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    Clinical Trial Results:
    Efficacy of infusions of mesenchymal stem cells from Wharton jelly in the moderate to severe SARS-Cov-2 related acute respiratory distress syndrome (COVID-19) : A Phase IIa double-blind randomized controlled trial Brief name : MSC-COVID19

    Summary
    EudraCT number
    		 2020-002772-12
    Trial protocol
    		 FR  
    Global end of trial date
    01 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2023
    First version publication date
    19 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2020PI088
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04625738
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CHRU de NANCY
    Sponsor organisation address
    29 avenue du Maréchal de Lattre de Tassigny - CO 60034, NANCY Cedex, France, 54035
    Public contact
    Project Manager, Délégation à la Recherche Clinique et à l'Innovation, 0033 383155286, dripromoteur@chru-nancy.fr
    Scientific contact
    Project Manager, Délégation à la Recherche Clinique et à l'Innovation, 0033 383155286, dripromoteur@chru-nancy.fr
    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
    02 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate efficacy of WJ-MSCs, compared to a placebo, on respiratory function in patients with SARS-CoV-2 related moderate to severe ARDS.
    Protection of trial subjects
    Patients were included in emergency situation. The involved risks are minor compared to the expected benefit. The standard of care for COVID-19 was at the discretion of the physicians. The use of corticosteroids, vasopressors, tocilizumab, and antibiotics was allowed.
    Background therapy
    		 -
    Evidence for comparator
    		 In the control group, patients were assigned to receive three infusions of placebo (albumin 4%, NaCl 0.9%, and ACD formula A, 75 to 100 mL) with an interval of two days between two infusions.
    Actual start date of recruitment
    10 Nov 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    17
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted between 10 Nov 2020 (first inclusion) and 01 Sep 2021 (last patient last visit) in 2 French intensive care units (ICUs), in the Nancy University Hospital. The patients admitted in ICUs were included in emergency situation with inclusion/exclusion criteria verification.

    Pre-assignment
    Screening details
    		 Not applicable

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Patients were randomly assigned in a 1:1 ratio to receive either WJ-MSCs plus standard of care (experimental group) or placebo plus standard of care (control group). Randomization was performed using a computer-generated allocation sequence, with permuted blocks of four and stratified according to the PaO2 / FiO2 ratio at inclusion (≤ 100 or > 100).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental group
    Arm description
    		 Patients were assigned to receive three infusions of WJ-MSCs at a total dose of 2. 106/ kg, in a solution of albumin 4% (40% of final volume), NaCl 0,9% (50% of final volume), and ACD formula A (10% of final volume). This treatment was planned to be administered intravenously for ten minutes according to the following scheme: - 1x106 MSC/kg of body weight (with a maximum of 80x106 MSC) at day 0 (or day 1) of inclusion, - then two infusions 0.5x106 MSC/kg (with a maximum of 40x106 MSC) with an interval of 48 hours (+/- 5 hours) minimum and 72 hours (+/- 5 hours) maximum between each injection. The maximum duration of treatment is 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mesenchymal Stem Cells (MSCs) from wharton jelly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 injections over a period of 7 days

    Investigational medicinal product name
    VIALEBEX 40 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Included in the 3 injections of MSCWJ suspension Total dose : 225 ml Concentration : 40 g/l

    Investigational medicinal product name
    Chlorure de Sodium 0.9 %, solution pour perfusion
    Investigational medicinal product code
    Other name
    SODIUM CHLORIDE SOLUTION 0.9%
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Included in CSMWJ suspension Total dose = 0.9 %

    Investigational medicinal product name
    ACD formule A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Included in MSCWJ suspension Total dose = 10 % Medical device ANTICOAGULANT CITRATE DEXTROSE A : monohydrate citric acid, trisodium citrate dihydrate and glucose solution

    Arm title
    		 Control group
    Arm description
    		 Patients were assigned to receive three infusions of placebo (albumin 4%, NaCl 0.9%, and ACD formula A, 75 to 100 mL) according to the same scheme as the experimental group.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Chlorure de Sodium 0.9 %, solution pour perfusion
    Investigational medicinal product code
    Other name
    SODIUM CHLORIDE SOLUTION 0.9%
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total dose = 0.9 % 50% of final volume

