interval 95%)
    -7.9 (-13.6 to -2.2)
    -1.4 (-6.4 to 3.6)
    -5.1 (-11.9 to 1.6)
    -3.8 (-9.5 to 2.0)
    Statistical analysis title
    		 Placebo vs 0.15mg
    Comparison groups
    PBO QD v 0.15 mg QD
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.535
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted means
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 11.6
    Statistical analysis title
    		 Placebo vs 0.30mg
    Comparison groups
    PBO QD v 0.30 mg QD
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.309
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted means
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 12.2
    Statistical analysis title
    		 Placebo vs 0.45mg
    Comparison groups
    PBO QD v 0.45 mg QD
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.091
    Method
    		 longitudinal data analysis model
    Parameter type
    		 Difference in adjusted means
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 14.1

    Secondary: The total corticosteroid dose from Baseline through Week 24

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    End point title
    		 The total corticosteroid dose from Baseline through Week 24
    End point description
    Standardized total oral corticosteroid (OCS) dose.
    End point type
    Secondary
    End point timeframe
    Through Week 24
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    83
    81
    42
    82
    Units: mg
        arithmetic mean (standard deviation)
    1139.7 ( 916.9 )
    1105.5 ( 969.3 )
    1101.9 ( 827.1 )
    1071.8 ( 965.0 )
    No statistical analyses for this end point

    Secondary: Number of participants with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of participants with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    Number of participants who experienced a TEAE during the course of the study
    End point type
    Secondary
    End point timeframe
    from first dose to 28 days post-last dose through Week 24 (placebo-controlled phase), approximately 28 weeks total
    End point values
    		 PBO QD 0.45 mg QD 0.15 mg QD 0.30 mg QD
    Number of subjects analysed
    83
    81
    42
    82
    Units: Number of participants
        Any TEAE
    54
    63
    31
    64
        Any Drug-related TEAE
    24
    32
    14
    36
        Any Serious TEAE
    7
    6
    3
    4
        Any Severe TEAE
    5
    1
    3
    4
        Any TEAE Leading to Drug Interruption
    15
    23
    10
    14
        Any TEAE Leading to Drug Withdrawal
    6
    4
    2
    11
        Any TEAE Leading to Death
    1
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Cause Mortality: Approximately up to 51 months and 1 week Serious Adverse Events and Other (Not Including Serious) Adverse Events: Approximately up to 48 months
    Adverse event reporting additional description
    The number at Risk for All-Cause Mortality represents all Randomized Participants; From date of randomization to 100 days post last dose. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication; 28 days post last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    0.15 mg QD throughout the study
    Reporting group description
    		 Participants dosed with CC-220 at 0.15 mg once a day

    Reporting group title
    0.30 mg QD throughout the study
    Reporting group description
    		 Participants dosed with CC-220 at 0.30 mg once a day

    Reporting group title
    0.45 mg QD throughout the study
    Reporting group description
    		 Participants dosed with CC-220 at 0.45 mg once a day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matching treatment once a day

    Reporting group title
    Placebo up to W24 and then 0.30 mg
    Reporting group description
    		 Placebo-matching treatment once a day up to week 24, then started 0.30mg once a day

    Reporting group title
    Placebo up to W24 and then 0.45 mg
    Reporting group description
    		 Placebo-matching treatment once a day up to week 24, then started 0.45mg once a day

