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    Clinical Trial Results:
    Multicenter, open-label, safety and tolerability study of ascending doses of HepaStem in patients with cirrhotic and pre-cirrhotic non-alcoholic steato-hepatitis (NASH).

    Summary
    EudraCT number
    		 2018-004449-18
    Trial protocol
    		 FR   BE   BG   PL   ES   RO  
    Global end of trial date
    31 Aug 2020

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    HEP201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03963921
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 PANASH: HEP201
    Sponsors
    Sponsor organisation name
    Cellaïon
    Sponsor organisation address
    Rue Granbonpré 11, Mont-Saint-Guibert, Belgium, 1435
    Public contact
    Welcome desk, Cellaïon, 32 10 394300, info@cellaion.com
    Scientific contact
    Welcome desk, Cellaïon, 32 10 394300, info@cellaion.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
    21 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to determine the safety and tolerability of ascending single and repeated doses of HepaStem up to Day 28 administered to patients with cirrhotic and pre cirrhotic NASH.
    Protection of trial subjects
    The study was conducted in accordance with the ICH Guideline for GCP (specific to ATMP), the guiding principles of the "Declaration of Helsinki", the local data protection and all other applicable regulatory requirements. All patients received HepaStem at the study site under the surveillance of appropriate study personnel. The patients were to stay hospitalized for a minimum duration of 24 hours after the infusion of HepaStem to ensure their continuous monitoring. In order to prevent transfusion-like reaction, a bolus of 100 mg hydrocortisone or equivalent glucocorticoid was given 15 to 30 minutes before each HepaStem infusion. Successive dose cohorts received progressively larger doses through a stepwise approach evaluated by the Safety Monitoring Committee. After completion of the study, all participants who received at least 1 infusion of HepaStem were invited to participate in the long-term follow-up PROLONGSTEM study for 5 additional years (EudraCT 2017-003989-27, EU-CTR 2022-500251-22-00).
    Background therapy
    		 The participants were recruited at hospitals with specialized hepatology and intensive care units. The patients’ profile consisted of NASH with stage F3 or (compensated/early decompensated) F4 fibrosis with proven diagnosis of NASH demonstrated by liver biopsy before screening, available within 6 months for F3 patients or 2 years for F4 patients. If biopsy was not available within these time windows, a biopsy was to be performed at screening. F4 patients for whom the biopsy did not confirm the diagnosis of NASH could be included, provided that any other causes of underlying liver diseases were excluded. Decompensated F4 patients had to present one of the following clinical signs of decompensation: • Total bilirubin > 2 mg/dL (direct bilirubin > 1.5 mg/dL in case of suspected Gilbert’s syndrome), and/or • Clinical signs of ascites, and/or • Clinical or electroencephalography evidence of HE up to grade II
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    15 Mar 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    France: 1
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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
    6
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Ten investigational sites in 6 countries recruited 23 participants: 2 in Bulgaria, 2 in Belgium, 1 in France, 1 in Poland, 3 in Spain, and 1 in Romania. The recruitment period lasted approximately 10 months (FPFV 19-APR-2019 - LPFV 20-FEB-20120).

    Pre-assignment
    Screening details
    		 The screening period lasted up to 14 days following informed consent signature and allowed assessing participant’s eligibility. Participants were hospitalized during the screening period. 31 participants were screened, 23 were eligible and included in the safety analysis set (SAF).

    Period 1
    Period 1 title
    Infusion Day 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    All participants enrolled in the study were administered a single or 3 repeated weekly infusions of 0.5 or 1.0 x 10^6 cells of HepaStem/kg body weight (BW). There was no blinding in this study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 1: 0.5 x 10^6 cells of HepaStem/kg body weight (BW), administered as single intravenous infusion.

    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 2: 1.0 x 10^6 cells of HepaStem/kg BW, administered as single intravenous infusion.

    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 3: 0.5 x 10^6 cells of HepaStem/kg BW, administered as 3 repeated weekly intravenous infusions for a total dose of 1.5 x 10^6 cells of HepaStem/kg BW.

    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 4: 1.0 x 10^6 cells of HepaStem/kg BW, administered as 3 repeated weekly intravenous infusions for a total dose of 3.0 x 10^6 cells of HepaStem/kg BW.

    Number of subjects in period 1
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    6
    7
    4
    Period 2
    Period 2 title
    Infusion Day 1 (post infusion)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    6
    7
    4
    Period 3
    Period 3 title
    Infusion Day 8
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 3: 0.5 x 10^6 cells of HepaStem/kg BW, administered as 3 repeated weekly intravenous infusions for a total dose of 1.5 x 10^6 cells of HepaStem/kg BW.

