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    Clinical Trial Results:
    Effisayil™ 1: Multi-center, double-blind, randomized, placebo-controlled, Phase II study to evaluate efficacy, safety and tolerability of a single intravenous dose of spesolimab (BI 655130) in patients with Generalized Pustular Psoriasis (GPP) presenting with an acute flare of moderate to severe intensity

    Summary
    EudraCT number
    		 2017-004231-37
    Trial protocol
    		 FR   DE  
    Global end of trial date
    05 Jan 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Mar 2022
    First version publication date
    11 Jan 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1368-0013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03782792
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.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
    01 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy, tolerability, and safety of spesolimab (BI 655130) compared with placebo in patients with Generalized Pustular Psoriasis (GPP) presenting with an acute flare of moderate to severe intensity.
    Protection of trial subjects
    Week1/Day 2 to D7: - If the severity and progression of the disease worsened within the 1st week and required immediate treatment, then the investigator could treat the patient with the escape medication of his/her choice. After Day 8: - Patients who did not achieve a clinical response (Generalized Pustular Psoriasis Physician Global Assessment 0 or 1) but had disease worsening subsequent to Day 8 could receive an escape treatment chosen by the investigator - Patients who achieved a clinical response and later had disease worsening that was not severe enough to meet the criteria for recurrence for Generalized Pustular Psoriasis (GPP) flare could receive the escape medication. However, it was recommended to wait until the patient met the criteria for recurrence of GPP flare since there was an option to administer rescue medication with Open Label spesolimab instead at this time. Patients were allowed to withdraw their consent at any time without the need to justify the decision.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Feb 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 9
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Malaysia: 20
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    Tunisia: 9
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    85
    EEA total number of subjects
    24
    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)
    79
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized, placebo-controlled, double-blind, parallel-group, single-dose trial with 2 treatment groups (spesolimab and placebo) in patients with Generalized Pustular Psoriasis (GPP) presenting with an acute flare of moderate to severe intensity.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

    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
    Blinding implementation details
    Patients and investigators involved in the trial conduct remained blinded with regard to the randomized treatment assignments until after database lock for the final trial analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients received intravenously (i.v.) solution for infusion containing 900 mg of placebo to spesolimab on Day 1 (D1) of Week 1 (Wk1). If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing an escape medication (SoC) since there was an option to administer open label (OL) spesolimab instead at this time. If escape medication was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patients worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab (only one single rescue i.v. dose of 900 mg spesolimab) after Wk1 to Wk 12.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received intravenously (i.v.) solution for infusion containing 900 milligram (mg) of placebo to spesolimab on Day 1 (D1) of Week 1 (Wk1).

    Arm title
    		 Spesolimab 900 mg i.v SD
    Arm description
    		 Patients received intravenously (i.v.) a single dose (SD) of solution for infusion containing 900 milligram (mg) of spesolimab on Day 1 (D1) of Week 1 (Wk1). If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing an escape medication (SoC) since there was an option to administer open label (OL) spesolimab instead at this time. If escape medication was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patients worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab (only one single rescue i.v. dose of 900 mg spesolimab) after Wk1 to Wk 12.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spesolimab
    Investigational medicinal product code
    Other name
    BI 655130
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received intravenously (i.v.) a single dose (SD) of solution for infusion containing 900 milligram (mg) of spesolimab on Day 1 (D1) of Week 1 (Wk1).

    Number of subjects in period 1 [1]
    		Placebo Spesolimab 900 mg i.v SD
    Started
    18
    35
    Received OL Spesolimab at Wk1/D8
    15 [2]
    12 [3]
    Received rescue Spesolimab after Wk1
    2 [4]
    4 [5]
    Completed
    17
    32
    Not completed
    1
    3
         Consent withdrawn by subject
    1
    2
         Patient left the country
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 85 patients were screened, of whom 53 were randomised.
    [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: Out of 18 subjects that were treated with Placebo on Day 1 only 2 received rescue Spesolimab after Week 1.
    [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: Out of 35 subjects that were treated with Spesolimab 900 mg i.v on Day 1 only 12 received Open Label Spesolimab at Week 1/Day 8.
    [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: Out of 18 subjects that were treated with Placebo on Day 1 only 15 received Open Label Spesolimab at Week 1/Day 8.
    [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: Out of 35 subjects that were treated with Spesolimab 900 mg i.v on Day 1 only 4 received rescue Spesolimab after Week 1.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received intravenously (i.v.) solution for infusion containing 900 mg of placebo to spesolimab on Day 1 (D1) of Week 1 (Wk1). If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing an escape medication (SoC) since there was an option to administer open label (OL) spesolimab instead at this time. If escape medication was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patients worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab (only one single rescue i.v. dose of 900 mg spesolimab) after Wk1 to Wk 12.

