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    Clinical Trial Results:
    A Randomised Dose-Optimisation Study to Evaluate the Efficacy and Safety of Cobitolimod in Moderate to Severe Active left-sided Ulcerative Colitis Patients- CONDUCT

    Summary
    EudraCT number
    		 2016-004217-26
    Trial protocol
    		 DE   HU   SE   ES   CZ   FR   IT  
    Global end of trial date
    30 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2020
    First version publication date
    30 Nov 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CSUC-01/16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03178669
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    InDex Pharmaceuticals AB
    Sponsor organisation address
    Berzeliusväg 13, Solna, Sweden, 171 65
    Public contact
    Karin Arnesson, InDex Pharmaceuticals AB, +46 8 122 038 57, karin.arnesson@indexpharma.com
    Scientific contact
    Thomas Knittel, InDex Pharmaceuticals AB, +46 8 122 038 50, thomas.knittel@indexpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of cobitolimod treatment at different dose levels and frequencies compared to placebo with regard to clinical remission 6 weeks after first treatment, in patients with moderate to severe active left-sided ulcerative colitis (UC).
    Protection of trial subjects
    The protocol, Informed Consent Form and recruitment material were approved by Independent Ethics Committee before study initiation. The study was conducted according to international scientific and ethical standards.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Apr 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    Serbia: 19
    Country: Number of subjects enrolled
    Ukraine: 47
    Worldwide total number of subjects
    211
    EEA total number of subjects
    99
    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)
    177
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 91 sites in Czech Republic (2), France (9), Germany (10), Hungary (6), Italy (6), Poland (15), Romania (4), Russian Federation (15), Serbia (4), Spain (5), Sweden (1) and Ukraine (14). First Patient Randomized June 30, 2017 and Last Patient Randomized June 26, 2019

    Pre-assignment
    Screening details
    		 A total of 383 participants were screened, of these 213 participants were randomized in a 1:1:1:1:1 ratio and 211 patients received either cobitolimod 2 x 31 mg, 2 x 125 mg , 2 x 250 mg, 4 x 125 or placebo. In the treatment arms with 2 treatment occasions of cobitolimod, placebo was also given at 2 times to ensure the blindness of the study.

    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, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cobitolimod 2x31 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobitolimod 2x31 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Rectal solution
    Routes of administration
    Rectal use
    Dosage and administration details
    Participants were treated with an enema containing 31 mg cobitolimod at Week 0 and 3 and with an enema containing placebo at Week 1 and 2, to ensure the blindness of the study.

    Arm title
    		 Cobitolimod 2x125 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobitolimod 2 x 125 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Rectal solution
    Routes of administration
    Rectal use
    Dosage and administration details
    Participants were treated with an enema containing 125 mg cobitolimod at Week 0 and 3 and with an enema containing placebo at Week 1 and 2, to ensure the blindness of the study.

    Arm title
    		 Cobitolimod 2x250 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobitolimod 2 x 250 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Rectal solution
    Routes of administration
    Rectal use
    Dosage and administration details
    Participants were treated with an enema containing 250 mg cobitolimod at Week 0 and 3 and with an enema containing placebo at Week 1 and 2, to ensure the blindness of the study.

    Arm title
    		 Cobitolimod 4x125 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobitolimod 4 x 125 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Rectal solution
    Routes of administration
    Rectal use
    Dosage and administration details
    Participants were treated with an enema containing 125 mg cobitolimod at Week 0, 1, 2 and 3.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Rectal solution
    Routes of administration
    Rectal use
    Dosage and administration details
    Participants were treated with an enema containing placebo at Week 0,1,2 and 3.

    Number of subjects in period 1
    		Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Started
    40
    43
    42
    42
    44
    Completed
    35
    42
    35
    38
    40
    Not completed
    5
    1
    7
    4
    4
         Adverse event, serious fatal
    -
    -
    -
    -
    1
         Physician decision
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    4
    1
    4
    3
    1
         Participant decision to withdraw
    1
    -
    -
    -
    -
         Patients decision to withdraw from study
    -
    -
    1
    1
    -
         Lack of efficacy
    -
    -
    2
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cobitolimod 2x31 mg
    Reporting group description
    		 -

    Reporting group title
    Cobitolimod 2x125 mg
    Reporting group description
    		 -

    Reporting group title
    Cobitolimod 2x250 mg
    Reporting group description
    		 -

