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    Clinical Trial Results:
    A Phase III, Randomized, Double Blind, Parallel Group, Placebo Controlled, International, Multicentre Study to Assess Efficacy and Safety of Cx601, Adult Allogeneic Expanded Adipose-Derived Stem Cells (eASC), for the Treatment of Complex Perianal Fistula(s) in Patients With Crohn’s Disease Over a Period of 24 Weeks and a Follow-Up Period Up to 52 Weeks

    Summary
    EudraCT number
    		 2017-000725-12
    Trial protocol
    		 CZ   BE   ES   HU   PL   GB   DE   FR   SE   DK   IT  
    Global end of trial date
    26 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2024
    First version publication date
    28 Jul 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Cx601-0303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03279081
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TiGenix, S.A.U.
    Sponsor organisation address
    Parque Tecnológico de Madrid, Tres Cantos, Madrid, Spain, 28760
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.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
    26 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy of darvadstrocel compared with placebo in participants with complex Crohn’s perianal fistulas (CPFs) to achieve combined remission at week 24.
    Protection of trial subjects
    Each participant signed an informed consent form (ICF) before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 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
    Belgium: 34
    Country: Number of subjects enrolled
    Czechia: 38
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Israel: 25
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Spain: 68
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    United States: 231
    Worldwide total number of subjects
    568
    EEA total number of subjects
    281
    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)
    557
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 113 investigative sites in Belgium, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Poland, Spain, United Kingdom, Canada, and United States from 15 September 2017 to 26 July 2023.

    Pre-assignment
    Screening details
    		 A total of 568 participants with a diagnosis of Crohn’s disease were enrolled in a 1:1 ratio to receive either Cx601 or matching placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo (saline) 24 milliliters (mL) was administered once by local injection.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Placebo (saline) 24 milliliters (mL) was administered once by local injection.

    Arm title
    		 Cx601
    Arm description
    		 Cx601 expanded adipose-derived stem cells (eASCs) 120 million cells (5 million cells per mL) was administered once by local injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cx601
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Cx601 expanded adipose-derived stem cells (eASCs) 120 million cells (5 million cells per mL) was administered once by local injection.

    Number of subjects in period 1
    		Placebo Cx601
    Started
    285
    283
    Completed
    246
    249
    Not completed
    39
    34
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    12
    20
         Physician decision
    4
    1
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    8
    8
         Reason not Specified
    14
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (saline) 24 milliliters (mL) was administered once by local injection.

    Reporting group title
    Cx601
    Reporting group description
    		 Cx601 expanded adipose-derived stem cells (eASCs) 120 million cells (5 million cells per mL) was administered once by local injection.

    Reporting group values
    		 Placebo Cx601 Total
    Number of subjects
    		 285 283
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.7 ( 10.78 ) 38.4 ( 11.91 ) -
    Gender categorical
    Units: Subjects
        Female
    		 130 121 251
        Male
    		 155 162 317
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 13 13 26
        Not Hispanic or Latino
    		 250 240 490
        Unknown or Not Reported
    		 22 30 52
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 5 8 13
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 7 8 15
        White
    		 254 243 497
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 18 24 42
    Body Mass Index (BMI)
    Units: Subjects
        Less than 18.5 kilograms per square meter(kg/m^2)
    		 4 9 13
        18.5 to <25.0 kg/m^2
    		 132 110 242
        25.0 to <30.0 kg/m^2
    		 81 92 173
        30.0 kg/m^2 or Higher
    		 57 67 124
        Not recorded
    		 11 5 16
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo (saline) 24 milliliters (mL) was administered once by local injection.

    Subject analysis set title
    Cx601
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cx601 expanded adipose-derived stem cells (eASCs) 120 million cells (5 million cells per mL) was administered once by local injection.

    Subject analysis sets values
    		 Placebo Cx601
    Number of subjects
    274
    278
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Body Mass Index (BMI)
    Units: Subjects
        Less than 18.5 kilograms per square meter(kg/m^2)
        18.5 to <25.0 kg/m^2
        25.0 to <30.0 kg/m^2
        30.0 kg/m^2 or Higher
        Not recorded
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    171.78 ( 9.088 )
    171.59 ( 9.429 )
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    77.69 ( 16.675 )
    78.73 ( 19.620 )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (saline) 24 milliliters (mL) was administered once by local injection.

    Reporting group title
    Cx601
    Reporting group description
    		 Cx601 expanded adipose-derived stem cells (eASCs) 120 million cells (5 million cells per mL) was administered once by local injection.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo (saline) 24 milliliters (mL) was administered once by local injection.

    Subject analysis set title
    Cx601
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cx601 expanded adipose-derived stem cells (eASCs) 120 million cells (5 million cells per mL) was administered once by local injection.