    Reporting group title
    Spesolimab 900 mg i.v SD
    Reporting group description
    		 Patients received intravenously (i.v.) a single dose (SD) of solution for infusion containing 900 milligram (mg) of spesolimab on Day 1 (D1) of Week 1 (Wk1). If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing an escape medication (SoC) since there was an option to administer open label (OL) spesolimab instead at this time. If escape medication was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patients worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab (only one single rescue i.v. dose of 900 mg spesolimab) after Wk1 to Wk 12.

    Reporting group values
    		 Placebo Spesolimab 900 mg i.v SD Total
    Number of subjects
    		 18 35 53
    Age categorical
    Randomized Set (RS): This patient set included all randomized patients.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 18 33 51
        From 65-84 years
    		 0 2 2
        85 years and over
    		 0 0 0
    Age Continuous
    Randomized Set (RS): This patient set included all randomized patients.
    Units: years
        arithmetic mean (standard deviation)
    		 42.6 ± 8.4 43.2 ± 12.1 -
    Sex: Female, Male
    Randomized Set (RS): This patient set included all randomized patients.
    Units: Participants
        Female
    		 15 21 36
        Male
    		 3 14 17
    Race (NIH/OMB)
    Randomized Set (RS): This patient set included all randomized patients.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 13 16 29
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 5 19 24
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Randomized Set (RS): This patient set included all randomized patients.
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 18 35 53
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received intravenously (i.v.) solution for infusion containing 900 mg of placebo to spesolimab on Day 1 (D1) of Week 1 (Wk1). If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing an escape medication (SoC) since there was an option to administer open label (OL) spesolimab instead at this time. If escape medication was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patients worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab (only one single rescue i.v. dose of 900 mg spesolimab) after Wk1 to Wk 12.

    Reporting group title
    Spesolimab 900 mg i.v SD
    Reporting group description
    		 Patients received intravenously (i.v.) a single dose (SD) of solution for infusion containing 900 milligram (mg) of spesolimab on Day 1 (D1) of Week 1 (Wk1). If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing an escape medication (SoC) since there was an option to administer open label (OL) spesolimab instead at this time. If escape medication was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patients worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab (only one single rescue i.v. dose of 900 mg spesolimab) after Wk1 to Wk 12.

    Primary: Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 indicating no visible pustules at Week 1

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    End point title
    		 Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 indicating no visible pustules at Week 1
    End point description
    The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) relies on clinical assessment of the Generalized Pustular Psoriasis (GPP) patient’s skin presentation. The investigator (or qualified site personnel) scored the erythema, pustules, and scaling of all GPP lesions from 0 to 4. The GPPGA pustulation subscore ranges from 0 to 4 where: 0 = clear; 1 = almost clear; 2 = mild: 3 = moderate; 4 = severe. A lower GPPGA pustulation subscore indicates a better outcome. A GPPGA pustulation subscore of 0 means no visible pustules. The proportion of patients who achieved a GPPGA pustulation subscore of 0 at Week 1 is reported. Randomized Set (RS) (via estimand EN-NRI): EN = Any assessments after death, or any use of escape medication due to disease worsening prior to Week 1 were considered to represent a non-response. NRI = Non-response imputation for any missing data.
    End point type
    Primary
    End point timeframe
    At Week 1.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [1]
    35 [2]
    Units: Proportion of participants
        number (confidence interval 95%)
    0.056 (0.010 to 0.258)
    0.543 (0.382 to 0.695)
    Notes
    [1] - RS via estimand EN-NRI
    [2] - RS via estimand EN-NRI
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The Suissa-Shuster Z-pooled test was implemented to test the treatment effect on the primary endpoint on the RS (estimand EN) at a 1-sided, alpha level of 0.025. Confidence intervals (95%) around the risk difference were produced using the Chan and Zhang method.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.0004 [4]
    Method
    		 Suissa-Shuster Z-pooled test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.487
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.215
         upper limit
    		 0.672
    Notes
    [3] - Risk difference=Response rate of spesolimab - response rate of placebo.
    [4] - One-sided P Value.

    Secondary: Proportion of patients with a Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 at Week 4

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    End point title
    		 Proportion of patients with a Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 at Week 4
    End point description
    Generalized Pustular Psoriasis Area and Severity Index (GPPASI) provides a numeric scoring for a patient’s overall Generalized Pustular Psoriasis (GPP) disease state, ranging from 0 to 72. It is a linear combination of percent of surface area of skin affected by erythema, pustules, and scaling and the severity of erythema, pustules, and scaling (desquamation) over 4 body regions (head, trunk, upper limbs and lower limbs). A higher score indicates a worse disease state, while a score of 0 indicates no disease. GPPASI 75 is based on the percent reduction from baseline, generally summarized as a dichotomous outcome based on achieving over an 75% reduction. Proportion of patients with GPPASI 75 at Week 4 is reported. Randomized Set (RS) (via estimand EN-NRI): EN = Any assessments after death, or any use of escape medication due to disease worsening prior to Week 1 were considered to represent a non-response. NRI = Non-response imputation for any missing data.
    End point type
    Secondary
    End point timeframe
    At Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [5]
    35 [6]
    Units: Proportion of participants
        number (confidence interval 95%)
    0.111 (0.031 to 0.328)
    0.457 (0.305 to 0.618)
    Notes
    [5] - RS via estimand EN-NRI
    [6] - RS via estimand EN-NRI
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The Suissa-Shuster Z-pooled test was implemented to test the treatment effect on the RS (estimand EN) at a 1-sided, alpha level of 0.025. Confidence intervals (95%) around the risk difference were produced using the Chan and Zhang method.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.0081 [8]
    Method
    		 Suissa-Shuster Z-pooled test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.346
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.058
         upper limit
    		 0.554
    Notes
    [7] - Risk difference=Response rate of spesolimab - response rate of placebo.
    [8] - One-sided P Value.

