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    Clinical Trial Results:
    A Phase IIb, Multicenter, Randomized, Double-blind, Placebo-controlled, Multidose, 24-week Study to Evaluate the Efficacy and Safety of Atacicept in Subjects with Systemic Lupus Erythematosus (SLE)

    Summary
    EudraCT number
    		 2013-002773-21
    Trial protocol
    		 CZ   DE   BG   GB   ES   IT  
    Global end of trial date
    08 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Nov 2017
    First version publication date
    22 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR700461-023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01972568
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Center Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Center Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.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
    30 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of atacicept compared to placebo in reducing SLE disease activity in subjects treated with standard of care (SoC) therapy and to investigate the dose-response relationship
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Philippines: 21
    Country: Number of subjects enrolled
    Bulgaria: 27
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Argentina: 52
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Chile: 19
    Country: Number of subjects enrolled
    Mexico: 55
    Country: Number of subjects enrolled
    Peru: 7
    Country: Number of subjects enrolled
    United States: 63
    Worldwide total number of subjects
    306
    EEA total number of subjects
    51
    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)
    301
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was conducted at 136 sites in 18 countries in Asia, Europe, North America, Central America, and South America.

    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
    		 Atacicept 75 mg
    Arm description
    		 Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atacicept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received atacicept 75 mg as once-weekly subcutaneous injection for 24 weeks.

    Arm title
    		 Atacicept 150 mg
    Arm description
    		 Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atacicept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.

    Number of subjects in period 1
    		Atacicept 75 mg Atacicept 150 mg Placebo
    Started
    102
    104
    100
    Completed
    86
    92
    84
    Not completed
    16
    12
    16
         Consent withdrawn by subject
    6
    3
    7
         Adverse event, non-fatal
    5
    6
    5
         Lost to follow-up
    1
    -
    -
         Other events
    3
    -
    -
         Protocol deviation
    1
    2
    2
         Lack of efficacy
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atacicept 75 mg
    Reporting group description
    		 Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.

    Reporting group title
    Atacicept 150 mg
    Reporting group description
    		 Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.

    Reporting group values
    		 Atacicept 75 mg Atacicept 150 mg Placebo Total
    Number of subjects
    		 102 104 100 306
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37 ± 11.2 39 ± 11.6 40 ± 13.0 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 93 97 90 280
        Male
    		 9 7 10 26

    End points

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    End points reporting groups
    Reporting group title
    Atacicept 75 mg
    Reporting group description
    		 Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.

    Reporting group title
    Atacicept 150 mg
    Reporting group description
    		 Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.

    Primary: Percentage of Subjects With Systemic Lupus Erythematosus Responder Index (SRI) Response at Week 24 Using Screening Visit as Baseline

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    End point title
    		 Percentage of Subjects With Systemic Lupus Erythematosus Responder Index (SRI) Response at Week 24 Using Screening Visit as Baseline
    End point description
    SRI response, a composite measure of reduced SLE disease activity, was defined as a reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity score of greater than or equal to (>=) 4 points; no significant worsening in Physician’s Global Assessment (PGA) score (<10 % increase, defined as <0.3 point increase for statistical analyses); no new British Isles Lupus Assessment Group (BILAG) A organ domain scores and <=1 (defined as no more than one) new BILAG B organ domain score. Modified intent-to-treat (mITT) analysis set included all randomised subjects who had received at least 1 dose of IMP.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    102
    104
    100
    Units: percentage of subjects
        number (not applicable)
    57.8
    53.8
    44.0
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atacicept 150 mg v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1208
    Method
    		 Logistic regression model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 2.72

    Primary: Percentage of Subjects With Systemic Lupus Erythematosus (SLE) Responder Index (SRI) Response at Week 24 Using Day 1 as Baseline

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    End point title
    		 Percentage of Subjects With Systemic Lupus Erythematosus (SLE) Responder Index (SRI) Response at Week 24 Using Day 1 as Baseline
    End point description
    SRI response, a composite measure of reduced SLE disease activity, was defined as a reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity score of greater than or equal to (>=) 4 points; no significant worsening in Physician’s Global Assessment (PGA) score (<10 % increase, defined as <0.3 point increase for statistical analyses); no new British Isles Lupus Assessment Group (BILAG) A organ domain scores and <=1 (defined as no more than one) new BILAG B organ domain score. mITT analysis set included all randomized subjects who had received at least 1 dose of IMP.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    102
    104
    100
    Units: percentage of subjects
        number (not applicable)
    55.9
    55.8
    41.0
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atacicept 150 mg v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0202
    Method
    		 Logistic regression model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 3.46