    Primary: Percentage of Participants with Combined Remission at Week 24

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    End point title
    		 Percentage of Participants with Combined Remission at Week 24
    End point description
    Combined remission was defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression and absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by blinded central magnetic resonance imaging (MRI) assessment. Percentages are rounded off to whole number at the nearest decimal. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    285
    283
    Units: percentage of participants
        number (confidence interval 95%)
    46.32 (40.53 to 52.10)
    48.76 (42.94 to 54.59)
    Statistical analysis title
    		 Combined Remission at Week 24
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.571 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Combined Remission Rate
    Point estimate
    2.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.82
         upper limit
    		 10.55
    Notes
    [1] - P-value was based on stratified Cochran-Mantel-Haenszel (CMH) test adjusting for interactive web response system (IWRS) randomization stratification factors.

    Secondary: Percentage of Participants with Clinical Remission at Week 24

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    End point title
    		 Percentage of Participants with Clinical Remission at Week 24
    End point description
    Clinical remission was defined as closure of all treated external openings that were draining at baseline despite gentle finger compression. Percentages are rounded off to whole number at the nearest decimal. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    285
    283
    Units: percentage of participants
        number (confidence interval 95%)
    47.02 (41.22 to 52.81)
    49.82 (44.00 to 55.65)
    Statistical analysis title
    		 Clinical Remission at Week 24
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.515 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Clinical Remission Rate
    Point estimate
    2.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.47
         upper limit
    		 10.9
    Notes
    [2] - P-value was based on stratified CMH test adjusting for IWRS randomization stratification factors.

    Secondary: Percentage of Participants with Combined Remission at Week 52

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    End point title
    		 Percentage of Participants with Combined Remission at Week 52
    End point description
    Combined remission was defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression, and absence of collections >2 cm (in at least 2 dimensions) confirmed by blinded central MRI assessment. Percentages are rounded off to whole number at the nearest decimal. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    285
    283
    Units: percentage of participants
        number (confidence interval 95%)
    39.65 (33.97 to 45.33)
    40.99 (35.26 to 46.72)
    Statistical analysis title
    		 Combined Remission at Week 52
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.757 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Combined Remission Rate
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.77
         upper limit
    		 9.31
    Notes
    [3] - P-value was based on stratified CMH test adjusting for IWRS randomization stratification factors.

    Secondary: Percentage of Participants with Clinical Remission at Week 52

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    End point title
    		 Percentage of Participants with Clinical Remission at Week 52
    End point description
    Clinical remission was defined as closure of all treated external openings that were draining at baseline despite gentle finger compression. Percentages are rounded off to whole number at the nearest decimal. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    285
    283
    Units: percentage of participants
        number (confidence interval 95%)
    41.40 (35.69 to 47.12)
    43.11 (37.34 to 48.88)
    Statistical analysis title
    		 Clinical Remission at Week 52
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.697 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Clinical Remission Rate
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.46
         upper limit
    		 9.66
    Notes
    [4] - P-value was based on stratified CMH test adjusting for IWRS randomization stratification factors.

    Secondary: Percentage of Participants with Clinical Response at Week 24

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    End point title
    		 Percentage of Participants with Clinical Response at Week 24
    End point description
    Clinical response was defined as closure of at least 50 percent (%) of all treated external openings that were draining at baseline despite gentle finger compression. Percentages are rounded off to whole number at the nearest decimal. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    285
    283
    Units: percentage of participants
        number (confidence interval 95%)
    58.60 (52.88 to 64.31)
    61.84 (56.18 to 67.50)
    Statistical analysis title
    		 Clinical Response at Week 24
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.428 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Clinical Response Rate
    Point estimate
    3.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.76
         upper limit
    		 11.21
    Notes
    [5] - P-value was based on stratified CMH test adjusting for IWRS randomization stratification factors.

    Secondary: Percentage of Participants with Clinical Response at Week 52

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    End point title
    		 Percentage of Participants with Clinical Response at Week 52
    End point description
    Clinical response was defined as closure of at least 50% of all treated external openings that were draining at baseline, despite gentle finger compression. Percentages are rounded off to whole number at the nearest decimal. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    285
    283
    Units: percentage of participants
        number (confidence interval 95%)
    50.88 (45.07 to 56.68)
    53.71 (47.90 to 59.52)
    Statistical analysis title
    		 Clinical Response at Week 52
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.497 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Clinical Response Rate
    Point estimate
    2.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.35
         upper limit
    		 11.03
    Notes
    [6] - P-value was based on stratified CMH test adjusting for IWRS randomization stratification factors.

