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    Clinical Trial Results:
    A phase 2, multicenter, randomized, double-blind, placebo controlled, dose-finding study to evaluate the efficacy and safety of IMU-838 for induction and maintenance therapy in moderate-to-severe ulcerative colitis (CALDOSE-1)

    Summary
    EudraCT number
    		 2017-003703-22
    Trial protocol
    		 GB   ES   NL   PL   PT   HR   BG   RO  
    Global end of trial date
    16 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2023
    First version publication date
    01 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    P2-IMU-838-UC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03341962
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Immunic AG
    Sponsor organisation address
    Lochhamer Schlag 21, Gräfelfing, Germany, 82166
    Public contact
    Chief Medical Officer, Dr Andreas Muehler , andreas.muehler@imux.com
    Scientific contact
    Chief Medical Officer, Dr Andreas Muehler , andreas.muehler@imux.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
    16 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the optimal dose of IMU-838 to induce symptomatic remission and endoscopic healing in patients with moderate-to-severe ulcerative colitis (UC)
    Protection of trial subjects
    The trial was conducted in a manner consistent with all applicable regulatory authority and independent ethics committee regulations (e.g. International Council for Harmonisation [ICH] Guideline for Good Clinical Practice [GCP, CPMP/ICH/135/95], the Declaration of Helsinki [in its currently acknowledged version] as well as in keeping with applicable local law(s) and regulation(s). Before any clinical trial-related activities were performed, the investigator (or authorized designee) reviewed the informed consent form and explained the study to the patient. The investigator ensured that the patient was fully informed about the aims, procedures, potential risks, any discomforts, and expected benefits of the clinical trial. Further risk minimisation procedures included: • specific inclusion and exclusion criteria which ensured that patients who presented with characteristics that may have increased the risk for an adverse outcome were excluded • close monitoring for red blood cells in urine • regular monitoring of liver enzymes • a 1-week initiation dose at half-dose level.
    Background therapy
    		 In induction phase the following concomitant medication was allowed: •Oral corticosteroids: Stable dose of ≤20 mg/day prednisolone equivalent allowed, if a stable dose was given for at least 2 weeks before randomization •Oral budesonide MMX: Stable dose of ≤9 mg/day allowed, if a stable dose was given for at least 2 weeks before randomization •Oral beclomethasone dipropionate: Stable dose of ≤5 mg/day allowed, if same stable dose was given for at least 2 weeks before randomization •Oral aminosalicylates (eg, mesalazines): Stable dose of ≤4 g/day allowed, if same stable dose was given for at least 3 weeks before randomization At the start of the maintenance phase (at Weeks 10 or 22) a corticosteroid tapering regimen was to be initiated for patients receiving oral steroids. For prednisone, the dose was to be reduced at a rate of 5 mg (or equivalent) every 2 weeks. For beclomethasone dipropionate and budesonide other suitable tapering regimen were to be used according to the investigator’s discretion.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Albania: 13
    Country: Number of subjects enrolled
    Belarus: 6
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 5
    Country: Number of subjects enrolled
    North Macedonia: 10
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Serbia: 16
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Ukraine: 85
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 55
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Czechia: 9
    Worldwide total number of subjects
    263
    EEA total number of subjects
    80
    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)
    242
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study had 3 phases, induction, maintenance and open-label. Patients who achieved symptomatic remission during the induction phase (IP) either at Week 10 (IP) or 22 (extended IP) could proceed to the maintenance phase (MP). Patients who were treated for at least 6 weeks could proceed into the open-label treatment extension phase (OLE).

    Pre-assignment
    Screening details
    		 Of the 598 screened patients, 263 were randomized and treated with 10, 30 or 45 mg IMU-838 or placebo.

    Period 1
    Period 1 title
    Induction phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    To maintain the blind, the IMU-838 as well as the placebo tablets had identical appearance, shape and color, and had identical labeling and packaging. To minimize the potential for bias, treatment randomization information was kept confidential by the responsible personnel and was not released to investigators, other study center personnel, or the sponsor’s designee(s) until after database hard lock for the final analysis of the induction and maintenance phase, respectively.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 10 mg IMU-838
    Arm description
    		 Two 5 mg tablets once daily of IMU-838.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMU-838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the first 7 days of treatment, patients received 1 tablet once daily, ie, 5 mg/day IMU-838 on Days 0 to 6. Thereafter, all patients were dosed with 2 tablets once daily, ie, 10 mg/day IMU 838 after Day 7. Tablets were to be taken once daily in the morning in fasted state with 1 glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets needed to be taken, these were to be taken at the same time.

