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    Clinical Trial Results:
    Mechanism of Action and Clinical Effect of BI 655130 in Patients with fistulizing Crohn’s Disease

    Summary
    EudraCT number
    		 2017-003090-34
    Trial protocol
    		 AT   BE   DE   NL   HU   DK  
    Global end of trial date
    04 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2023
    First version publication date
    16 Jul 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1368-0008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03752970
    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
    31 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the pathomechanisms involved in the generation and healing of Crohn’s disease associated perianal fistulas. To understand the mode of action (MoA) of spesolimab in patients with Crohn’s disease and draining perianal fistulas.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Apr 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    28
    EEA total number of subjects
    27
    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)
    28
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Screening Cohort did not receive study treatment. Study Cohort was a randomised, double-blind, placebo-controlled, Phase IIa design, in 2 periods each of 12 weeks’ duration. Patients who had clinical benefit were offered continued treatment in an open label, long-term extension study. Patients who did not continue were followed up at Week 36.

    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
    Screening Cohort was non-randomised and not blinded. Study Cohort was randomised and double blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Screening Cohort
    Arm description
    		 Patients enrolled in the Screening Cohort did not receive study treatment. This was a feasibility phase for fistula preparation and seton placement to determine the tissue samples that were suitable for analysis of the primary endpoint in the Study Cohort.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Study Cohort - Placebo
    Arm description
    		 Patients with perianal fistulising Crohn’s disease received Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20).
    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 with perianal fistulising Crohn’s disease received Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20).

    Arm title
    		 Study Cohort - Spesolimab
    Arm description
    		 Patients with perianal fistulising Crohn’s disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spesolimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients with perianal fistulising Crohn’s disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20).

    Number of subjects in period 1 [1]
    		Screening Cohort Study Cohort - Placebo Study Cohort - Spesolimab
    Started
    6
    10
    11
    Completed
    6
    9
    8
    Not completed
    0
    1
    3
         Consent withdrawn by subject
    -
    -
    2
         Lost to follow-up
    -
    -
    1
         Lack of efficacy
    -
    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: Out of the 28 subjects enrolled, 27 subjects were entered.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Screening Cohort
    Reporting group description
    		 Patients enrolled in the Screening Cohort did not receive study treatment. This was a feasibility phase for fistula preparation and seton placement to determine the tissue samples that were suitable for analysis of the primary endpoint in the Study Cohort.

    Reporting group title
    Study Cohort - Placebo
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20).

    Reporting group title
    Study Cohort - Spesolimab
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20).

    Reporting group values
    		 Screening Cohort Study Cohort - Placebo Study Cohort - Spesolimab Total
    Number of subjects
    		 6 10 11 27
    Age categorical
    All subjects who entered the Screening Cohort or the Study Cohort.
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 6 10 11 27
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    All subjects who entered the Screening Cohort or the Study Cohort.
    Units: years
        arithmetic mean (standard deviation)
    		 42.5 ( 10.8 ) 34.0 ( 8.3 ) 39.2 ( 10.8 ) -
    Sex: Female, Male
    All subjects who entered the Screening Cohort or the Study Cohort.
    Units: Participants
        Female
    		 4 3 2 9
        Male
    		 2 7 9 18
    Race (NIH/OMB)
    All subjects who entered the Screening Cohort or the Study Cohort.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 1 1
        White
    		 6 8 10 24
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    All subjects who entered the Screening Cohort or the Study Cohort.
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0
        Not Hispanic or Latino
    		 6 10 11 27
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Screening Cohort
    Reporting group description
    		 Patients enrolled in the Screening Cohort did not receive study treatment. This was a feasibility phase for fistula preparation and seton placement to determine the tissue samples that were suitable for analysis of the primary endpoint in the Study Cohort.

    Reporting group title
    Study Cohort - Placebo
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20).

    Reporting group title
    Study Cohort - Spesolimab
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20).