    Secondary: Key secondary: Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 at Week 1

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    End point title
    		 Key secondary: Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 at Week 1
    End point description
    GPPGA relied on clinical assessment of the Generalized Pustular Psoriasis (GPP) patient’s skin presentation. The GPPGA total score was calculated by taking the mean of the erythema subscore, pustules subscore and scaling/crusting subscore. The severity of each subscore was assessed using a 5 point scale score ranging from 0 to 4 (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe). The final GPPGA score is assigned as follows: - 0, if scores for all three subscores are 0, - 1, if 0 < mean < 1.5, - 2, if 1.5 ≤ mean < 2.5, - 3, if 2.5 ≤ mean < 3.5, - 4, if mean ≥ 3.5. A lower GPPGA score indicates a better outcome, with 0 being clear and 1 being almost clear. The proportion of patients with a GPPGA score of 0 or 1 at Week 1 is reported. Randomized Set (RS) (via estimand EN-NRI): EN = Any assessments after death, or any use of escape medication due to disease worsening prior to Week 1 were considered to represent a non-response. NRI = Non-response imputation for any missing data.
    End point type
    Secondary
    End point timeframe
    At Week 1.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [9]
    35 [10]
    Units: Proportion of participants
        number (confidence interval 95%)
    0.111 (0.031 to 0.328)
    0.429 (0.280 to 0.591)
    Notes
    [9] - RS via estimand EN-NRI
    [10] - RS via estimand EN-NRI
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The Suissa-Shuster Z-pooled test was implemented to test the treatment effect on the RS (estimand EN) at a 1-sided, alpha level of 0.025. Confidence intervals (95%) around the risk difference were produced using the Chan and Zhang method.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.0118 [12]
    Method
    		 Suissa-Shuster Z-pooled test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.317
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.022
         upper limit
    		 0.527
    Notes
    [11] - Risk difference=Response rate of spesolimab - response rate of placebo.
    [12] - One-sided P Value.

    Secondary: Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4

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    End point title
    		 Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4
    End point description
    The Pain VAS is a participant-administered single-item scale designed to measure skin pain intensity from generalized pustular psoriasis (GPP) using a 100 millimeter (mm) horizontal VAS. Overall severity of participant's skin pain from GPP is indicated by placing a single mark on the horizontal 100 mm scale from 0 mm (no pain) to 100 mm (pain as bad as one can imagine). Change from baseline was calculated by subtracting the VAS score at baseline from the VAS score at Week 4. A negative change indicates an improvement from baseline. Death, any use of escape medication, OL Spesolimab at Day 8, or rescue medication with Spesolimab after Day 8, prior to observing the endpoint is considered to reflect a failure to achieve the endpoint outcome, i.e. non-response (NR). NR is not a missing value but the worst possible outcome of the endpoint. For example, if the achieved data is (NR, NR, NR, NR, NR, NR, 2, 3, 3, 3, 5) then Q1 is NR, median is NR and Q3 is 3. -99999 and 99999= NR
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [13]
    35 [14]
    Units: Units on a scale
        median (inter-quartile range (Q1-Q3))
    99999 (-99999 to 99999)
    -22.45 (-70.41 to 99999)
    Notes
    [13] - RS-last observation carried forward (LOCF)
    [14] - RS-LOCF
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The effect of spesolimab was evaluated by a Wilcoxon rank test using the RS. Any assessments after death, the use of escape medication (before or after Day 8), open label spesolimab on Day 8, or rescue medication with spesolimab after Day 8 were assigned worst ranks for the testing. Missing data at Week 4 were imputed and handled via assessment of ranks.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.0012 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - The difference between treatments, based on the RS, using a modified Hodges-Lehmann (HL) estimate of the median difference and 95% Confidence Intervals could not be calculated due to lack of valid data.
    [16] - One-sided P Value.