    Reporting group title
    Cobitolimod 4x125 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo Total
    Number of subjects
    		 40 43 42 42 44 211
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 32 35 37 35 38 177
        From 65-84 years
    		 8 8 5 7 6 34
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 46.5 ± 16.38 51.0 ± 16.87 44.0 ± 14.94 44.5 ± 14.94 45.0 ± 15.38 -
    Gender categorical
    Units: Subjects
        Female
    		 14 23 16 18 11 82
        Male
    		 26 20 26 24 33 129
    Race
    Units: Subjects
        Asian
    		 0 1 1 2 2 6
        White
    		 39 42 40 39 42 202
        Other
    		 1 0 1 1 0 3
    BMI
    Units: kg/m2
        median (standard deviation)
    		 24.7 ± 4.54 24.9 ± 4.65 24.7 ± 3.70 23.8 ± 5.06 26.0 ± 4.80 -

    End points

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    End points reporting groups
    Reporting group title
    Cobitolimod 2x31 mg
    Reporting group description
    		 -

    Reporting group title
    Cobitolimod 2x125 mg
    Reporting group description
    		 -

    Reporting group title
    Cobitolimod 2x250 mg
    Reporting group description
    		 -

    Reporting group title
    Cobitolimod 4x125 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Clinical Remission

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    End point title
    		 Clinical Remission
    End point description
    Proportion of patients with clinical remission at Week 6, defined by Modified Mayo sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), and iii) endoscopy score of 0 or 1 (excluding friability).
    End point type
    Primary
    End point timeframe
    Week 6
    End point values
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Number of subjects analysed
    40
    43
    42
    42
    44
    Units: Frequency
        Yes
    5
    2
    9
    4
    3
        No
    35
    41
    33
    38
    41
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Non Responder Imputation (NRI)
    Comparison groups
    Cobitolimod 2x31 mg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1806 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 5.47
    Variability estimate
    Standard deviation
    Notes
    [1] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Non Responder Imputation (NRI)
    Comparison groups
    Placebo v Cobitolimod 2x125 mg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6649 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 2.24
    Variability estimate
    Standard deviation
    Notes
    [2] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Non Responder Imputation (NRI)
    Comparison groups
    Placebo v Cobitolimod 2x250 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0247 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.8
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.53
         upper limit
    		 9.47
    Variability estimate
    Standard deviation
    Notes
    [3] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Non Responder Imputation (NRI)
    Comparison groups
    Placebo v Cobitolimod 4x125 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3279 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 3.88
    Variability estimate
    Standard deviation
    Notes
    [4] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.

    Secondary: Symptomatic Remission

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    End point title
    		 Symptomatic Remission
    End point description
    Proportion of patients with symptomatic remission at Week 6, defined by the Mayo sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), (patient reported outcome) [PRO2]
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Number of subjects analysed
    37
    42
    37
    40
    43
    Units: Frequency
        Yes
    10
    11
    13
    10
    9
        No
    27
    31
    24
    30
    34
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Cobitolimod 2x31 mg v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2335 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 2.94
    Variability estimate
    Standard deviation
    Notes
    [5] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x125 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2511 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 2.69
    Variability estimate
    Standard deviation
    Notes
    [6] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x250 mg
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1162 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 3.52
    Variability estimate
    Standard deviation
    Notes
    [7] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 4x125 mg
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3467 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.2
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 2.4
    Variability estimate
    Standard deviation
    Notes
    [8] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.

    Secondary: Endoscopic Remission

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    End point title
    		 Endoscopic Remission
    End point description
    Proportion of patients with endoscopic remission at Week 6, defined by the Modified Mayo endoscopic sub score of 0 or 1 (excluding friability)
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Number of subjects analysed
    34
    41
    37
    39
    40
    Units: Frequency
        Yes
    7
    5
    15
    10
    12
        No
    27
    36
    22
    29
    28
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Cobitolimod 2x31 mg v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7994 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.27
    Variability estimate
    Standard deviation
    Notes
    [9] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x125 mg
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9665 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.3
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.72
    Variability estimate
    Standard deviation
    Notes
    [10] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x250 mg
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2049 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 2.82
    Variability estimate
    Standard deviation
    Notes
    [11] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 4x125 mg
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6504 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.6
    Variability estimate
    Standard deviation
    Notes
    [12] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.

    Secondary: Modified Clinical Remission

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    End point title
    		 Modified Clinical Remission
    End point description
    Proportion of patients with modified clinical remission at Week 6, defined by the Modified Mayo score ≤ 2 and sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), iii) endoscopy score of 0 or 1 (excluding friability ) and iiii) physician´s global assessment (PGA) of 0 or 1
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Number of subjects analysed
    33
    41
    35
    39
    39
    Units: Frequency
        Yes
    5
    1
    7
    3
    3
        No
    28
    40
    28
    36
    36
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Cobitolimod 2x31 mg v Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2115 [13]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 4.99
    Variability estimate
    Standard deviation
    Notes
    [13] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x125 mg
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8498 [14]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.3
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 1.34
    Variability estimate
    Standard deviation
    Notes
    [14] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x250 mg
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0977 [15]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.6
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 6.62
    Variability estimate
    Standard deviation
    Notes
    [15] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 4x125 mg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.522 [16]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 2.84
    Variability estimate
    Standard deviation
    Notes
    [16] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.