    Primary: The total number of deregulated genes at Week 4

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    End point title
    		 The total number of deregulated genes at Week 4 [1] [2]
    End point description
    The total number of deregulated genes based on biopsies from the inner fistula orifice at Week 4 comparing changes in gene expression from baseline between the two treatment groups. For each gene, a repeated measures linear regression model was utilized with treatment, visit (baseline, week 4), treatment by visit interaction as fixed effect and patient as a blocking factor. Changes were quantified by log2 fold changes (FC) and associated False Discovery Rate (FDR) adjusted p-values. Genes will be considered deregulated if they fulfil the following criteria: - FDR adjusted p-value ≤ 0.05 - |fold change| ≥ 1.5 (|log2 fold change| ≥ 0.58) RNA Sequencing Set: All patients who were randomised and treated with any amount of study drug and who provide a valid baseline and at least one valid post-baseline observation for at least one gene expression variable of biopsy. Data analysed with original results (OR) approach, implying the presentation of data exactly as observed.
    End point type
    Primary
    End point timeframe
    Biopsies taken at screening (Week -3) and at week 4 of treatment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses was performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As stated in the SAP and Protocol, the endpoint was only planned to be analyzed for the Study Cohort.
    End point values
    		 Study Cohort - Placebo Study Cohort - Spesolimab
    Number of subjects analysed
    9
    7
    Units: Deregulated genes
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with perianal fistula response at Week 12

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    End point title
    		 Number of patients with perianal fistula response at Week 12 [3]
    End point description
    Number of patients with perianal fistula response at Week 12 defined as closure of at least 50% of external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas. Includes all patients of the Study Cohort who provided a baseline value and at least one post-baseline value for at least one secondary endpoint or further efficacy endpoint. Following the intent-to-treat principle, patients will be analysed according to the treatment they were assigned to at randomisation. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing..
    End point type
    Secondary
    End point timeframe
    At baseline (day 1) and week 12 (day 85) of treatment.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses was performed.
    End point values
    		 Study Cohort - Placebo Study Cohort - Spesolimab
    Number of subjects analysed
    10
    11
    Units: Participants
    7
    1
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Study Cohort - Placebo v Study Cohort - Spesolimab
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.609
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 -0.186

    Secondary: Number of patients with perianal fistula remission at Week 12

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    End point title
    		 Number of patients with perianal fistula remission at Week 12 [4]
    End point description
    Proportion of patients with perianal fistula remission at Week 12 defined as closure of all external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas. Includes all patients of the Study Cohort who provided a baseline value and at least one post-baseline value for at least one secondary endpoint or further efficacy endpoint. Following the intent-to-treat principle, patients will be analysed according to the treatment they were assigned to at randomisation. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing.
    End point type
    Secondary
    End point timeframe
    At baseline (day 1) and week 12 (day 85) of treatment.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As stated in the SAP and Protocol, the endpoint was only planned to be analyzed for the Study Cohort.
    End point values
    		 Study Cohort - Placebo Study Cohort - Spesolimab
    Number of subjects analysed
    10
    11
    Units: Participants
    6
    1
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Study Cohort - Placebo v Study Cohort - Spesolimab
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.509
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.816
         upper limit
    		 -0.087

    Secondary: Number of patients with combined perianal fistula remission at Week 12

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    End point title
    		 Number of patients with combined perianal fistula remission at Week 12 [5]
    End point description
    Number of patients with combined perianal fistula remission at Week 12 defined as closure of all external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas, AND absence collections of >2 centimeter, confirmed by magnetic resonance imaging (MRI) in at least 2 of 3 dimensions – blinded and centrally read. Includes all patients of the Study Cohort who provided a baseline value and at least one post-baseline value for at least one secondary endpoint or further efficacy endpoint. Following the intent-to-treat principle, patients will be analysed according to the treatment they were assigned to at randomisation. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing.
    End point type
    Secondary
    End point timeframe
    At baseline (day 1) and week 12 (day 85) of treatment.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As stated in the SAP and Protocol, the endpoint was only planned to be analyzed for the Study Cohort.
    End point values
    		 Study Cohort - Placebo Study Cohort - Spesolimab
    Number of subjects analysed
    10
    11
    Units: Participants
    6
    1
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Study Cohort - Placebo v Study Cohort - Spesolimab
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.509
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.816
         upper limit
    		 -0.087

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening cohort: up to 56 days. Period 1: from treatment start in period 1 till start in period 2, up to 84 days. Period 2: from treatment start in period 2 till end of last infusion in period 2 + residual effect period of 112 days, up to 182 days.
    Adverse event reporting additional description
    Screening cohort: all patients of the Screening Cohort who entered the trial. Study cohort: all patients who were randomised and treated with any amount of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Study Cohort period 2: Placebo - Spesolimab
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). The arm only considers adverse events reported in period 2.

    Reporting group title
    Study Cohort period 2: Spesolimab - Spesolimab
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). The arm only considers adverse events reported in period 2

    Reporting group title
    Study Cohort period 2: Placebo - Placebo
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Placebo intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). The arm only considers adverse events reported in period 2.

    Reporting group title
    Study Cohort period 1: Placebo
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Placebo intravenously every 4 weeks (week 0, 4, 8). The arm only considers adverse events reported in period 1.