    Investigational medicinal product name
    ACD formule A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total dose = 10 % 10% of final volume Medical device ANTICOAGULANT CITRATE DEXTROSE A : monohydrate citric acid, trisodium citrate dihydrate and glucose solution

    Investigational medicinal product name
    VIALEBEX 40 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total dose : 225 ml Concentration : 40 g/l

    Number of subjects in period 1
    		Experimental group Control group
    Started
    15
    15
    Completed
    11
    10
    Not completed
    4
    5
         Adverse event, serious fatal
    3
    3
         Consent withdrawn by subject
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 Patients were assigned to receive three infusions of WJ-MSCs at a total dose of 2. 106/ kg, in a solution of albumin 4% (40% of final volume), NaCl 0,9% (50% of final volume), and ACD formula A (10% of final volume). This treatment was planned to be administered intravenously for ten minutes according to the following scheme: - 1x106 MSC/kg of body weight (with a maximum of 80x106 MSC) at day 0 (or day 1) of inclusion, - then two infusions 0.5x106 MSC/kg (with a maximum of 40x106 MSC) with an interval of 48 hours (+/- 5 hours) minimum and 72 hours (+/- 5 hours) maximum between each injection. The maximum duration of treatment is 7 days.

    Reporting group title
    Control group
    Reporting group description
    		 Patients were assigned to receive three infusions of placebo (albumin 4%, NaCl 0.9%, and ACD formula A, 75 to 100 mL) according to the same scheme as the experimental group.

    Reporting group values
    		 Experimental group Control group Total
    Number of subjects
    		 15 15 30
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 61 (49 to 66) 66 (61 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 2 8 10
        Male
    		 13 7 20
    Comorbidities : Chronic heart failure
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 15 14 29
    Comorbisities : HTA
    Units: Subjects
        Yes
    		 5 10 15
        No
    		 10 5 15
    Comorbidities : Diabetes
    Units: Subjects
        Yes
    		 3 4 7
        No
    		 12 11 23
    Invasive mechanical ventilation
    Units: Subjects
        Yes
    		 15 15 30
        No
    		 0 0 0
    Prone positioning
    Units: Subjects
        Yes
    		 7 7 14
        No
    		 8 8 16
    Corticosteroids
    Units: Subjects
        Yes
    		 6 9 15
        No
    		 9 6 15
    Vasopressors
    Units: Subjects
        Yes
    		 6 7 13
        No
    		 9 8 17
    Renal replacement therapy
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 15 15 30
    BMI
    Units: kg/m²
        median (inter-quartile range (Q1-Q3))
    		 30 (27 to 35) 34 (32 to 36) -
    Symptoms duration
    Units: Days
        median (inter-quartile range (Q1-Q3))
    		 9 (5 to 11) 7 (4 to 13) -
    SAPS II
    Units: other
        median (inter-quartile range (Q1-Q3))
    		 31 (25 to 42) 41 (34 to 47) -
    SOFA
    Units: other
        median (inter-quartile range (Q1-Q3))
    		 4 (3 to 6) 5 (3 to 8) -
    Pa02/Fi02
    Units: other
        arithmetic mean (standard deviation)
    		 138 ( 49 ) 137 ( 36 ) -
    PEEP
    Units: cmH20
        median (inter-quartile range (Q1-Q3))
    		 13 (12 to 15) 12.5 (10 to 14) -
    Compliance
    Units: mL/cmH2O
        median (inter-quartile range (Q1-Q3))
    		 38 (32 to 50) 33 (27 to 39) -

    End points

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    End points reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 Patients were assigned to receive three infusions of WJ-MSCs at a total dose of 2. 106/ kg, in a solution of albumin 4% (40% of final volume), NaCl 0,9% (50% of final volume), and ACD formula A (10% of final volume). This treatment was planned to be administered intravenously for ten minutes according to the following scheme: - 1x106 MSC/kg of body weight (with a maximum of 80x106 MSC) at day 0 (or day 1) of inclusion, - then two infusions 0.5x106 MSC/kg (with a maximum of 40x106 MSC) with an interval of 48 hours (+/- 5 hours) minimum and 72 hours (+/- 5 hours) maximum between each injection. The maximum duration of treatment is 7 days.