    Arm title
    		 30 mg IMU-838
    Arm description
    		 Two 15 mg tablets once daily of IMU-838.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMU-838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the first 7 days of treatment, patients received 1 tablet once daily, ie, 15 mg/day IMU-838 on Days 0 to 6. Thereafter, all patients were dosed with 2 tablets once daily, ie, 30 mg/day IMU 838 after Day 7. Tablets were to be taken once daily in the morning in fasted state with 1 glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets needed to be taken, these were to be taken at the same time.

    Arm title
    		 45 mg IMU-838
    Arm description
    		 Two 22.5 mg tablets once daily of IMU-838.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMU-838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the first 7 days of treatment, patients received 1 tablet once daily, ie, 22.5 mg/day IMU-838 on Days 0 to 6. Thereafter, all patients were dosed with 2 tablets once daily, ie, 45 mg/day IMU 838 after Day 7. Tablets were to be taken once daily in the morning in fasted state with 1 glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets needed to be taken, these were to be taken at the same time.

    Arm title
    		 Placebo
    Arm description
    		 Two placebo tablets once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the first 7 days of treatment, patients received 1 placebo tablet once daily on Days 0 to 6. Thereafter, all patients were dosed with 2 placebo tablets once daily. The placebo tablets were identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging.

    Arm title
    		 Combined IMU-838
    Arm description
    		 Two 15 or 22.5 mg tablets once daily of IMU-838 for 10 to 22 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMU-838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the first 7 days of treatment, patients received 1 tablet once daily, ie, 15 mg/day or 22.5 mg/day IMU-838 on Days 0 to 6. Thereafter, all patients were dosed with 2 tablets once daily, ie, 30 mg/day or 45 mg/day IMU-838 after Day 7. Tablets were to be taken once daily in the morning in fasted state with 1 glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets needed to be taken, these were to be taken at the same time.

    Number of subjects in period 1 [1]
    		10 mg IMU-838 30 mg IMU-838 45 mg IMU-838 Placebo Combined IMU-838
    Started
    67
    66
    66
    64
    132
    Completed
    53
    48
    50
    52
    98
    Not completed
    14
    19
    16
    12
    35
         Consent withdrawn by subject
    5
    8
    3
    5
    11
         Physician decision
    4
    4
    9
    3
    13
         Other
    3
    5
    3
    2
    8
         Transferred to other arm/group
    -
    -
    -
    1
    -
         Liver enzymes
    -
    -
    1
    -
    1
         Lost to follow-up
    2
    1
    -
    1
    1
         Prohibited concomitant medication
    -
    1
    -
    -
    1
    Joined
    0
    1
    0
    0
    1
         Transferred in from other group/arm
    -
    1
    -
    -
    1
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: One patient was randomized to placebo (pbo) and erroneously received 30 mg IMU-838 instead of pbo and was included in the 30 mg IMU-838 group (and combined IMU-838 group) for the SAF but in the pbo group for the FAS. Therefore the patient was marked as transferring to another group in the pbo group and as joining from another group in the 30 mg and combined IMU-838 group. SAF: 67 patients in the 30 mg and 63 patients in pbo group FAS: 66 patients in the 30 mg and 64 patients in pbo group
    Period 2
    Period 2 title
    Maintenance phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    To maintain the blind, the IMU-838 as well as the placebo tablets had identical appearance, shape and color, and had identical labeling and packaging. To minimize the potential for bias, treatment randomization information was kept confidential by the responsible personnel and was not released to investigators, other study center personnel, or the sponsor’s designee(s) until after database hard lock for the final analysis of the induction and maintenance phase, respectively.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 30 mg IMU-838
    Arm description
    		 Two 15 mg tablets once daily of IMU-838.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMU-838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients were dosed with 2 tablets once daily, ie, 30 mg/day IMU 838. The IMP was to be administered once daily as oral tablets. Tablets were to be taken once daily in the morning in fasted state with 1 glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets needed to be taken, these were to be taken at the same time.