    Secondary: Percentage of Subjects at Week 24 Whose Prednisone-Equivalent Corticosteroid (CS) Dose Reduced From Screening by >=25% and to a dose of =<7.5mg/day, and no British Isles Lupus Assessment Group(BILAG) A or 2B Flare in Disease Activity

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    End point title
    		 Percentage of Subjects at Week 24 Whose Prednisone-Equivalent Corticosteroid (CS) Dose Reduced From Screening by >=25% and to a dose of =<7.5mg/day, and no British Isles Lupus Assessment Group(BILAG) A or 2B Flare in Disease Activity
    End point description
    BILAG A or 2B flare defined by 1 new BILAG A organ domain score and/or 2 new BILAG B organ domain scores compared to the Screening Visit.The BILAG disease activity index evaluates systemic lupus erythematosus (SLE) activity in 8 organ systems,using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone >20 mg daily or immunosuppressants); BILAG B: moderate disease activity requiring treatment with systemic low-dose oral glucocorticoids,intramuscular or soft tissue CS injection,topical CS or immunosuppressants,or symptomatic therapy such as antimalarials or NSAIDs. BILAG C: mild disease; BILAG D: system previously affected but now inactive and BILAG E: system never involved. mITT analysis set included included all randomised subjects who had received at least 1 dose of IMP.Here “Number of Subjects Analysed” signifies those subjects whose CS dose >=10mg at Screening.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    56
    53
    53
    Units: percentage of subjects
        number (not applicable)
    17.9
    11.3
    18.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Patient Global Impression of Change (PGIC) Categories at Week 24

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    End point title
    		 Percentage of Subjects With Patient Global Impression of Change (PGIC) Categories at Week 24
    End point description
    The PGIC is self-rated scale that asks the subject to describe the change in activity limitations, symptoms, emotions, and overall Quality of life (QoL) related to the subject's painful condition on the following scale: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse) and 7 (very much worse). Percentage of subjects in the PGIC categories of very much or much improved (1 or 2), minimally improved or no change or minimally worse (3 or 4 or 5) and much or very much worse (6 or 7) at Week 24 were presented. mITT analysis set included all randomised subjects who had received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    102
    104
    100
    Units: percentage of subjects
    number (not applicable)
        Very much or much improved
    57.8
    53.8
    46.0
        Minimally improved or no change or minimally worse
    39.2
    44.2
    46.0
        Much or very much worse
    2.0
    1.0
    6.0
        Missing
    1.0
    1.0
    2.0
    No statistical analyses for this end point

    Secondary: Change From Screening in Prednisolone-Equivalent Corticosteroid (CS) Daily Dose at Week 24

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    End point title
    		 Change From Screening in Prednisolone-Equivalent Corticosteroid (CS) Daily Dose at Week 24
    End point description
    Change From screening visit to Week 24 of prednisolone-equivalent CS daily dose was presented. mITT analysis set included all randomised subjects who had received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Screening and Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    102
    104
    100
    Units: mg per day
        arithmetic mean (standard deviation)
    -2.64 ± 6.106
    -1.87 ± 4.653
    -1.89 ± 5.588
    No statistical analyses for this end point

    Secondary: Time From Randomization to First SRI Response During Treatment Period

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    End point title
    		 Time From Randomization to First SRI Response During Treatment Period
    End point description
    SRI response, a composite measure of reduced SLE disease activity, was defined as a reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity score of greater than or equal to (>=) 4 points; no significant worsening in Physician’s Global Assessment (PGA) score (<10 % increase, defined as <0.3 point increase for statistical analyses); no new British Isles Lupus Assessment Group (BILAG) A organ domain scores and <=1 (defined as no more than one) new BILAG B organ domain score. Time to randomization to first SRI response during treatment period was presented. mITT analysis set included all randomised subjects who had received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 Weeks
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    102
    104
    100
    Units: weeks
        median (confidence interval 95%)
    12.4 (12.1 to 16.7)
    16.1 (12.0 to 16.4)
    16.1 (12.1 to 20.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With British Isles Lupus Assessment Group (BILAG)-Based Combined Lupus Assessment (BICLA) Response at Week 24