    Reporting group title
    Control group
    Reporting group description
    		 Patients were assigned to receive three infusions of placebo (albumin 4%, NaCl 0.9%, and ACD formula A, 75 to 100 mL) according to the same scheme as the experimental group.

    Primary: Percentage of patients with a PaO2/FiO2 ratio > 200 at D10 of treatment with MSC-GW or placebo

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    End point title
    		 Percentage of patients with a PaO2/FiO2 ratio > 200 at D10 of treatment with MSC-GW or placebo
    End point description
    End point type
    Primary
    End point timeframe
    at D10 of treatment with MSC-GW or placebo
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    11
    13
    Units: number
        PaO2/FiO2 ratio > 200
    2
    2
        PaO2/FiO2 ratio <= 200
    9
    11
    Statistical analysis title
    		 Fisher Exact test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [1]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - No significant difference between the two groups has been detected in our sample.

    Primary: Percentage of patients with a PaO2/FiO2 ratio > 200 at D10 of treatment with MSC-GW or placebo (imputed)

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    End point title
    		 Percentage of patients with a PaO2/FiO2 ratio > 200 at D10 of treatment with MSC-GW or placebo (imputed)
    End point description
    If patient did not have the value at D10 (hospital discharge before D10 for example), the last collected value was taken.
    End point type
    Primary
    End point timeframe
    at D10 of treatment
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: number
        PaO2/FiO2 <=200
    10
    11
        PaO2/FiO2 > 200
    5
    4
    Statistical analysis title
    		 Fisher Exact test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - No significant difference between the two groups was detected in our sample.

    Secondary: respiratory function evolution

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    End point title
    		 respiratory function evolution
    End point description
    As it is not possible to indicate evolution of a parameter, baseline PaO2/FiO2 was described in each group. Analysis indicated concerned the evolution of PaO2/FiO2.
    End point type
    Secondary
    End point timeframe
    During the 14 days following the first injection (between D0 or D1 and D13 or D14)
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: other
        arithmetic mean (standard error)
    138.5 ( 49.3 )
    137.1 ( 36 )
    Attachments
    		 Evolution of PaO2/FiO2 between the two groups
    Statistical analysis title
    		 Repeated mesure ANOVA
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [3]
    Method
    		 Repeated mesure ANOVA
    Confidence interval
    Notes
    [3] - The p-value indicates that no difference about evolution of PaO2/FiO2 between the first 14 days after the first injection was detected in our sample between experimental or control group.

    Secondary: Respiratory assistance

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    End point title
    		 Respiratory assistance
    End point description
    the proportion of days without invasive respiratory assistance during the hospital stay and maximum on Day 28 (number of days without invasive respiratory assistance / number of hospital days fixed at day 28)
    End point type
    Secondary
    End point timeframe
    between day 0 (or 1) and day 28
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: percent
        arithmetic mean (standard deviation)
    41.93 ( 36.59 )
    24.2 ( 30.97 )
    Statistical analysis title
    		 Mann-Whitney
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - No significant difference between the two groups was detected in our sample.

    Secondary: Organ failure 1 : SOFA change D14 - D0

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    End point title
    		 Organ failure 1 : SOFA change D14 - D0
    End point description
    Difference in sequential organ failure assessment score (SOFA score), grading 0 (best) to 4 (worst), between D14-Day 0
    End point type
    Secondary
    End point timeframe
    Day 0 to day 14
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    13
    12
    Units: other
        median (inter-quartile range (Q1-Q3))
    -1 (-2 to 0)
    -2.5 (-4 to -0.5)
    Statistical analysis title
    		 Mann-Whitney
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - No significant difference between the two groups was detected in our sample.