    Secondary: Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4

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    End point title
    		 Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4
    End point description
    PSS is a 4-item patient-reported outcome instrument that assesses the severity of psoriasis symptoms in moderate to severe psoriasis patients. The symptoms included are: pain, redness, itching, and burning. The symptom severity was assessed using a 5 point scale ranging from 0 to 4 where 0=none, 1=mild, 2=moderate, 3=severe, 4=very severe. The symptom scores are added to an unweighted total score (range: 0 to 16). A lower PSS score indicates a better outcome. Change from baseline =PSS score at Week 4 - PSS score at baseline. Death, any use of escape medication, OL Spesolimab at Day 8, or rescue medication with Spesolimab after Day 8, prior to observing the endpoint is considered to reflect a failure to achieve the endpoint outcome, i.e. non-response (NR). NR is not a missing value but the worst possible outcome of the endpoint. For example, if the achieved data is (NR, NR, NR, NR, NR, NR, 2, 3, 3, 3, 5) then Q1 is NR, median is NR and Q3 is 3. 99999 and 99999= NR.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [17]
    35 [18]
    Units: Units on a scale
        median (inter-quartile range (Q1-Q3))
    99999 (-99999 to 99999)
    -2.0 (-9.0 to 99999)
    Notes
    [17] - RS via estimand EN-LOCF
    [18] - RS via estimand EN-LOCF
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    The effect of spesolimab was evaluated by a Wilcoxon rank test using the RS. Any assessments after death, the use of escape medication (before or after Day 8), open label spesolimab on Day 8, or rescue medication with spesolimab after Day 8 were assigned worst ranks for the testing. Missing data at Week 4 were imputed and handled via assessment of ranks.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    P-value
    		 = 0.0044 [20]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - The difference between treatments, based on the RS, using a modified Hodges-Lehmann (HL) estimate of the median difference and 95% Confidence Intervals could not be calculated due to lack of valid data.
    [20] - One-sided P Value.

    Secondary: Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue score at Week 4

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    End point title
    		 Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue score at Week 4
    End point description
    The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Each items is scored from 0 to 4. Score range is 0 (extreme fatigue)-52 (no fatigue). Change from baseline=FACIT Fatigue score at Week 4- FACIT-Fatigue score at baseline. Death, any use of escape medication, OL Spesolimab at Day 8, or rescue medication with Spesolimab after Day 8, prior to observing the endpoint is considered to reflect a failure to achieve the endpoint outcome, i.e. non-response (NR). NR is not a missing value but the worst possible outcome of the endpoint. For example, if the achieved data is s (NR, NR, NR, NR, NR, NR, 2, 3, 3, 3, 5) then Q1 is NR, median is NR and Q3 is 3. RS via estimand EN-LOCF. -99999 and 99999= NR
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [21]
    35 [22]
    Units: Units on a scale
        median (inter-quartile range (Q1-Q3))
    99999 (-99999 to 99999)
    3.00 (-99999 to 30.00)
    Notes
    [21] - RS via estimand EN-LOCF
    [22] - RS via estimand EN-LOCF
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    The effect of spesolimab was evaluated by a Wilcoxon rank test using the RS. Any assessments after death, the use of escape medication (before or after Day 8), open label spesolimab on Day 8, or rescue medication with spesolimab after Day 8 were assigned worst ranks for the testing. Missing data at Week 4 were imputed and handled via assessment of ranks.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [23]
    P-value
    		 = 0.0012 [24]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [23] - The difference between treatments, based on the RS, using a modified Hodges-Lehmann (HL) estimate of the median difference and 95% Confidence Intervals could not be calculated due to lack of valid data.
    [24] - One-sided P Value.

    Secondary: Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 at Week 4

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    End point title
    		 Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 at Week 4
    End point description
    GPPGA relied on clinical assessment of the Generalized Pustular Psoriasis (GPP) patient’s skin presentation. The GPPGA total score is calculated by taking the mean of the erythema subscore, pustules subscore and scaling/crusting subscore. The severity of each subscore was assessed using a 5 point scale score ranging from 0 to 4 (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe). The final GPPGA score is assigned as follows: - 0, if scores for all three scores are 0, - 1, if 0 < mean < 1.5, - 2, if 1.5 ≤ mean < 2.5, - 3, if 2.5 ≤ mean < 3.5, - 4, if mean ≥ 3.5. A lower GPPGA score indicates a better outcome, with 0 being clear and 1 being almost clear. Randomized Set (RS) (via estimand EN-NRI):EN = Any assessments after death, or the use of escape medication (before or after Day 8), or open-label Spesolimab at Day 8, or rescue medication with Spesolimab after Day 8, was considered a non-response. NRI = Non-response imputation for any missing data.
    End point type
    Secondary
    End point timeframe
    At Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [25]
    35 [26]
    Units: Proportion of participants
        number (confidence interval 95%)
    0.111 (0.031 to 0.328)
    0.486 (0.330 to 0.644)
    Notes
    [25] - RS via estimand EN-NRI
    [26] - RS via estimand EN-NRI
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Confidence intervals (95%) around the risk difference were produced using the Chan and Zhang method.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [27]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.375
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.058
         upper limit
    		 0.581
    Notes
    [27] - Risk difference=Response rate of spesolimab - response rate of placebo.