    Arm title
    		 10 mg IMU-838
    Arm description
    		 Two 5 mg tablets once daily of IMU-838.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMU-838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients were dosed with 2 tablets once daily, ie, 10 mg/day IMU 838. The IMP was to be administered once daily as oral tablets. Tablets were to be taken once daily in the morning in fasted state with 1 glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets needed to be taken, these were to be taken at the same time.

    Arm title
    		 Placebo
    Arm description
    		 Two placebo tablets once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were dosed with 2 placebo tablets once daily. The placebo tablets were identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging.

    Number of subjects in period 2
    		30 mg IMU-838 10 mg IMU-838 Placebo
    Started
    40
    45
    27
    Completed
    29
    35
    21
    Not completed
    11
    10
    6
         Physician decision
    3
    5
    3
         Consent withdrawn by subject
    4
    3
    -
         Other
    3
    2
    3
         Pregnancy
    1
    -
    -
    Period 3
    Period 3 title
    Open-label treatment extension (OLE)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The blinding of the individual randomized treatment assignments during the blinded treatment phase was maintained for investigators and other study personnel, as well as for patients entering the OLE arm.

    Arms
    Arm title
    		 30 mg IMU-838 (OLE)
    Arm description
    		 Two 15 mg tablets once daily of IMU-838.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMU-838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients were dosed with 2 tablets once daily, ie, 30 mg/day IMU 838. The IMP was to be administered once daily as oral tablets. Tablets were to be taken once daily in the morning in fasted state with 1 glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets needed to be taken, these were to be taken at the same time.

    Number of subjects in period 3 [2] [3]
    		30 mg IMU-838 (OLE)
    Started
    75
    Completed
    0
    Not completed
    190
         Consent withdrawn by subject
    51
         Physician decision
    14
         Study termination
    115
         Other
    10
    Joined
    115
         Transferred in from other group/arm
    115
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Patients who had been treated for at least 6 weeks in the IP and fulfilled further eligibility criteria could proceed into the OLE. 115 patients transitioned directly from the IP to the OLE and received 30 mg IMU-838 and an additional 75 patients entered the OLE after the MP, resulting in a total of 190 patients in the OLE.
    [3] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Patients who had been treated for at least 6 weeks in the IP and fulfilled further eligibility criteria could proceed into the OLE. 115 patients transitioned directly from the IP to the OLE (transferred) and received 30 mg IMU-838 and an additional 75 patients entered the OLE after the MP, resulting in a total of 190 patients in the OLE.

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Induction phase
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects enrolled is 263 worldwide and in the induction phase period (Baseline). The arms defined in the induction phase are not mutually exclusive.
    Reporting group values
    		 Induction phase Total
    Number of subjects
    		 263 263
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 242 242
        From 65-84 years
    		 21 21
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 40.0 (18 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 115 115
        Male
    		 148 148
    Current tobacco user
    Units: Subjects
        yes
    		 13 13
        no
    		 250 250
    Duration of disease
    Duration of underlying disease recorded at Baseline.
    Units: years
        arithmetic mean (standard deviation)
    		 6.4 ( 6.4 ) -
    Full Mayo score at Baseline
    Combined, partial (non-invasive) Mayo score (stool frequency, rectal bleeding, and physician’s global assessment) and Mayo endoscopy score
    Units: score
        arithmetic mean (standard deviation)
    		 9.1 ( 1.4 ) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) consisted of all randomized patients who had received at least one dose of study medication, ie, any dose of IMU-838 or placebo. The analyses based on the FAS were conducted on an intention-to-treat procedure, ie, all patients were analyzed by the groups to which they were randomized to (“intention-to-treat”). One patient was randomized to placebo but erroneously received 30 mg IMU-838 and was included in the placebo group here.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set (SAF) consisted of all randomized patients who had received at least one dose of study medication, ie, any dose of IMU-838 or placebo. If it was uncertain if the patient had received any study medication, the patient was included in the SAF. The analyses based on the SAF was conducted on an “as treated” basis, ie, all patients were analyzed by the treatment they had actually received (according to the kits dispensed, not according to the actual dose received in consideration of treatment compliance). One patient was randomized to placebo but erroneously received 30 mg IMU-838 and was included in the 30 mg group here.