    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 4: 1.0 x 10^6 cells of HepaStem/kg BW, administered as 3 repeated weekly intravenous infusions for a total dose of 3.0 x 10^6 cells of HepaStem/kg BW.

    Number of subjects in period 3
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    6
    7
    4
    Period 4
    Period 4 title
    Infusion Day 8 (post infusion)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    6
    7
    4
    Period 5
    Period 5 title
    Infusion Day 15
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 3: 0.5 x 10^6 cells of HepaStem/kg BW, administered as 3 repeated weekly intravenous infusions for a total dose of 1.5 x 10^6 cells of HepaStem/kg BW.

    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Dose Cohort 4: 1.0 x 10^6 cells of HepaStem/kg BW, administered as 3 repeated weekly intravenous infusions for a total dose of 3.0 x 10^6 cells of HepaStem/kg BW.

    Number of subjects in period 5
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    6
    7
    4
    Period 6
    Period 6 title
    Infusion Day 15 (post infusion)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 6
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    6
    7
    4
    Period 7
    Period 7 title
    Follow-up period (up to Day 28)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 7
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    6
    7
    4
    Period 8
    Period 8 title
    Follow-up period (up to Month 6)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single arm - Dose Cohort 1
    Arm description
    		 Dose Cohort 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 2
    Arm description
    		 Dose Cohort 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 3
    Arm description
    		 Dose Cohort 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Single arm - Dose Cohort 4
    Arm description
    		 Dose Cohort 4
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 8
    		Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Started
    6
    6
    7
    4
    Completed
    6
    4
    7
    3
    Not completed
    0
    2
    0
    1
         Consent withdrawn by subject
    -
    2
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4