    Serious adverse events
    		 0.15 mg QD throughout the study 0.30 mg QD throughout the study 0.45 mg QD throughout the study Placebo Placebo up to W24 and then 0.30 mg Placebo up to W24 and then 0.45 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 42 (14.29%)
    10 / 82 (12.20%)
    14 / 81 (17.28%)
    5 / 11 (45.45%)
    4 / 36 (11.11%)
    3 / 36 (8.33%)
         number of deaths (all causes)
    1
    0
    0
    1
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 82 (3.66%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    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
    Hypertensive crisis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    General disorders and administration site conditions
    Implant site pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Influenza like illness
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Abnormal uterine bleeding
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Uterine haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypoxia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Epistaxis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Laryngeal oedema
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary embolism
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Forearm fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Joint injury
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Ligament rupture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    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
    Radius fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Traumatic fracture
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Suture related complication
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Pericarditis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Encephalopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Headache
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Hemiparesis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Polyneuropathy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Ischaemic stroke
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Diverticular perforation
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Cholelithiasis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    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
    Urticaria
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Nephrotic syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Proteinuria
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Joint instability
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    3 / 11 (27.27%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Bronchitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Cellulitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    3 / 81 (3.70%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Varicella zoster pneumonia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.15 mg QD throughout the study 0.30 mg QD throughout the study 0.45 mg QD throughout the study Placebo Placebo up to W24 and then 0.30 mg Placebo up to W24 and then 0.45 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 42 (76.19%)
    66 / 82 (80.49%)
    63 / 81 (77.78%)
    10 / 11 (90.91%)
    23 / 36 (63.89%)
    27 / 36 (75.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 82 (4.88%)
    5 / 81 (6.17%)
    1 / 11 (9.09%)
    2 / 36 (5.56%)
    3 / 36 (8.33%)
         occurrences all number
    3
    5
    5
    1
    2
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Gait disturbance
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 82 (1.22%)
    3 / 81 (3.70%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    3
    1
    3
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    2 / 81 (2.47%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    1
    0
    2
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 82 (4.88%)
    2 / 81 (2.47%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    4
    2
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 82 (2.44%)
    1 / 81 (1.23%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    2 / 81 (2.47%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    0
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 82 (3.66%)
    4 / 81 (4.94%)
    1 / 11 (9.09%)
    3 / 36 (8.33%)
    3 / 36 (8.33%)
         occurrences all number
    4
    3
    5
    1
    4
    4
    Dysgeusia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 82 (4.88%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    4 / 36 (11.11%)
         occurrences all number
    0
    4
    0
    0
    2
    4
    Hypoaesthesia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    4 / 36 (11.11%)
         occurrences all number
    0
    1
    1
    0
    2
    4
    Migraine
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 82 (3.66%)
    2 / 81 (2.47%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    2
    1
    0
    0
    Optic neuritis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 82 (1.22%)
    2 / 81 (2.47%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    2
    1
    0
    1
    Parosmia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tension headache
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 82 (6.10%)
    6 / 81 (7.41%)
    0 / 11 (0.00%)
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    6
    6
    9
    0
    6
    3
    Leukopenia
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 82 (3.66%)
    10 / 81 (12.35%)
    0 / 11 (0.00%)
    5 / 36 (13.89%)
    1 / 36 (2.78%)
         occurrences all number
    4
    5
    14
    0
    12
    1
    Lymphopenia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    4 / 81 (4.94%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    5
    0
    0
    3
    Neutropenia
         subjects affected / exposed
    2 / 42 (4.76%)
    8 / 82 (9.76%)
    16 / 81 (19.75%)
    1 / 11 (9.09%)
    2 / 36 (5.56%)
    4 / 36 (11.11%)
         occurrences all number
    2
    13
    28
    1
    4
    10
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    2
    0
    2
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 42 (14.29%)
    5 / 82 (6.10%)
    8 / 81 (9.88%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    10
    6
    9
    0
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 82 (2.44%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    3 / 36 (8.33%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    1
    0
    3
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    1
    0
    2
    1
    Gastritis
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 82 (4.88%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    3 / 36 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    4
    1
    0
    3
    0
    Nausea
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 82 (4.88%)
    5 / 81 (6.17%)
    1 / 11 (9.09%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    4
    4
    6
    1
    1
    2
    Vomiting
         subjects affected / exposed
    6 / 42 (14.29%)
    5 / 82 (6.10%)
    3 / 81 (3.70%)
    1 / 11 (9.09%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    9
    5
    3
    1
    1
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 82 (1.22%)
    4 / 81 (4.94%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    5
    0
    2
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    2
    1
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 82 (4.88%)
    5 / 81 (6.17%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    4
    6
    0
    0
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    0
    0
    3
    2
    Pain in extremity
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    4 / 81 (4.94%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    4
    1
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 42 (9.52%)
    6 / 82 (7.32%)
    5 / 81 (6.17%)
    0 / 11 (0.00%)
    4 / 36 (11.11%)
    1 / 36 (2.78%)
         occurrences all number
    4
    6
    8
    0
    4
    2
    COVID-19
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 82 (2.44%)
    3 / 81 (3.70%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    2
    3
    0
    2
    1
    Cystitis
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 82 (0.00%)
    4 / 81 (4.94%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    5
    0
    5
    0
    Cellulitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 82 (3.66%)
    3 / 81 (3.70%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    4
    4
    0
    2
    1
    Herpes zoster
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 82 (2.44%)
    1 / 81 (1.23%)
    2 / 11 (18.18%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    1
    2
    1
    2
    2
    1
    Infected skin ulcer
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 11 (9.09%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 42 (11.90%)
    7 / 82 (8.54%)
    10 / 81 (12.35%)
    1 / 11 (9.09%)
    4 / 36 (11.11%)
    3 / 36 (8.33%)
         occurrences all number
    8
    7
    11
    1
    4
    3
    Influenza
         subjects affected / exposed
    4 / 42 (9.52%)
    5 / 82 (6.10%)
    8 / 81 (9.88%)
    0 / 11 (0.00%)
    3 / 36 (8.33%)
    3 / 36 (8.33%)
         occurrences all number
    4
    8
    15
    0
    4
    7
    Oral herpes
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 82 (1.22%)
    2 / 81 (2.47%)
    0 / 11 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    5
    1
    2
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    5 / 42 (11.90%)
    6 / 82 (7.32%)
    4 / 81 (4.94%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    5
    7
    5
    0
    2
    1
    Sinusitis
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 82 (6.10%)
    5 / 81 (6.17%)
    0 / 11 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    1
    5
    6
    0
    1
    2
    Urinary tract infection
         subjects affected / exposed
    7 / 42 (16.67%)
    24 / 82 (29.27%)
    15 / 81 (18.52%)
    0 / 11 (0.00%)
    4 / 36 (11.11%)
    6 / 36 (16.67%)
         occurrences all number
    10
    37
    21
    0
    14
    6
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 42 (14.29%)
    11 / 82 (13.41%)
    15 / 81 (18.52%)
    1 / 11 (9.09%)
    3 / 36 (8.33%)
    8 / 36 (22.22%)
         occurrences all number
    7
    16
    27
    1
    4
    10
    Wound infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 82 (3.66%)
    2 / 81 (2.47%)
    0 / 11 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    6
    3
    3
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2017
    Protocol Amendment 1 contains changes to the study based on the implementation of an Urgent Safety Measure regarding thromboembolic risk and prophylaxis. These changes were in line with recommendations from the Study Advisory and Data Monitoring (DMC) Committees.
    03 Apr 2018
    Protocol Amendment 1 has been written to implement changes to the study for all participating sites. The overall intent of the amendment is to provide an option for extended treatment with CC-220 for additional one year, address changes in regards to study eligibility criteria and improve protocol clarity.
    15 Aug 2018
    Protocol Amendment 2 has been written to implement changes to the study for all participating sites. The overall intent of the amendment is to provide an option for extended treatment with CC-220 for additional 52 weeks, address changes in regards to study eligibility criteria and improve protocol clarity.

    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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    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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