    Secondary: organ failures 2 : proportion of days without extra-renal treatment at day 28

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    End point title
    		 organ failures 2 : proportion of days without extra-renal treatment at day 28
    End point description
    proportion of days without extra-renal treatment during 28 first days
    End point type
    Secondary
    End point timeframe
    day 0 to day 28
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: other
        median (inter-quartile range (Q1-Q3))
    100 (100 to 100)
    100 (100 to 100)
    Statistical analysis title
    		 Mann-Whitney
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - No significant difference between the two groups was detected in our sample.

    Secondary: organ failures 3 : vasopressor support

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    End point title
    		 organ failures 3 : vasopressor support
    End point description
    Percent of days without vasopressor support during the first 28 days
    End point type
    Secondary
    End point timeframe
    day 0 to day 28
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: other
        median (inter-quartile range (Q1-Q3))
    90 (69 to 97)
    86 (72 to 97)
    Statistical analysis title
    		 Mann-Whitney
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - No significant difference between groups was detected in our sample.

    Secondary: Duration of intensive care

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    End point title
    		 Duration of intensive care
    End point description
    The duration of stay in intensive care unit
    End point type
    Secondary
    End point timeframe
    day 0 to 90
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: days
        median (inter-quartile range (Q1-Q3))
    19 (12 to 30)
    23 (13 to 42)
    Statistical analysis title
    		 Mann-Whitney
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - No significant difference between groups was detected in our sample.

    Secondary: Death at D90

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    End point title
    		 Death at D90
    End point description
    number of death on Day 90 was described for the two groups. Log rank test with a Kaplan Meier curve was performed to detect a difference between the two groups.
    End point type
    Secondary
    End point timeframe
    day 0 to 90
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: number
    3
    3
    Attachments
    		 Death at D90 - Kaplan-Meier curve
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92 [9]
    Method
    		 Logrank
    Confidence interval
    Notes
    [9] - No significant difference between groups was detected in our sample.

    Secondary: respiratory morbidity at Day 90

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    End point title
    		 respiratory morbidity at Day 90
    End point description
    respiratory morbidity on Day 90
    End point type
    Secondary
    End point timeframe
    day 90
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    14
    Units: number
        Yes
    13
    12
        No
    2
    2
    Statistical analysis title
    		 Fisher Exact test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [10]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [10] - No significant difference between groups was detected in our sample.

    Secondary: viral load

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    End point title
    		 viral load
    End point description
    he evolution of the viral load is evaluated by RT PCR SARS-Cov-2 monitoring on a nasopharyngeal swab (or any other sample) at diagnosis, at Day 7, Day 14, Day 21, Day 28 or on the last day of hospitalisation
    End point type
    Secondary
    End point timeframe
    day 0 to day 28 (or last day of hospitalization if before day 28)
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    13
    15
    Units: number
        Positive
    10
    8
        Negative
    3
    7
    Statistical analysis title
    		 Fisher Exact test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [11]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [11] - No significant difference between groups was detected in our sample.

    Secondary: Anti-HLA antibody rate

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    End point title
    		 Anti-HLA antibody rate
    End point description
    The anti-HLA antibody rate measured on Day 0 (before initiating treatment), on Day 28 and on Day 90 The rate on Day 90 was described.
    End point type
    Secondary
    End point timeframe
    day 0 to day 90
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    10
    10
    Units: number
        Yes
    2
    0
        No
    8
    10
    No statistical analyses for this end point

    Secondary: Immediate hypersensitivity reactions

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    End point title
    		 Immediate hypersensitivity reactions
    End point description
    The number of patients with at least one reaction of immediate hypersensitivity occuring after one of the three injections was described.
    End point type
    Secondary
    End point timeframe
    After each injection day 0, day 3, day 5 (+/- 1day)
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: number
        Yes
    10
    15
        No
    5
    0
    Statistical analysis title
    		 Fisher Exact test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04 [12]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [12] - The CSM group does not present more immediate hypersensitivity reactions than the placebo group. The Fisher exact test is significativ but in defavor of the placebo group.