    Secondary: Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation sub-score of 0 indicating no visible pustules at Week 4

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    End point title
    		 Proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation sub-score of 0 indicating no visible pustules at Week 4
    End point description
    The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) relies on clinical assessment of the Generalized Pustular Psoriasis (GPP) patient’s skin presentation. The investigator (or qualified site personnel) scores the erythema, pustules, and scaling of all GPP lesions from 0 to 4. The GPPGA pustulation subscore ranges from 0 to 4 where: 0 = clear; 1 = almost clear; 2 = mild: 3 = moderate; 4 = severe. A lower GPPGA pustulation subscore indicates a better outcome. Randomized Set (RS) (via estimand EN-NRI):EN = Any assessments after death, or the use of escape medication (before or after Day 8), or open-label spesolimab at Day 8, or rescue medication with spesolimab after Day 8, was considered a non-response. NRI = Non-response imputation for any missing data.
    End point type
    Secondary
    End point timeframe
    At Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [28]
    35 [29]
    Units: Proportion of participants
        number (confidence interval 95%)
    0.111 (0.031 to 0.328)
    0.514 (0.356 to 0.670)
    Notes
    [28] - RS via estimand EN-NRI
    [29] - RS via estimand EN-NRI
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Confidence intervals (95%) around the risk difference were produced using the Chan and Zhang method.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [30]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.403
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.096
         upper limit
    		 0.607
    Notes
    [30] - Risk difference=Response rate of spesolimab - response rate of placebo.

    Secondary: Proportion of patients with a Generalized Pustular Psoriasis Area and Severity Index (GPPASI) 50 at Week 4

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    End point title
    		 Proportion of patients with a Generalized Pustular Psoriasis Area and Severity Index (GPPASI) 50 at Week 4
    End point description
    Generalized Pustular Psoriasis Area and Severity Index (GPPASI) provides a numeric scoring for a patient’s overall Generalized Pustular Psoriasis (GPP) disease state, ranging from 0 to 72. It is a linear combination of percent of surface area of skin affected by erythema, pustules, and scaling and the severity of erythema, pustules, and scaling (desquamation) over 4 body regions (head, trunk, upper limbs and lower limbs). A higher score indicates a worse disease state, while a score of 0 indicates no disease. GPPASI 50 is based on the percent reduction from baseline, generally summarized as a dichotomous outcome based on achieving over an 50 % reduction. Randomized Set (RS) (via estimand EN-NRI):EN = Any assessments after death, or the use of escape medication (before or after Day 8), or open-label spesolimab at Day 8, or rescue medication with spesolimab after Day 8, was considered a non-response. NRI = Non-response imputation for any missing data.
    End point type
    Secondary
    End point timeframe
    At Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [31]
    35 [32]
    Units: Proportion of participants
        number (confidence interval 95%)
    0.111 (0.031 to 0.328)
    0.543 (0.382 to 0.695)
    Notes
    [31] - RS via estimand EN-NRI
    [32] - RS via estimand EN-NRI
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Confidence intervals (95%) around the risk difference were produced using the Chan and Zhang method.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [33]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.432
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.096
         upper limit
    		 0.636
    Notes
    [33] - Risk difference=Response rate of spesolimab - response rate of placebo.

    Secondary: Percent change in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) from baseline at Week 4

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    End point title
    		 Percent change in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) from baseline at Week 4
    End point description
    GPPASI provides a numeric scoring for a patient’s overall Generalized Pustular Psoriasis (GPP) disease state, ranging from 0 (no disease) to 72 (worse disease state). It is a linear combination of percent of surface area of skin affected by erythema, pustules, and scaling and the severity of erythema, pustules, and scaling (desquamation) over 4 body regions (head, trunk, upper limbs and lower limbs). %GPPASI change from baseline=(GPPASI at Week 4-GPPASI at baseline) *100/(GPPASI at baseline). Death, any use of escape medication, OL Spesolimab at Day 8, or rescue medication with Spesolimab after Day 8, prior to observing the endpoint is considered to reflect a failure to achieve the endpoint outcome, i.e. non-response (NR). NR is not a missing value but the worst possible outcome of the endpoint. For example, if the achieved data is (NR, NR, NR, NR, NR, NR, 2, 3, 3, 3, 5) then Q1 is NR, median is NR and Q3 is 3. RS via estimand EN-LOCF. -99999 and 99999= Non- response
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 4.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [34]
    35 [35]
    Units: Percentage change
        median (inter-quartile range (Q1-Q3))
    99999 (-99999 to 99999)
    -60.50 (-88.37 to 99999)
    Notes
    [34] - RS via estimand EN-LOCF
    [35] - RS via estimand EN-LOCF
    No statistical analyses for this end point

    Secondary: Proportion of patients with a Generalized Pustular Psoriasis Area and Severity Index (GPPASI) 50 at Week 1