    Reporting group title
    Study Cohort period 1: Spesolimab
    Reporting group description
    		 Patients with perianal fistulising Crohn’s disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8). The arm only considers adverse events reported in period 1.

    Reporting group title
    Screening cohort
    Reporting group description
    		 Patients enrolled in the Screening Cohort did not receive study treatment. This was a feasibility phase for fistula preparation and seton placement to determine the tissue samples that were suitable for analysis of the primary endpoint in the Study Cohort.

    Serious adverse events
    		 Study Cohort period 2: Placebo - Spesolimab Study Cohort period 2: Spesolimab - Spesolimab Study Cohort period 2: Placebo - Placebo Study Cohort period 1: Placebo Study Cohort period 1: Spesolimab Screening cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Proctalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Peritonsillar abscess
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Study Cohort period 2: Placebo - Spesolimab Study Cohort period 2: Spesolimab - Spesolimab Study Cohort period 2: Placebo - Placebo Study Cohort period 1: Placebo Study Cohort period 1: Spesolimab Screening cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    5 / 9 (55.56%)
    3 / 5 (60.00%)
    9 / 10 (90.00%)
    6 / 11 (54.55%)
    1 / 6 (16.67%)
    Vascular disorders
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Enanthema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Anal fissure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Crohn's disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Anal fistula
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    Arthropathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rheumatic disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Abscess limb
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    COVID-19
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Clostridium difficile infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Latent tuberculosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    3 / 11 (27.27%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    3
    0
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Sep 2019
    - The outcome of the Screening Cohort was added, and the samples required during fistula preparation visits were clarified - Screening of patients for the Study Cohort was extended because a minimum of approximately 15 patients with valid baseline and post treatment biopsies were needed for primary endpoint analysis - Crohn’s disease activity index clinical response was updated according to standards in the indication Crohn’s disease (CD) - Fistula relapse was added as a further endpoint, based on expert recommendation - Endoscopy at Visit 9, and requirements for Adverse Events (AE) reporting was amended for harmonisation with requirements in study 1368-0007 - The visit window for Visit 9 was extended to 7 days for flexibility of scheduling investigations - The wording of instructions for steroid tapering was amended for flexibility
    02 Apr 2020
    - Adjustments were made to some of the inclusion and exclusion criteria, and to visit windows, to facilitate screening visits, reduce the burden on patients, and to improve recruitment. Changes were made to variables that would not affect primary or secondary endpoint analysis - The number of sites was increased - Ileocolonoscopy at baseline, and Visits 6 and 9 ceased to be mandatory. Recto- or proctoscopy was required instead - Definitions for perianal fistula activity were amended to clarify that assessments were performed by investigators at the study sites. Central reading was used for efficacy assessments - The bioanalytical laboratory received the randomisation code to avoid unnecessary testing of samples for Pharmacokinetic (PK) and Anti-drug antibodies (ADA) from patients who received placebo - A staged approach for biomarker sample analysis was introduced due to the exploratory nature of the mechanism under test and the timing of effect on candidate biomarkers in the study
    23 Oct 2020
    - The interim analysis was added - Description of the development programme of spesolimab was updated following the decision by BI to discontinue development of the drug in ulcerative colitis. The decision was based on efficacy results, which showed a lower than expected efficacy of clinical endpoints. The decision was not related to, or triggered by, any safety findings - The requirement to remove seton drainage 2 weeks before the first surgical visit was removed to improve feasibility of the trial. Fistulas had to be actively draining to protect the primary endpoint analysis - It was clarified that surgical procedures to treat fistulas (except for seton drainage) was not allowed after randomisation. At the time this amendment was implemented, fistula repair had already been performed on 2 patients, which, therefore, were not reported as Important protocol deviations - Exclusion criterion 10 was amended to allow patients to continue pre-existing anti-tumour necrosis factor (TNF) treatment. Discontinuation of anti-TNF therapy was not possible for most of the target population because of the need to ensure controlled luminal activity throughout the study - Peri-operative antibiotics were permitted on the day before until the day after fistula preparation visits, if required according to standard of care - The benefit-risk section was updated to add an assessment of the effect of the COVID-19 pandemic on patients receiving spesolimab. It was concluded that there was no additional risk. However, challenges due to the pandemic were acknowledged, including restrictions on physical visits to study sites. Therefore, flexibility was added to allow administration of trial medication at the patient’s home, if acceptable according to local law and regulations

    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.
    For the primary endpoint, due to the limited number of evaluable samples from the curettage at baseline and at Week 4, curettage biopsies were not included in the gene expression 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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