    Secondary: Time to Clinical Remission at Week 24

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    End point title
    		 Time to Clinical Remission at Week 24
    End point description
    Time to clinical remission was defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not. Overall number analyzed is the number of participants who had clinical remission at Week 24.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    202
    211
    Units: weeks
        median (confidence interval 95%)
    7.14 (7.00 to 11.29)
    7.00 (6.71 to 7.29)
    Statistical analysis title
    		 Time to Clinical Remission at Week 24
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.374 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.32
    Notes
    [7] - P-value was based on a stratified log-rank test adjusting for IWRS randomization stratification factors.

    Secondary: Percentage of Participants with Relapse by Week 52 After Achieving Combined Remission at Week 24

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    End point title
    		 Percentage of Participants with Relapse by Week 52 After Achieving Combined Remission at Week 24
    End point description
    Relapse was defined as reopening of any of the treated fistulas external openings with active drainage as clinically assessed, or the development of a perianal fluid collection >2 cm of the treated perianal fistula confirmed by centrally read MRI assessment in participants who were in combined remission at week 24. Percentages are rounded off to whole number at the nearest decimal. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not. Overall number analyzed is the number of participants who were responders (achieved combined remission) at Week 24.
    End point type
    Secondary
    End point timeframe
    From Week 24 to Week 52
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    132
    138
    Units: percentage of participants
        number (confidence interval 95%)
    31.06 (23.17 to 38.95)
    34.06 (26.15 to 41.96)
    Statistical analysis title
    		 Relapse by Week 52
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.599 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Relapse Rate
    Point estimate
    3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.28
         upper limit
    		 14.34
    Notes
    [8] - P-value was based on stratified CMH test adjusting for IWRS randomization stratification factors.

    Secondary: Time to Clinical Response at Week 52

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    End point title
    		 Time to Clinical Response at Week 52
    End point description
    Time to clinical response was defined as time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not. Overall number analyzed is the number of participants with clinical response at Week 52.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    240
    241
    Units: weeks
        median (confidence interval 95%)
    6.71 (6.29 to 6.86)
    6.71 (6.43 to 7.00)
    Statistical analysis title
    		 Time to Clinical Response at Week 52
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.717 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.16
    Notes
    [9] - P-value was based on a stratified log-rank test adjusting for IWRS randomization stratification factors.

    Secondary: Time to Clinical Response at Week 24

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    End point title
    		 Time to Clinical Response at Week 24
    End point description
    Time to clinical response was defined as the time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline, despite gentle finger compression, as clinically assessed. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not. Overall number analyzed is the number of participants with clinical response at Week 24.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    232
    236
    Units: weeks
        median (confidence interval 95%)
    6.71 (6.29 to 6.86)
    6.71 (6.43 to 7.00)
    Statistical analysis title
    		 Time to Clinical Response at Week 24
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.833 [10]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.18
    Notes
    [10] - P-value was based on a stratified log-rank test adjusting for IWRS randomization stratification factors.

    Secondary: Time to Clinical Remission at Week 52

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    End point title
    		 Time to Clinical Remission at Week 52
    End point description
    Time to clinical remission was defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. The ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not. Overall number analyzed is the number of participants with clinical remission at Week 52.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    209
    221
    Units: weeks
        median (confidence interval 95%)
    7.14 (7.00 to 11.29)
    7.00 (6.71 to 7.29)
    Statistical analysis title
    		 Time to Clinical Remission at Week 52
    Comparison groups
    Placebo v Cx601
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.363 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.32
    Notes
    [11] - P-value was based on a stratified log-rank test adjusting for IWRS randomization stratification factors.

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Treatment-emergent Adverse Events of Special Interest (TEAESIs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Treatment-emergent Adverse Events of Special Interest (TEAESIs)
    End point description
    An adverse event(AE)=any untoward medical occurrence in a clinical investigation participant receiving a medicinal product; it did not necessarily have to have a causal relationship with this treatment. Serious adverse event(SAE)=any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital abnormality/birth defect, or was a medically significant event or required intervention to prevent at least one of the outcomes listed above, or was a suspected transmission of an infectious agent. AESIs included tumorigenicity, ectopic tissue formation, hypersensitivity reactions, transmission of infectious agents, immunogenicity/alloimmune reactions, and medication errors, as reported by the investigator. TEAE=AE whose onset occurred, severity worsened, or intensity increased after receiving the study treatment.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to end of follow up period (up to Week 52)
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    274
    278
    Units: participants
        TEAEs
    201
    203
        TESAEs
    35
    41
        TEAESIs
    3
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes in Vital Sign Parameters

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    End point title
    		 Number of Participants With Clinically Significant Changes in Vital Sign Parameters
    End point description
    Vital signs included measurement of pulse rate, systolic and diastolic blood pressure, respiratory rate, and body temperature. Clinically significant vital signs assessment was based on investigator interpretation. Number of participants with clinically significant changes in vital signs were reported. The Safety (SAF) Analysis Set included all randomized participants who received the actual study treatment.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to end of follow up period (up to Week 52)
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    274
    278
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes in Laboratory Parameters