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    End point title
    		 Proportion of patients with a Generalized Pustular Psoriasis Area and Severity Index (GPPASI) 50 at Week 1
    End point description
    Generalized Pustular Psoriasis Area and Severity Index (GPPASI) provides a numeric scoring for a patient’s overall Generalized Pustular Psoriasis (GPP) disease state, ranging from 0 to 72. It is a linear combination of percent of surface area of skin affected by erythema, pustules, and scaling and the severity of erythema, pustules, and scaling (desquamation) over 4 body regions (head, trunk, upper limbs and lower limbs). A higher score indicates a worse disease state, while a score of 0 indicates no disease. GPPASI 50 is based on the percent reduction from baseline, generally summarized as a dichotomous outcome based on achieving over an 50 % reduction. Randomized Set (RS) (via estimand EN-NRI).
    End point type
    Secondary
    End point timeframe
    At Week 1.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [36]
    35 [37]
    Units: Proportion of participants
        number (confidence interval 95%)
    0.278 (0.125 to 0.509)
    0.429 (0.280 to 0.591)
    Notes
    [36] - RS via estimand EN-NRI
    [37] - RS via estimand EN-NRI
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Confidence intervals (95%) around the risk difference were produced using the Chan and Zhang method.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [38]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.151
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.138
         upper limit
    		 0.401
    Notes
    [38] - Risk difference=Response rate of spesolimab - response rate of placebo.

    Secondary: Percent change in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) from baseline at Week 1

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    End point title
    		 Percent change in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) from baseline at Week 1
    End point description
    Generalized Pustular Psoriasis Area and Severity Index (GPPASI) provides a numeric scoring for a patient’s overall Generalized Pustular Psoriasis (GPP) disease state, ranging from 0 to 72. It is a linear combination of percent of surface area of skin affected by erythema, pustules, and scaling and the severity of erythema, pustules, and scaling (desquamation) over 4 body regions (head, trunk, upper limbs and lower limbs). A higher score indicates a worse disease state, while a score of 0 indicates no disease. The percent change from baseline at Week 1 is calculated as: % GPPASI change from baseline = (GPPASI at Week 1 - GPPASI at baseline) *100/GPPASI at baseline. If % GPPASI change from baseline is positive, it means the disease is becoming worse. Randomized Set (RS) via estimand EN-LOCF.
    End point type
    Secondary
    End point timeframe
    At Week 1.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [39]
    35 [40]
    Units: Percentage change
        median (inter-quartile range (Q1-Q3))
    1.02 (-60.47 to 36.68)
    -42.80 (-69.84 to 9.49)
    Notes
    [39] - RS via estimand EN-LOCF
    [40] - RS via estimand EN-LOCF
    Statistical analysis title
    		 Statistical Analysis 11
    Statistical analysis description
    Any assessments after death, the use of escape medication (before or after Day 8), open label spesolimab on Day 8, or rescue medication with spesolimab after Day 8 and assigned with the worst possible outcomes in rank analysis. Missing data at Week 4 were imputed and handled via assessment of ranks.
    Comparison groups
    Placebo v Spesolimab 900 mg i.v SD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [41]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -16.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -67.32
         upper limit
    		 12.76
    Notes
    [41] - Median difference was calculated by modified Hodges−Lehmann method.

    Secondary: Occurrence of Treatment Emergent Adverse Events (TEAEs) up to Week 1

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    End point title
    		 Occurrence of Treatment Emergent Adverse Events (TEAEs) up to Week 1
    End point description
    TEAEs were all Adverse Events (AEs) occurring between start of treatment and Day 8 (Day 8 excluded). AEs that started before first drug intake and deteriorated under treatment were also considered as ‘treatment-emergent’. The exposure-adjusted incidence rate was calculated as: Incidence rate [1/100 patients-years] = 100 × number of patients with AE / Total AE specific time at risk [patient-years] where: Time at risk [patient-years] = (date of onset of TEAE – study drug start date + 1) /365.25 Safety Analysis set (SAF): This patient set included all patients who were randomized and received at least one dose ofstudy drug on Day 1. Patients were analyzed according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    From start of treatment until Day 7, up to 7 days.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [42]
    35 [43]
    Units: events per 100 patient-years at risk
        number (not applicable)
    6445.6
    8650.7
    Notes
    [42] - SAF
    [43] - SAF
    No statistical analyses for this end point

    Secondary: Number of patients with Treatment Emergent Adverse Events (TEAEs) up to Week 1

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    End point title
    		 Number of patients with Treatment Emergent Adverse Events (TEAEs) up to Week 1
    End point description
    TEAEs were all Adverse Events (AEs) occurring between start of treatment and Day 8 (Day 8 excluded). AEs that started before first drug intake and deteriorated under treatment were also considered as ‘treatment-emergent’. Safety Analysis set (SAF): This patient set included all patients who were randomized and received at least one dose of study drug on Day 1. Patients were analyzed according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    From start of treatment until Day 7, up to 7 days.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [44]
    35 [45]
    Units: Participants
    12
    27
    Notes
    [44] - SAF
    [45] - SAF
    No statistical analyses for this end point

    Secondary: Occurrence of Treatment Emergent Adverse Events (TEAEs) within the treatment phase