    Secondary: Histological Remission

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    End point title
    		 Histological Remission
    End point description
    Proportion of patients with histological remission at Week 6, defined by the Nancy histological index of grade 0 or 1
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Number of subjects analysed
    35
    41
    37
    39
    41
    Units: Frequency
        Yes
    4
    5
    8
    7
    10
        No
    11
    36
    29
    32
    31
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Cobitolimod 2x31 mg v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9207 [17]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.93
    Notes
    [17] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x125 mg
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9228 [18]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.92
    Notes
    [18] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x250 mg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6636 [19]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.61
    Notes
    [19] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 4x125 mg
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7449 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.41
    Notes
    [20] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.

    Secondary: Clinical Response

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    End point title
    		 Clinical Response
    End point description
    Proportion of patients with clinical response at Week 6, defined as clinical remission or a three point and ≥30 % decrease from Baseline, Week 0 in the sum of the Modified Mayo score, i) rectal bleeding, ii) stool frequency and iii) endoscopy score (excluding friability), iiii) physicians global assessment (PGA)
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Number of subjects analysed
    33
    41
    35
    39
    39
    Units: Frequency
        Yes
    17
    18
    20
    15
    20
        No
    16
    23
    15
    24
    19
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x31 mg
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6326 [21]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.5
    Notes
    [21] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x125 mg
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7127 [22]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.37
    Notes
    [22] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 2x250 mg
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2658 [23]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 2.34
    Notes
    [23] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which consists of all randomised patients who meet the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and receive at least one dose of the study drug (active or placebo). Missing data was replaced using Placebo Multiple Imputation (PMI)
    Comparison groups
    Placebo v Cobitolimod 4x125 mg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8301 [24]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.16
    Notes
    [24] - one-sided and adjusted for stratification factors, p values of less than 0.10 were regarded as statistically significant.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Collection of AEs started directly after the Informed Consent Form was signed. During the screening period only AEs related to study procedure was reported. Patient was asked at each visits if any AEs had occurred.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Cobitolimod 2x31 mg
    Reporting group description
    		 Participants were treated with 31 mg cobitolimod at Week 0 and 3 and with placebo at Week 1 and 2 to ensure the blindness of the study.

    Reporting group title
    Cobitolimod 2x125 mg
    Reporting group description
    		 Participants were treated with 125 mg cobitolimod at Week 0 and 3 and with placebo at Week 1 and 2 to ensure the blindness of the study.

    Reporting group title
    Cobitolimod 2x250 mg
    Reporting group description
    		 Participants were treated with 250 mg cobitolimod at Week 0 and 3 and with placebo at Week 1 and 2 to ensure the blindness of the study.

    Reporting group title
    Cobitolimod 4x125 mg
    Reporting group description
    		 Participants were treated with 125 mg cobitolimod at Week 0, 1, 2 and 3.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were treated with placebo at Week 0, 1, 2 and 3.

    Serious adverse events
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 43 (0.00%)
    4 / 42 (9.52%)
    2 / 42 (4.76%)
    2 / 44 (4.55%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Wound dehiscence
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    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
    Vascular disorders
    Deep vein thrombosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal hernia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    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
    Colitis ulcerative
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    1 / 42 (2.38%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Pruritus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash erythematous
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cobitolimod 2x31 mg Cobitolimod 2x125 mg Cobitolimod 2x250 mg Cobitolimod 4x125 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 40 (12.50%)
    12 / 43 (27.91%)
    8 / 42 (19.05%)
    10 / 42 (23.81%)
    11 / 44 (25.00%)
    Investigations
    Faecal calprotectin increased
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 44 (2.27%)
         occurrences all number
    2
    0
    0
    1
    1
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 40 (0.00%)
    5 / 43 (11.63%)
    2 / 42 (4.76%)
    2 / 42 (4.76%)
    0 / 44 (0.00%)
         occurrences all number
    0
    5
    2
    2
    0
    General disorders and administration site conditions
    Colitis ulcerative
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 40 (10.00%)
    5 / 43 (11.63%)
    7 / 42 (16.67%)
    3 / 42 (7.14%)
    5 / 44 (11.36%)
         occurrences all number
    5
    5
    8
    4
    6
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    3 / 44 (6.82%)
         occurrences all number
    1
    1
    0
    2
    4
    Infections and infestations
    Viral upper respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 43 (2.33%)
    2 / 42 (4.76%)
    2 / 42 (4.76%)
    4 / 44 (9.09%)
         occurrences all number
    0
    1
    2
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33031757
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