    Reporting group values
    		 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Total
    Number of subjects
    		 6 6 7 4 23
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 4 6 5 2 17
        From 65-84 years
    		 2 0 2 2 6
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.0 ± 11.6 52.2 ± 10.1 61.7 ± 4.0 56.0 ± 14.0 -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 2 1 10
        Male
    		 2 3 5 3 13
    Fibrosis stage
    Units: Subjects
        F3
    		 3 3 3 2 11
        F4
    		 3 3 4 2 12
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 169.5 ± 12.1 168.3 ± 13.0 164.4 ± 10.9 164.5 ± 11.1 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 102.0 ± 21.3 95.0 ± 21.8 86.7 ± 12.3 94.3 ± 11.0 -
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 35.2 ± 4.4 33.4 ± 5.9 32.2 ± 4.2 34.9 ± 2.7 -
    Waist circumference
    Units: centimetre
        arithmetic mean (standard deviation)
    		 109.2 ± 10.9 110.2 ± 9.1 108.3 ± 11.6 115.5 ± 11.3 -
    NAS
    Non-alcoholic fatty liver disease (NAFLD) activity score
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 6.17 ± 1.60 5.83 ± 1.17 4.00 ± 1.63 4.50 ± 1.29 -
    SAF steatosis score
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 2.50 ± 0.84 2.60 ± 0.55 1.43 ± 0.79 1.50 ± 0.58 -
    SAF activity score
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 3.17 ± 0.98 2.33 ± 1.37 2.14 ± 1.57 3.50 ± 0.58 -
    Liver stiffness measurement
    Units: kPa
        arithmetic mean (standard deviation)
    		 7.77 ± 0.88 14.29 ± 7.97 14.43 ± 4.21 25.63 ± 20.87 -
    Controlled attenuation parameter
    Units: dB/m
        arithmetic mean (standard deviation)
    		 348.0 ± 40.4 348.4 ± 46.7 309.9 ± 72.9 325.8 ± 71.0 -
    White blood cell count
    Units: 10⁹/L
        arithmetic mean (standard deviation)
    		 7.51 ± 2.08 8.15 ± 2.01 6.55 ± 0.77 5.81 ± 0.33 -
    Creatinine
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 0.97 ± 0.21 0.78 ± 0.22 0.65 ± 0.10 0.76 ± 0.09 -
    Urea
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 5.27 ± 2.16 4.73 ± 1.86 5.27 ± 0.65 5.13 ± 1.28 -
    D-dimers
    Units: mg/L
        arithmetic mean (standard deviation)
    		 0.37 ± 0.17 0.35 ± 0.15 0.26 ± 0.15 0.34 ± 0.38 -
    Fibrinogen
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 375.3 ± 58.1 369.8 ± 145.5 409.7 ± 57.3 316.1 ± 75.2 -
    INR
    Units: ratio
        arithmetic mean (standard deviation)
    		 1.01 ± 0.05 1.10 ± 0.11 1.02 ± 0.10 1.17 ± 0.08 -
    Platelets
    Units: 10⁹/L
        arithmetic mean (standard deviation)
    		 189.0 ± 65.8 174.7 ± 63.0 206.3 ± 45.9 174.6 ± 70.8 -
    Protein C
    Units: percentage
        arithmetic mean (standard deviation)
    		 113.8 ± 27.0 89.4 ± 25.1 105.8 ± 6.4 105.8 ± 41.1 -
    Protein S
    Units: percentage
        arithmetic mean (standard deviation)
    		 97.3 ± 27.4 101.4 ± 13.0 92.0 ± 20.2 90.4 ± 15.3 -
    Thrombin time
    Units: second
        arithmetic mean (standard deviation)
    		 18.2 ± 2.6 17.4 ± 3.7 14.9 ± 3.0 15.9 ± 1.2 -
    Plasminogen activator inhibitor-1 activity
    Units: UA/mL
        arithmetic mean (standard deviation)
    		 26.0 ± 5.7 18.8 ± 7.7 25.8 ± 11.3 24.7 ± 7.0 -
    Total bilirubin
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 0.66 ± 0.26 1.17 ± 0.59 0.71 ± 0.42 1.09 ± 0.87 -
    Alkaline phosphatase
    Units: U/L
        arithmetic mean (standard deviation)
    		 76.0 ± 18.0 83.3 ± 22.9 97.4 ± 39.4 87.5 ± 35.1 -
    Alanine aminotransferase
    Units: U/L
        arithmetic mean (standard deviation)
    		 64.5 ± 29.9 44.8 ± 34.4 63.4 ± 26.9 47.3 ± 28.6 -
    Aspartate aminotransferase
    Units: U/L
        arithmetic mean (standard deviation)
    		 50.5 ± 23.0 38.9 ± 15.6 41.4 ± 12.3 35.8 ± 15.5 -
    γ-glutamyl transferase
    Units: U/L
        arithmetic mean (standard deviation)
    		 72.4 ± 35.1 84.9 ± 47.7 64.1 ± 57.9 76.0 ± 48.4 -
    Fasting glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 7.15 ± 1.76 8.51 ± 2.67 7.20 ± 1.48 7.38 ± 1.36 -
    Hemoglobin A1c
    Units: L/L
        arithmetic mean (standard deviation)
    		 6.52 ± 1.16 5.80 ± 1.12 6.42 ± 1.10 6.73 ± 0.95 -
    High density lipoprotein
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.08 ± 0.22 0.94 ± 0.24 1.10 ± 0.22 1.16 ± 0.24 -
    Low density lipoprotein
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 3.26 ± 0.87 1.98 ± 0.80 2.46 ± 1.18 4.28 ± 1.18 -
    Triglyceride
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 3.23 ± 2.23 2.58 ± 1.03 2.52 ± 0.57 4.10 ± 3.36 -
    Total cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 5.48 ± 1.06 3.72 ± 0.85 4.06 ± 1.23 5.96 ± 1.16 -
    Uric acid
    Units: µmol/L
        arithmetic mean (standard deviation)
    		 393.5 ± 109.4 323.3 ± 69.2 304.0 ± 59.2 393.3 ± 87.8 -
    Hyaluronic acid
    Units: µg/L
        median (full range (min-max))
    		 22.5 (12.0 to 329.0) 53.5 (28.0 to 294.0) 83.0 (13.0 to 152.5) 81.0 (21.6 to 128.5) -
    Tissue inhibitor of metalloproteinase-1
    Units: ng/L
        median (full range (min-max))
    		 129.4 (105.2 to 199.2) 142.9 (97.9 to 243.3) 116.4 (80.3 to 194.4) 148.0 (63.7 to 172.3) -
    N-terminal propeptide of Type III collagen
    Units: U/mL
        median (full range (min-max))
    		 1.01 (0.60 to 1.30) 1.04 (0.63 to 1.47) 0.91 (0.59 to 1.14) 0.91 (0.51 to 1.09) -
    C-reactive protein
    Units: mg/L
        median (full range (min-max))
    		 3.65 (0.90 to 11.00) 4.50 (2.20 to 21.10) 2.80 (0.00 to 15.60) 2.56 (0.00 to 7.70) -
    Interleukin-6
    Units: pg/mL
        median (full range (min-max))
    		 1.79 (1.14 to 4.32) 4.75 (1.51 to 7.88) 2.88 (0.93 to 3.44) 2.44 (1.58 to 4.30) -
    Adiponectin
    Units: µg/mL
        median (full range (min-max))
    		 5.18 (3.20 to 10.47) 5.24 (2.52 to 7.04) 7.43 (3.46 to 8.83) 4.59 (3.87 to 5.20) -
    MELD-Na
    Units: score
        arithmetic mean (standard deviation)
    		 7.33 ± 0.82 8.33 ± 1.97 7.00 ± 1.15 9.00 ± 2.16 -
    Child-Pugh
    Units: score
        arithmetic mean (standard deviation)
    		 5.00 ± 0.00 5.17 ± 0.41 5.14 ± 0.38 5.25 ± 0.50 -
    CLIF-C AD
    Units: score
        arithmetic mean (standard deviation)
    		 43.2 ± 6.4 43.7 ± 3.1 42.3 ± 3.0 43.3 ± 5.4 -
    APRI
    Aspartate aminotransferase to platelet ratio index
    Units: score
        arithmetic mean (standard deviation)
    		 0.73 ± 0.50 0.63 ± 0.26 0.56 ± 0.17 0.65 ± 0.30 -
    FIB-4
    Fibrosis-4 (score)
    Units: score
        arithmetic mean (standard deviation)
    		 -0.12 ± 1.35 0.10 ± 1.26 -0.43 ± 0.60 0.23 ± 2.02 -
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety analysis set (SAF) included all patients entered in the study who received at least one dose of the IMP.