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    End point title
    		 Percentage of Subjects With British Isles Lupus Assessment Group (BILAG)-Based Combined Lupus Assessment (BICLA) Response at Week 24
    End point description
    The BICLA response is defined as BILAG-2004 improvement (all screening visit BILAG A improving to B/C/D, all screening visit BILAG B to C/D, and <=1 new BILAG B and no new BILAG A); no deterioration in SLEDAI total score’; PGA increase by <10% (defined as <0.3 point increase for the statistical analyses) and no nonpermitted medication/treatment. mITT analysis set included all randomised subjects who had received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    88
    100
    93
    Units: percentage of subjects
        number (not applicable)
    53.4
    49.0
    45.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 48 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs. Safety analysis set included all randomised subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    102
    104
    100
    Units: percentage of subjects
    number (not applicable)
        TEAEs
    81.4
    80.8
    72.0
        Serious TEAEs
    8.8
    5.8
    12.0
    No statistical analyses for this end point

    Secondary: Change From Week 0 Day 1 in SF-36 Components at Week 24

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    End point title
    		 Change From Week 0 Day 1 in SF-36 Components at Week 24
    End point description
    The 36-Item Short-Form Health Survey (SF-36) is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component summary scores. Total of 10 variables were analyzed (8 aspects, 2 component summary scores). The score for each of the 8 aspects and 2 component summary scores was scaled from 0 to 100, where 0 = lowest level of functioning and 100 = highest level of functioning.
    End point type
    Secondary
    End point timeframe
    Week 0 Day 1 and Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    102
    104
    100
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical Component Summary (n=101,100, 97)
    4.7 ± 7.95
    3.4 ± 7.57
    3.5 ± 10.33
        Mental Component Summary (n=101,100, 97)
    1.9 ± 12.01
    1.8 ± 9.08
    0.7 ± 11.44
        Physical Functioning (n=85, 89, 82)
    3.5 ± 9.30
    3.8 ± 8.42
    3.3 ± 8.62
        Role-Physical (n=85, 89, 82)
    4.3 ± 10.26
    2.3 ± 8.64
    3.9 ± 9.51
        Bodily Pain (n=85, 89, 82)
    6.0 ± 10.22
    4.4 ± 9.30
    5.6 ± 10.72
        General Health (n=84, 89, 82)
    2.9 ± 8.43
    3.0 ± 7.72
    4.4 ± 8.00
        Vitality (n=84, 89, 82)
    3.9 ± 9.86
    3.7 ± 9.76
    3.5 ± 9.57
        Social Functioning (n=85, 89, 82)
    3.8 ± 11.45
    2.2 ± 10.06
    4.3 ± 11.08
    No statistical analyses for this end point

    Post-hoc: High Disease Activity Subpopulation (SLEDAI-2K >=10 at Screening): Logistic Regression of Percentage of Subjects With SRI-6 Response at Week 24

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    End point title
    		 High Disease Activity Subpopulation (SLEDAI-2K >=10 at Screening): Logistic Regression of Percentage of Subjects With SRI-6 Response at Week 24
    End point description
    SRI-6 response, a composite measure of reduced SLE disease activity, was defined as a reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity score of greater than or equal to (>=) 6 points; no significant worsening in Physician’s Global Assessment (PGA) score (<10 % increase, defined as <0.3 point increase for statistical analyses); no new British Isles Lupus Assessment Group (BILAG) A organ domain scores and <=1 (defined as no more than one) new BILAG B organ domain score. Logistic regression of number of subjects with SRI-6 response was analzed by using Logistic regression model. mITT_HDA analysis set included mITT population with high disease activity (HDA) defined as screening SLE Disease Activity Index (SLEDAI) >=10.
    End point type
    Post-hoc
    End point timeframe
    Week 24
    End point values
    		 Atacicept 75 mg Atacicept 150 mg Placebo
    Number of subjects analysed
    55
    51
    52
    Units: percentage of subjects
        number (not applicable)
    43.6
    54.9
    28.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atacicept 150 mg v Placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.0048
    Method
    		 Logistic regression model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.44
         upper limit
    		 7.61

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Atacicept 75 mg
    Reporting group description
    		 Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.