    Subject analysis sets values
    		 Full analysis set (FAS) Safety analysis set (SAF)
    Number of subjects
    263
    263
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    242
    242
        From 65-84 years
    21
    21
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    40.0 (18 to 77)
    40.0 (18 to 77)
    Gender categorical
    Units: Subjects
        Female
    115
    115
        Male
    148
    148
    Current tobacco user
    Units: Subjects
        yes
    13
    13
        no
    250
    250
    Duration of disease
    Duration of underlying disease recorded at Baseline.
    Units: years
        arithmetic mean (standard deviation)
    6.4 ( 6.4 )
    6.4 ( 6.4 )
    Full Mayo score at Baseline
    Combined, partial (non-invasive) Mayo score (stool frequency, rectal bleeding, and physician’s global assessment) and Mayo endoscopy score
    Units: score
        arithmetic mean (standard deviation)
    9.1 ( 1.4 )
    9.1 ( 1.4 )

    End points

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    End points reporting groups
    Reporting group title
    10 mg IMU-838
    Reporting group description
    		 Two 5 mg tablets once daily of IMU-838.

    Reporting group title
    30 mg IMU-838
    Reporting group description
    		 Two 15 mg tablets once daily of IMU-838.

    Reporting group title
    45 mg IMU-838
    Reporting group description
    		 Two 22.5 mg tablets once daily of IMU-838.

    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo tablets once daily.

    Reporting group title
    Combined IMU-838
    Reporting group description
    		 Two 15 or 22.5 mg tablets once daily of IMU-838 for 10 to 22 weeks.
    Reporting group title
    30 mg IMU-838
    Reporting group description
    		 Two 15 mg tablets once daily of IMU-838.

    Reporting group title
    10 mg IMU-838
    Reporting group description
    		 Two 5 mg tablets once daily of IMU-838.

    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo tablets once daily.
    Reporting group title
    30 mg IMU-838 (OLE)
    Reporting group description
    		 Two 15 mg tablets once daily of IMU-838.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) consisted of all randomized patients who had received at least one dose of study medication, ie, any dose of IMU-838 or placebo. The analyses based on the FAS were conducted on an intention-to-treat procedure, ie, all patients were analyzed by the groups to which they were randomized to (“intention-to-treat”). One patient was randomized to placebo but erroneously received 30 mg IMU-838 and was included in the placebo group here.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set (SAF) consisted of all randomized patients who had received at least one dose of study medication, ie, any dose of IMU-838 or placebo. If it was uncertain if the patient had received any study medication, the patient was included in the SAF. The analyses based on the SAF was conducted on an “as treated” basis, ie, all patients were analyzed by the treatment they had actually received (according to the kits dispensed, not according to the actual dose received in consideration of treatment compliance). One patient was randomized to placebo but erroneously received 30 mg IMU-838 and was included in the 30 mg group here.

    Primary: Symptomatic remission and endoscopic healing at Week 10

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    End point title
    		 Symptomatic remission and endoscopic healing at Week 10 [1]
    End point description
    Composite end point: Proportion of patients with both, symptomatic remission (Mayo rectal bleeding subscore = 0 and Mayo stool frequency subscore of 0 or 1) and endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 10. All patients who were randomized to 30 mg/day and 45 mg/day were used for the assessment of the primary efficacy end point.
    End point type
    Primary
    End point timeframe
    10 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pre-specified primary end point included only the comparison between the combined 30 and 45 mg IMU-838 groups and placebo.
    End point values
    		 Placebo Combined IMU-838
    Number of subjects analysed
    57 [2]
    116 [3]
    Units: patient
        yes
    8
    16
        no
    49
    100
    Notes
    [2] - FAS, N=7 missing
    [3] - FAS, N=16 missing
    Statistical analysis title
    		 Difference in proportion of patients
    Statistical analysis description
    Difference in proportion of patients achieving end point
    Comparison groups
    Placebo v Combined IMU-838
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5836 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.13
         upper limit
    		 15.28
    Notes
    [4] - 1-sided exact Cochran-Mantel-Haenszel test adjusted for stratification factors (prior use of any biologics and concurrent use of corticosteroids), α=0.097.