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    End point title
    		 Number of Participants With Clinically Significant Changes in Laboratory Parameters
    End point description
    Laboratory parameters included blood chemistry and hematology. Clinically significant laboratory parameters assessment was based on investigator interpretation. Number of participants with clinically significant changes in laboratory parameters (hematology and blood chemistry) were reported. The SAF Analysis Set included all randomized participants who received the actual study treatment.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to end of follow up period (up to Week 52)
    End point values
    		 Placebo Cx601
    Number of subjects analysed
    274
    278
    Units: participants
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to end of follow up period (up to Week 52)
    Adverse event reporting additional description
    All-cause Mortality: ITT Analysis Set included all randomized participants regardless of their being treated or not and regardless of their having any postbaseline efficacy measurements or not. Serious and Other Adverse Events: SAF Analysis Set included all randomized participants who received the actual study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Cx601
    Reporting group description
    		 Cx601 eASCs 120 million cells (5 million cells/mL) was administered once by local injection.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (saline) 24 mL was administered once by local injection.

    Serious adverse events
    		 Cx601 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 278 (14.75%)
    35 / 274 (12.77%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fallopian tube cancer
    Additional description: Number of participants at risk in each arm is based on the female population in this study.
         subjects affected / exposed [1]
    0 / 121 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian cancer
    Additional description: Number of participants at risk in each arm is based on the female population in this study.
         subjects affected / exposed [2]
    0 / 121 (0.00%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 278 (0.36%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    4 / 278 (1.44%)
    4 / 274 (1.46%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal inflammation
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal discomfort
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal disorder
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    2 / 278 (0.72%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 278 (0.00%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 278 (0.00%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    5 / 278 (1.80%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 278 (0.72%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 278 (0.00%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
    Additional description: Number of participants at risk in each arm is based on the female population in this study.
         subjects affected / exposed [3]
    1 / 121 (0.83%)
    1 / 130 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    12 / 278 (4.32%)
    12 / 274 (4.38%)
         occurrences causally related to treatment / all
    3 / 14
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 278 (1.08%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histoplasmosis disseminated
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 278 (0.36%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants at risk in each arm is based on the female population in this study.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants at risk in each arm is based on the female population in this study.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants at risk in each arm is based on the female population in this study.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cx601 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 278 (23.74%)
    67 / 274 (24.45%)
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    13 / 278 (4.68%)
    16 / 274 (5.84%)
         occurrences all number
    16
    18
    Proctalgia
         subjects affected / exposed
    40 / 278 (14.39%)
    40 / 274 (14.60%)
         occurrences all number
    43
    52
    Infections and infestations
    COVID-19
         subjects affected / exposed
    21 / 278 (7.55%)
    22 / 274 (8.03%)
         occurrences all number
    22
    23

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jan 2018
    The following changes were made as per Amendment 1: 1. Updated the number of study sites from approximately 100 to approximately 150. 2. Increased the screening period to a maximum of 5 weeks between signing of the ICF to the preparation visit and specified a minimum of 2 weeks and a maximum of 3 weeks between the preparation visit and Visit 0 (treatment administration visit). 3. Added a definition of severe anal and/or rectal stenosis to exclusion criterion. 4. Added major surgery within 6 months of screening to exclusion criterion. 5. Specified variables to assess safety throughout the study. 6. Added guidelines on rescheduling Visit 0 if needed. 7. Added classifications of possible causal relationships between AEs and the investigational medicinal product (IMP) administration procedure.
    27 Oct 2019
    The following changes were made as per Amendment 3: 1. Added an exploratory objective related to microbiome diversity. 2. Increased the study sample size 326 participants to 554 participants. 3. Added assessments to the screening visit. 4. Changed one of the key secondary endpoints from “clinical response” to “time to clinical remission.” 5. Consistency update to treatment administration. 6. Removed text specifying a shelf life of 48 hours for darvadstrocel. 7. Added text regarding steps to maintain study blind. 8. Added a new section defining AESIs to reflect editorial changes to safety endpoints. 9. Added AESI reporting requirements. 10. Updated pregnancy reporting requirements. 11. Added the per-protocol (PP) analysis set and removed the SAF analysis set. 12. Changed analysis population for exploratory efficacy variables from mITT to ITT. 13. Updated to the subgroup analysis section to include subgroup analysis for each of the 2 stratification factors, concomitant treatment (4 levels), and region with United States (US) and non-US as the subgroups of interest. 14. Updated the schedule of assessments table to include optional samples of fistula curettage, fistula exudate, fistula swab for microbiome analysis, and fecal sample for microbiome analysis.

    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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