    Secondary: Severity of respiratory morbidity

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    End point title
    		 Severity of respiratory morbidity
    End point description
    End point type
    Secondary
    End point timeframe
    At D90
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    13
    12
    Units: number
        Non severe
    3
    1
        Moderate
    1
    1
        Severe
    4
    2
        Very severe
    5
    8
    Statistical analysis title
    		 Fisher Exact test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61 [13]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [13] - No significant difference between the two groups has been detected in our sample.

    Secondary: Thromboembolic adverse events

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    End point title
    		 Thromboembolic adverse events
    End point description
    See adverse events section for this endpoint
    End point type
    Secondary
    End point timeframe
    During follow-up
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: number
        Yes
    4
    3
        No
    11
    12
    No statistical analyses for this end point

    Secondary: Infectious adverse events

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    End point title
    		 Infectious adverse events
    End point description
    See adverse events section for this endpoint.
    End point type
    Secondary
    End point timeframe
    During follow-up
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: number
        Yes
    9
    9
        No
    6
    6
    No statistical analyses for this end point

    Other pre-specified: Angiopoietin 2 change

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    End point title
    		 Angiopoietin 2 change
    End point description
    End point type
    Other pre-specified
    End point timeframe
    The change is evaluated between the day after the third injection and the day before the first injection
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    13
    15
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    914 (183 to 3037)
    105 (-715 to 1471)
    Statistical analysis title
    		 Mann-Whitney
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - No significant difference between the two groups was detected in our sample.

    Other pre-specified: RAGE change

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    End point title
    		 RAGE change
    End point description
    End point type
    Other pre-specified
    End point timeframe
    RAGE change between the day after the last injection and the day before the first infection
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    13
    15
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    -2656 (-3761 to -1599)
    -5469 (-9859 to -1801)
    Statistical analysis title
    		 Fisher Exact test
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13 [15]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - No significant difference between the two groups was detected in our sample.

    Other pre-specified: CRP evolution

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    End point title
    		 CRP evolution
    End point description
    CRP at Day 1 was described between groups. Evolution of CRP for the two groups is shown in a chart.
    End point type
    Other pre-specified
    End point timeframe
    Evolution of CRP is evaluated between Day 0 (or Day 1 depending on the date of first injection) and Day 13 (or Day 14)
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    14
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    109 (41 to 127)
    98 (57 to 218)
    Attachments
    		 Evolution of CRP
    No statistical analyses for this end point

    Other pre-specified: Plasmatic cytokines

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    End point title
    		 Plasmatic cytokines
    End point description
    Description of galectine 9 before the first infection is described. Violon plot for each cytokines before the first infection an at Day10 is shown : galectine-9, LAP, galectine-3, il10, IL1 alpha, IP10, IFN gamma, IL6, IL8, TNF alpha, VEGF A
    End point type
    Other pre-specified
    End point timeframe
    The day before first injection and Day 10
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    15
    Units: unit
        median (inter-quartile range (Q1-Q3))
    29.5 (18.3 to 45.1)
    28.9 (13.5 to 45.3)
    Attachments
    		 Plasmatic cytokins
    No statistical analyses for this end point

    Other pre-specified: Evolution of lymphocyte sub-population

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    End point title
    		 Evolution of lymphocyte sub-population
    End point description
    Description of CD3 before the first infection is described. Charts of evolution of lymphocyte sub-population by groups is joined
    End point type
    Other pre-specified
    End point timeframe
    The day before the first injection, Day 3, Day 5, Day 7, Day10, Day 14 and Day 28
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    15
    13
    Units: /mm3
        median (inter-quartile range (Q1-Q3))
    0.37 (0.30 to 0.71)
    0.5 (0.37 to 0.67)
    Attachments
    		 Evolution of lymphocyte sub-population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE and SAE were collected and transmitted without delay to the sponsor from the enrollment until the end of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    experimental group
    Reporting group description
    		 administration of allogeneic mesenchymal stem cells from Wharton's Jell

    Reporting group title
    control group
    Reporting group description
    		 administration of a placebo