    Secondary: Induction phase: Time to achieving symptomatic remission

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    End point title
    		 Induction phase: Time to achieving symptomatic remission [5]
    End point description
    Time to achieving symptomatic remission (Mayo rectal bleeding subscore = 0 and Mayo stool frequency subscore of 0 or 1)
    End point type
    Secondary
    End point timeframe
    22 weeks
    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: The pre-specified end point included only the comparison between the combined 30 and 45 mg IMU-838 groups and placebo.
    End point values
    		 Placebo Combined IMU-838
    Number of subjects analysed
    64 [6]
    132 [7]
    Units: days
        arithmetic mean (standard error)
    119.6 ( 7.1 )
    108.8 ( 5.5 )
    Notes
    [6] - FAS
    [7] - FAS
    No statistical analyses for this end point

    Secondary: Induction Phase: Proportion of patients with clinical response at Week 10

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    End point title
    		 Induction Phase: Proportion of patients with clinical response at Week 10 [8]
    End point description
    Proportion of patients with clinical response (decrease from Baseline in the full Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1) at Week 10
    End point type
    Secondary
    End point timeframe
    10 weeks
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pre-specified end point included only the comparison between the combined 30 and 45 mg IMU-838 groups and placebo.
    End point values
    		 Placebo Combined IMU-838
    Number of subjects analysed
    57 [9]
    114 [10]
    Units: Number of patients
        yes
    27
    50
        no
    30
    64
    Notes
    [9] - FAS, N=7 missing
    [10] - FAS, N=18 missing
    No statistical analyses for this end point

    Secondary: Induction Phase: Proportion of patients with endoscopic healing at Week 10

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    End point title
    		 Induction Phase: Proportion of patients with endoscopic healing at Week 10 [11]
    End point description
    Proportion of patients with endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 10
    End point type
    Secondary
    End point timeframe
    10 weeks
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pre-specified end point included only the comparison between the combined 30 and 45 mg IMU-838 groups and placebo.
    End point values
    		 Placebo Combined IMU-838
    Number of subjects analysed
    57 [12]
    112 [13]
    Units: number of patients
        yes
    12
    28
        no
    45
    84
    Notes
    [12] - FAS, N=7 missing
    [13] - FAS, N=20 missing
    No statistical analyses for this end point

    Secondary: Induction Phase: Proportion of patients with symptomatic response

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    End point title
    		 Induction Phase: Proportion of patients with symptomatic response [14]
    End point description
    Proportion of patients with symptomatic response (≥1-point decrease from Baseline in Mayo PRO-2 score [Mayo patient-reported outcome score, ie, stool frequency and rectal bleeding score on a 4-point scale]) during the extended IP
    End point type
    Secondary
    End point timeframe
    22 weeks
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pre-specified end point included only the comparison between the combined 30 and 45 mg IMU-838 groups and placebo.
    End point values
    		 Placebo Combined IMU-838
    Number of subjects analysed
    62 [15]
    128 [16]
    Units: number of patients
        yes
    49
    101
        no
    13
    27
    Notes
    [15] - FAS, N=2 missing
    [16] - FAS, N=4 missing
    No statistical analyses for this end point

    Secondary: Induction Phase: Full Mayo score

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    End point title
    		 Induction Phase: Full Mayo score
    End point description
    Change in full Mayo score from Baseline to Week 10. The full Mayo score is composed of 4 categories (bleeding, stool frequency, physician assessment, and endoscopic appearance) each rated from 0 to 3 that are added up to give a total score that ranges from 0 to 12. A higher score indicates a worse outcome.
    End point type
    Secondary
    End point timeframe
    10 weeks
    End point values
    		 10 mg IMU-838 30 mg IMU-838 45 mg IMU-838 Placebo Combined IMU-838
    Number of subjects analysed
    67 [17]
    65 [18]
    66 [19]
    64 [20]
    131 [21]
    Units: Mayo score
    arithmetic mean (standard deviation)
        Baseline Day 0
    9.0 ( 1.6 )
    9.1 ( 1.4 )
    9.1 ( 1.4 )
    9.1 ( 1.4 )
    9.1 ( 1.4 )
        Change from Baseline at Week 10
    -3.0 ( 2.6 )
    -2.5 ( 2.7 )
    -2.8 ( 2.7 )
    -2.3 ( 2.7 )
    -2.6 ( 2.7 )
    Notes
    [17] - N= 61 at Week 10
    [18] - N=53 at Week 10
    [19] - N=59 at Week 10
    [20] - N=57 at Week 10
    [21] - N=112 at Week 10
    No statistical analyses for this end point