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    End point title
    		 Occurrence of Treatment Emergent Adverse Events (TEAEs) within the treatment phase
    End point description
    TEAEs were all Adverse Events (AEs) occurring between start of treatment and end of the residual effect period (REP) (16 weeks). AEs that started before first drug intake and deteriorated under treatment were also considered as ‘treatment-emergent’. The exposure-adjusted incidence rate was calculated as: Incidence rate [1/100 patients-years] = 100 × number of patients with AE / Total AE specific time at risk [patient-years] where Time at risk where: Time at risk [patient-years] = (date of onset of TEAE – study drug start date + 1) /365.25 If, for a patient, the selected TEAE did not occur then the time at risk was censored at min - Date of death - For patients who did not roll over into the Open Label Extension (OLE) study: last contact date Visit14/15 - For patients who rolled over into the OLE study: the 1st dose in the OLE study - Drug stop date + 112 days - Date of Day 8 if OL spesolimab was given - Date of rescue medication if spesolimab was given.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of the residual effect period (REP) but censored at any use of open label spesolimab, up to 16 weeks.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [46]
    35 [47]
    Units: events per 100 patient-years at risk
        number (not applicable)
    3083.3
    2391.0
    Notes
    [46] - SAF.
    [47] - SAF
    No statistical analyses for this end point

    Secondary: Number of patients with Treatment Emergent Adverse Events (TEAEs) within the treatment phase

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    End point title
    		 Number of patients with Treatment Emergent Adverse Events (TEAEs) within the treatment phase
    End point description
    TEAEs were all Adverse Events (AEs) occurring between start of treatment and end of the residual effect period (REP) (16 weeks). AEs that started before first drug intake and deteriorated under treatment were also considered as ‘treatment-emergent’. Safety Analysis set (SAF): This patient set included all patients who were randomized and received at least one dose of study drug on Day 1. Patients were analyzed according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of the residual effect period (REP) but censored at any use of open label spesolimab, up to 16 weeks.
    End point values
    		 Placebo Spesolimab 900 mg i.v SD
    Number of subjects analysed
    18 [48]
    35 [49]
    Units: Participants
    13
    29
    Notes
    [48] - SAF
    [49] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Placebo and Spesolimab 900 mg i.v. SD arms: From the start of infusion of randomized medication at Day 1 (D1) of Week 1 (Wk1) until the end of its REP (16 weeks) but were censored at any use of open-label (OL) spesolimab.
    Adverse event reporting additional description
    Safety Analysis set (SAF) OL Spesolimab: From the start of OL spesolimab at Wk1/D8 until the end of its REP (16 weeks) but were censored at any use of rescue medication with spesolimab. Rescue Spesolimab: From the start of rescue medication with spesolimab until the end of its REP (16 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received intravenously (i.v.) solution for infusion containing 900 mg of placebo to spesolimab on Day 1 (D1) of Week 1 (Wk1). Based on the subsequent treatment response, participants were then to be followed up for 12 to 28 weeks. If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing SoC since there was an option to administer open label (OL) spesolimab instead at this time. If SoC was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patients worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab after Wk1 to Wk 12.

    Reporting group title
    Rescue Spesolimab 900 mg i.v.
    Reporting group description
    		 This arm included patients who in addition to the randomized treatment (either intravenously (i.v.) placebo solution to spesolimab at Day 1 or 900 milligram (mg) i.v spesolimab at Day 1) also one single rescue i.v. dose of 900 mg spesolimab between Week 1(Wk 1) to Week 12 (Wk 12).

    Reporting group title
    Open Label (OL) D8 Spesolimab 900 mg i.v.
    Reporting group description
    		 This arm included patients who in addition to the randomized treatment (either intravenously (i.v.) placebo solution to spesolimab at Day 1 or 900 milligram (mg) i.v. spesolimab at Day 1) received also Open Label Treatment with 900 mg I.V spesolimab at Week 1 (Wk1)/Day 8 (D8).

    Reporting group title
    Spesolimab 900 mg i.v. SD
    Reporting group description
    		 Patients received intravenously (i.v.) a single dose of solution for infusion containing 900 mg of spesolimab on Day 1 (D1) of Week 1 (Wk1). Based on the subsequent treatment response, participants were then to be followed up for 12 to 28 Wk. If the severity and progression of the disease worsened within the first week the investigator could treat the patient with a Standard of Care (SoC) treatment of his/her choice. If the disease condition was stable, it was recommended to wait until the primary endpoint visit (Wk1/D8) before prescribing SoC since there was an option to administer open label (OL) spesolimab instead at this time. If SoC was administered within the first week, the patient was not eligible to receive treatment with a single OL i.v. dose of 900 mg spesolimab on D8. If the condition of the patient worsened after Wk1/D8 patients were eligible to receive rescue treatment with open label spesolimab (only one single rescue i.v. dose of 900 mg spesolimab) after Wk1 to Wk 12.