    Serious adverse events
    		 experimental group control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 15 (40.00%)
    7 / 15 (46.67%)
         number of deaths (all causes)
    4
    2
         number of deaths resulting from adverse events
    4
    2
    Vascular disorders
    Shock
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bradycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Brain abscess
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fungal peritonitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyopneumothorax
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 experimental group control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 15 (93.33%)
    14 / 15 (93.33%)
    Vascular disorders
    Cyanosis
         subjects affected / exposed
    5 / 15 (33.33%)
    1 / 15 (6.67%)
         occurrences all number
    5
    1
    Haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    Hypertension
         subjects affected / exposed
    5 / 15 (33.33%)
    3 / 15 (20.00%)
         occurrences all number
    7
    5
    Hypotension
         subjects affected / exposed
    5 / 15 (33.33%)
    2 / 15 (13.33%)
         occurrences all number
    9
    3
    Thrombosis
         subjects affected / exposed
    4 / 15 (26.67%)
    3 / 15 (20.00%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    Respiratory distress
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    Emphysema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Hypoventilation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Lung opacity
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pneumomediastinum
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pneumothorax
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    Snoring
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Anxiety
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Delirium tremens
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Fibrin D dimer increased
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Blood sodium increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Eschar
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Extrasystoles
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Acute coronary syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Neurological decompensation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Neuromyopathy
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Polyneuropathy
         subjects affected / exposed
    2 / 15 (13.33%)
    4 / 15 (26.67%)
         occurrences all number
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 15 (26.67%)
    3 / 15 (20.00%)
         occurrences all number
    6
    4
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Eosinophilia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Lymphopenia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 15 (40.00%)
    5 / 15 (33.33%)
         occurrences all number
    7
    5
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dysphagia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Melaena
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Peptic ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Livedo reticularis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Petechiae
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    Bladder dilatation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Acute kidney injury
         subjects affected / exposed
    0 / 15 (0.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    5
    Endocrine disorders
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nosocomial infection
         subjects affected / exposed
    9 / 15 (60.00%)
    9 / 15 (60.00%)
         occurrences all number
    12
    14
    Paronychia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Sepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Hyperkalaemia
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    Hyperlactacidaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypernatraemia
         subjects affected / exposed
    4 / 15 (26.67%)
    4 / 15 (26.67%)
         occurrences all number
    4
    4
    Hypocalcaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 15 (26.67%)
    5 / 15 (33.33%)
         occurrences all number
    12
    13
    Hypophosphataemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypovolaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Granuloma
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Medical device site haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hyperthermia
         subjects affected / exposed
    6 / 15 (40.00%)
    3 / 15 (20.00%)
         occurrences all number
    8
    4
    Oedema
         subjects affected / exposed
    4 / 15 (26.67%)
    4 / 15 (26.67%)
         occurrences all number
    4
    4
    Oedema peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2020
    Change on principal investigator in one of the 2 investigator sites
    18 Jan 2021
    Reasons: Increase inclusion opportunities by simplifying the study process. Allow close monitoring by adding biological analyses to the protocol Improve the feasibility of surveillance Description of the changes Biological assays, procedures, and measurements, which were planned on a routine basis, become systematic to allow close monitoring, at the request of the Independent Monitoring Board. The evaluation criterion on thromboembolic risks, relating to secondary objective No. 5, is thus adapted. The injection dates have been reworded, thus expanding the possible days for inclusion. This increases the exposure time to the investigational drug from 6 to 7 days. The inclusion criteria have been clarified: a negative ßHCG test must be obtained for any woman under 60 years of age; only long-term immunosuppressive treatment (not ongoing) is a non-inclusion criterion. Concerning the release of the final product, and in particular the count: the number of cells obtained after defrosting and before injection to the patient In case the dose of 1.106 MSC/kg or 0.5.106 MSC/kg of patient weight cannot be reached, it was decided ito give preference to the administration of 3 injections whatever the number of cells, without exceeding the maximum defined dosage. These changes have no impact on the safety of the study.

    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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