    Secondary: Maintenance Phase: Proportion of patients in symptomatic remission

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    End point title
    		 Maintenance Phase: Proportion of patients in symptomatic remission
    End point description
    Proportion of patients in symptomatic remission (Mayo rectal bleeding subscore = 0 and Mayo stool frequency subscore of 0 or 1) by visit up to Week 50
    End point type
    Secondary
    End point timeframe
    50 weeks
    End point values
    		 30 mg IMU-838 10 mg IMU-838 Placebo
    Number of subjects analysed
    40 [22]
    45 [23]
    27 [24]
    Units: number of patients
        Week 14
    14
    16
    7
        Week 30
    23
    33
    19
        Week 50
    24
    27
    16
    Notes
    [22] - N=20 at Week 14 N=33 at Week 30 N=29 at Week 50
    [23] - N=19 at Week 14 N=40 at Week 30 N=33 at Week 50
    [24] - N=11 at Week 14 N=24 at Week 30 N=21 at Week 50
    No statistical analyses for this end point

    Secondary: Maintenance Phase: Corticosteroid-free clinical remission

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    End point title
    		 Maintenance Phase: Corticosteroid-free clinical remission
    End point description
    The proportion of patients with clinical remission at Week 50 and no receipt of systemic or local corticosteroids during 8 weeks before Week 50.
    End point type
    Secondary
    End point timeframe
    50 weeks
    End point values
    		 30 mg IMU-838 10 mg IMU-838 Placebo
    Number of subjects analysed
    26
    26
    18
    Units: number of patients
    16
    10
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4 years including induction phase (IP, up to 22 weeks), maintenance phase (MP, up to 40 weeks) and open-label treatment extension (OLE).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    10 mg IMU-838 (IP)
    Reporting group description
    		 Two 5 mg tablets once daily of IMU-838.

    Reporting group title
    30 mg IMU-838 (IP)
    Reporting group description
    		 Two 15 mg tablets once daily of IMU-838.

    Reporting group title
    45 mg IMU-838 (IP)
    Reporting group description
    		 Two 22.5 mg tablets once daily of IMU-838.

    Reporting group title
    Placebo (IP)
    Reporting group description
    		 Two placebo tablets once daily.

    Reporting group title
    10 mg IMU-838 (MP)
    Reporting group description
    		 Two 5 mg tablets once daily of IMU-838.

    Reporting group title
    30 mg IMU-838 (MP)
    Reporting group description
    		 Two 15 mg tablets once daily of IMU-838.

    Reporting group title
    Placebo (MP)
    Reporting group description
    		 Two placebo tablets once daily.

    Reporting group title
    30 mg IMU-838 (OLE)
    Reporting group description
    		 Two 15 mg tablets once daily of IMU-838.