    Serious adverse events
    		 Placebo Rescue Spesolimab 900 mg i.v. Open Label (OL) D8 Spesolimab 900 mg i.v. Spesolimab 900 mg i.v. SD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 6 (33.33%)
    6 / 27 (22.22%)
    6 / 35 (17.14%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pustular psoriasis
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 6 (33.33%)
    3 / 27 (11.11%)
    4 / 35 (11.43%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    2 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Rescue Spesolimab 900 mg i.v. Open Label (OL) D8 Spesolimab 900 mg i.v. Spesolimab 900 mg i.v. SD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    4 / 6 (66.67%)
    14 / 27 (51.85%)
    23 / 35 (65.71%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    1 / 35 (2.86%)
         occurrences all number
    1
    0
    1
    2
    Fatigue
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    2
    Inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    4 / 18 (22.22%)
    2 / 6 (33.33%)
    2 / 27 (7.41%)
    2 / 35 (5.71%)
         occurrences all number
    4
    3
    2
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypomenorrhoea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    3
    Eosinophil percentage increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    High density lipoprotein decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    High density lipoprotein increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Platelet count increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    0
    0
    1
    Protein total decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Tendon injury
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    4 / 35 (11.43%)
         occurrences all number
    1
    0
    1
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    0
    3
    Erythropenia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    2
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    3 / 27 (11.11%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    3
    1
    Nausea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    1
    0
    4
    Vomiting
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 6 (33.33%)
    1 / 27 (3.70%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    1
    2
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 27 (7.41%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pain of skin
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    1
    2
    Pruritus
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 27 (7.41%)
    1 / 35 (2.86%)
         occurrences all number
    0
    0
    2
    1
    Pustular psoriasis
         subjects affected / exposed
    4 / 18 (22.22%)
    2 / 6 (33.33%)
    5 / 27 (18.52%)
    17 / 35 (48.57%)
         occurrences all number
    4
    2
    6
    21
    Skin erosion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint effusion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 27 (3.70%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    1
    4
    Myalgia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    1 / 27 (3.70%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    1
    2
    Oligoarthritis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    2 / 27 (7.41%)
    2 / 35 (5.71%)
         occurrences all number
    1
    1
    2
    2
    Tendonitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    0
    0
    1
    Infections and infestations
    Otitis externa
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 27 (7.41%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Streptococcal infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pustule
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 27 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 27 (3.70%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    1
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 27 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jul 2019
    Amendment 1 Part 1: Based on Health Authority recommendation, the sample size was increased from 27 to 51 patients (placebo: 17, spesolimab: 34) to enhance the safety database and to allow a more robust assessment of efficacy and of the benefit-risk ratio. Based on Health Authority recommendation, the former 2 co-primary endpoints were changed into a primary and a key secondary endpoint. The statistical design - model, the null and alternative hypotheses, the statistical methods, and the analyses were updated. The methods for the handling of missing data were updated. For the estimand concept for the primary and secondary endpoints at Weeks 1 and 4, death was removed from the items considered as non-response. The wording for the AE collection and reporting was updated. For the Adverse events of special interest (AESI) “hepatic injury”, Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) ≥10× Upper limit of normal (ULN) was added to the definition. The AESI “Infusion reactions including anaphylactic reaction” was renamed to “systemic hypersensitivity including infusion reactions” and to the emergency procedures during or after infusion of spesolimab, “Systemic hypersensitivity” was added to the “Infusion reactions including anaphylactic reaction”. The definition of disease worsening and scenarios when escape treatment may have been given were clarified. Exclusion criterion #14 regarding active or latent tuberculosis was updated. Former exclusion criterion #16 regarding previous allergy immunotherapy was removed. Risankizumab was added as restricted medication. The washout period was reduced for all biologics to 2 months. The assessment of fever on dosing days was further specified. As tuberculosis test, T-Spot® was also allowed. The eligibility criteria for the open-label extension trial were updated.
    19 Jul 2019
    Amendment 1 Part 2: For the biomarker and pharmacogenomic analyses, a staged approach was introduced. Healthcare resource utilization (HCRU) data collection throughout the trial was added. Not flaring within the 6-month screening period was added as screening failure. The requirement to assign a new patient number in the case of re-screening was added.
    26 Jun 2020
    The following main changes were introduced by the amendment: To explore the efficacy and safety of open-label spesolimab i.v. treatment on Day 8 was added as additional objective. A set of further endpoints to explore the efficacy of OL spesolimab on Day 8 and information on their analyses were added. 2 further endpoints were added (change from baseline in GPPGA total score by visit, change from baseline in GPPGA pustulation subscore by visit). Time points for a primary analysis at Week 12 (i.e. including data up to Week 12) and a final analysis, if applicable, were added and the blinding plans for these analyses were updated. A sensitivity analysis for the primary endpoint using logistic regression and an estimand for the analysis of secondary continuous endpoints were added. The methods for the handling of missing data were updated. The wording for the AE collection for patients who continued in the extension trial was updated.

    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.
    A large proportion of patients in both arms had been treated as non-responders at Week 4, and the true efficacy outcomes for the randomized treatment at this time-point were never observed for the analysis.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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