    Reporting group title
    Atacicept 150 mg
    Reporting group description
    		 Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.

    Serious adverse events
    		 Atacicept 75 mg Placebo Atacicept 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 102 (8.82%)
    12 / 100 (12.00%)
    6 / 104 (5.77%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Uterine haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Aspiration
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Interstitial lung disease
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Pulmonary oedema
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Respiratory failure
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Injury, poisoning and procedural complications
    Ligament injury
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         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
    Angina pectoris
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Cardiac failure congestive
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Mitral valve prolapse
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Right ventricular dilatation
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Sciatica
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Temporal lobe epilepsy
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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 disorders
    Dyspepsia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 100 (2.00%)
    0 / 104 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Osteonecrosis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 100 (2.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Appendicitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Arthritis bacterial
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Bronchitis
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 100 (1.00%)
    0 / 104 (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
    Cardiac valve vegetation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Endocarditis bacterial
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         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
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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 viral
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Infective aortitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph node abscess
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Nasopharyngitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Parotitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Peritonitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Pharyngitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Pneumonia
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 100 (1.00%)
    0 / 104 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Sinusitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Sinusitis bacterial
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Streptococcal sepsis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 104 (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
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 104 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atacicept 75 mg Placebo Atacicept 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 102 (81.37%)
    72 / 100 (72.00%)
    84 / 104 (80.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 102 (10.78%)
    8 / 100 (8.00%)
    15 / 104 (14.42%)
         occurrences all number
    11
    8
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 102 (5.88%)
    2 / 100 (2.00%)
    3 / 104 (2.88%)
         occurrences all number
    6
    2
    3
    Injection site pain
         subjects affected / exposed
    12 / 102 (11.76%)
    7 / 100 (7.00%)
    14 / 104 (13.46%)
         occurrences all number
    12
    7
    14
    Injection site reaction
         subjects affected / exposed
    42 / 102 (41.18%)
    19 / 100 (19.00%)
    43 / 104 (41.35%)
         occurrences all number
    42
    19
    43
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 102 (7.84%)
    5 / 100 (5.00%)
    12 / 104 (11.54%)
         occurrences all number
    8
    5
    12
    Nausea
         subjects affected / exposed
    9 / 102 (8.82%)
    1 / 100 (1.00%)
    5 / 104 (4.81%)
         occurrences all number
    9
    1
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 102 (3.92%)
    7 / 100 (7.00%)
    3 / 104 (2.88%)
         occurrences all number
    4
    7
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 102 (5.88%)
    5 / 100 (5.00%)
    7 / 104 (6.73%)
         occurrences all number
    6
    5
    7
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 102 (9.80%)
    3 / 100 (3.00%)
    13 / 104 (12.50%)
         occurrences all number
    10
    3
    13
    Urinary tract infection
         subjects affected / exposed
    12 / 102 (11.76%)
    17 / 100 (17.00%)
    12 / 104 (11.54%)
         occurrences all number
    12
    17
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2014
    - Included additional detail and clarity in the secondary endpoints - Included additional detail and clarity in the study entry criteria - Included additional detail and clarity in the efficacy and safety assessments
    25 Mar 2015
    - Clarified hepatitis B and hepatitis C screening requirements - Clarified language regarding nonpermitted medications and provided further instruction regarding which will require IMP discontinuation and which will constitute a protocol violation - Clarified language regarding continuing with the trial visits if withdrawal of IMP - Clarified that other than TB testing, the Screening laboratory results could be re-assessed one time with the permission of the Medical Monitor - Clarified language regarding for flow cytometry of PD markers and deleted exploratory monocyte and neutrophils PD endpoints due to challenges encountered with developing a validated assay. Of note, the monocyte and neutrophil absolute numbers were continued to be measured by the cell blood count as the standard laboratory measurements - Clarified language regarding the vaccine recommendation for subjects with prior severe hypersensitivity reactions to the vaccines

    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
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