    Serious adverse events
    		 10 mg IMU-838 (IP) 30 mg IMU-838 (IP) 45 mg IMU-838 (IP) Placebo (IP) 10 mg IMU-838 (MP) 30 mg IMU-838 (MP) Placebo (MP) 30 mg IMU-838 (OLE)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 67 (2.99%)
    5 / 67 (7.46%)
    5 / 66 (7.58%)
    0 / 63 (0.00%)
    3 / 45 (6.67%)
    2 / 40 (5.00%)
    1 / 27 (3.70%)
    14 / 190 (7.37%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    1 / 45 (2.22%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 67 (1.49%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    1 / 45 (2.22%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    1 / 27 (3.70%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    1 / 45 (2.22%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Colon gangrene
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 10 mg IMU-838 (IP) 30 mg IMU-838 (IP) 45 mg IMU-838 (IP) Placebo (IP) 10 mg IMU-838 (MP) 30 mg IMU-838 (MP) Placebo (MP) 30 mg IMU-838 (OLE)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 67 (11.94%)
    7 / 67 (10.45%)
    12 / 66 (18.18%)
    13 / 63 (20.63%)
    7 / 45 (15.56%)
    6 / 40 (15.00%)
    2 / 27 (7.41%)
    24 / 190 (12.63%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 67 (4.48%)
    1 / 67 (1.49%)
    1 / 66 (1.52%)
    4 / 63 (6.35%)
    0 / 45 (0.00%)
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    5 / 190 (2.63%)
         occurrences all number
    3
    1
    1
    4
    0
    1
    0
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 67 (2.99%)
    5 / 67 (7.46%)
    3 / 66 (4.55%)
    3 / 63 (4.76%)
    1 / 45 (2.22%)
    1 / 40 (2.50%)
    2 / 27 (7.41%)
    5 / 190 (2.63%)
         occurrences all number
    2
    5
    3
    3
    1
    1
    2
    6
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
    0 / 66 (0.00%)
    3 / 63 (4.76%)
    0 / 45 (0.00%)
    0 / 40 (0.00%)
    0 / 27 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    1
    0
    0
    3
    0
    0
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 67 (0.00%)
    5 / 66 (7.58%)
    1 / 63 (1.59%)
    0 / 45 (0.00%)
    2 / 40 (5.00%)
    0 / 27 (0.00%)
    2 / 190 (1.05%)
         occurrences all number
    0
    0
    7
    1
    0
    2
    0
    2
    Infections and infestations
    COVID-19
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 67 (1.49%)
    2 / 66 (3.03%)
    2 / 63 (3.17%)
    5 / 45 (11.11%)
    1 / 40 (2.50%)
    0 / 27 (0.00%)
    14 / 190 (7.37%)
         occurrences all number
    2
    1
    2
    2
    5
    1
    0
    14
    Urinary tract infection
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
    1 / 66 (1.52%)
    1 / 63 (1.59%)
    1 / 45 (2.22%)
    2 / 40 (5.00%)
    0 / 27 (0.00%)
    3 / 190 (1.58%)
         occurrences all number
    0
    1
    1
    1
    1
    2
    0
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Oct 2017
    The following major changes were included in Version 2.0 compared with Version 1.0: o IP-10 (IFNγ induced protein) was deleted from the list of cytokines which were to be assessed.
    21 Nov 2017
    The following major changes were included in Version 3.0 compared with Version 2.0: o Label specification was modified o Storage conditions were modified due to new stability data
    17 Sep 2019
    The following major changes were included in Version 4.0 compared with Version 3.0: o The results of the interim analysis led to the conclusion that all 3 IMU-838 doses would be continued in Enrollment Period 2. o Additional countries in which the trial was to be performed were added ie, Albania, Belarus, Bosnia-Herzegovina, North Macedonia, Norway, and Turkey. o Additional requirement for active disease in Inclusion Criterion 4 (Mayo rectal bleeding score of >=1) was added. o It was specified that care should be exercised when using medications that are substrates of the breast cancer resistance protein transport system (other prohibited and restricted medication). o Time of interim analysis adjusted to what was to be specified in the statistical analysis plan (SAP) for the interim analysis, ie, that the interim analysis will be conducted when in Enrollment Period 1 approximately 60 patients have been randomized and had received at least 1 dose of investigational medicinal product instead of ‘after approximately 60 patients had completed their Week 10/end of induction assessments’. o For Screening Visit 1 (SCV1) the following footnote was added in the schedule of assessments: ‘Within 30 days of Day 0. If there is a delay in assessments from SCV1 or assessments need to be repeated due to technical difficulties, assessments from SCV1 are valid for up to 60 days between SCV1 and randomization. If 60 days are exceeded, SCV1-assessments must be repeated’. o It was decided not to disclose any group level data of the interim analysis after Enrollment Period 1 or of the exploratory analysis of the MP to the Steering Committee. o In addition, as group level data were no longer disclosed it was considered appropriate not to finalize all SAPs before the interim analysis. The SAP for the induction phase that describes the primary end point analysis, however, was finalized before the interim analysis as scheduled. o overdosing not AE but protocol deviation
    26 Feb 2021
    The following major changes were included in Version 5.0 compared with Version 4.0: o It was clarified that the pharmacodynamics period that is scheduled at the start of the OLE period could be performed not only after completion of the MP but also after the IP or extended IP. o It was clarified that any human immunodeficiency virus (HIV) , hepatitis B or C virus antigen or antibody screening test that shows reactive or borderline results (not as previously only a positive HIV-Ag/Ab test) were to be confirmed via Nucleic Acid Amplification Test (Exclusion criterion 9).
    14 Dec 2021
    The following major changes were included in Version 6.0 compared with Version 5.0: o It was added that patients in the OLE may be transferred to a separate long-term follow-up study or to commercial IMU-838 (if applicable and patients have access). o Uric acid was deleted from the urinalysis assessments.

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

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