    Subject analysis sets values
    		 Safety analysis set
    Number of subjects
    23
    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)
    17
        From 65-84 years
    6
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.5 ± 10.0
    Gender categorical
    Units: Subjects
        Female
    10
        Male
    13
    Fibrosis stage
    Units: Subjects
        F3
    11
        F4
    12
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    166.8 ± 11.2
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    94.2 ± 17.4
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    33.7 ± 4.4
    Waist circumference
    Units: centimetre
        arithmetic mean (standard deviation)
    110.3 ± 10.3
    NAS
    Non-alcoholic fatty liver disease (NAFLD) activity score
    Units: unit(s)
        arithmetic mean (standard deviation)
    5.13 ± 1.66
    SAF steatosis score
    Units: unit(s)
        arithmetic mean (standard deviation)
    2.00 ± 0.87
    SAF activity score
    Units: unit(s)
        arithmetic mean (standard deviation)
    2.70 ± 1.29
    Liver stiffness measurement
    Units: kPa
        arithmetic mean (standard deviation)
    14.60 ± 10.66
    Controlled attenuation parameter
    Units: dB/m
        arithmetic mean (standard deviation)
    332.6 ± 57.5
    White blood cell count
    Units: 10⁹/L
        arithmetic mean (standard deviation)
    7.09 ± 1.68
    Creatinine
    Units: mg/dL
        arithmetic mean (standard deviation)
    0.79 ± 0.20
    Urea
    Units: mmol/L
        arithmetic mean (standard deviation)
    5.10 ± 1.52
    D-dimers
    Units: mg/L
        arithmetic mean (standard deviation)
    0.33 ± 0.20
    Fibrinogen
    Units: mg/dL
        arithmetic mean (standard deviation)
    374.1 ± 90.9
    INR
    Units: ratio
        arithmetic mean (standard deviation)
    1.06 ± 0.10
    Platelets
    Units: 10⁹/L
        arithmetic mean (standard deviation)
    188.0 ± 57.7
    Protein C
    Units: percentage
        arithmetic mean (standard deviation)
    104.2 ± 25.6
    Protein S
    Units: percentage
        arithmetic mean (standard deviation)
    95.5 ± 19.4
    Thrombin time
    Units: second
        arithmetic mean (standard deviation)
    17.0 ± 2.9
    Plasminogen activator inhibitor-1 activity
    Units: UA/mL
        arithmetic mean (standard deviation)
    23.8 ± 8.5
    Total bilirubin
    Units: mg/dL
        arithmetic mean (standard deviation)
    0.89 ± 0.55
    Alkaline phosphatase
    Units: U/L
        arithmetic mean (standard deviation)
    86.4 ± 29.2
    Alanine aminotransferase
    Units: U/L
        arithmetic mean (standard deviation)
    56.0 ± 29.5
    Aspartate aminotransferase
    Units: U/L
        arithmetic mean (standard deviation)
    42.2 ± 16.7
    γ-glutamyl transferase
    Units: U/L
        arithmetic mean (standard deviation)
    73.8 ± 45.8
    Fasting glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    7.57 ± 1.89
    Hemoglobin A1c
    Units: L/L
        arithmetic mean (standard deviation)
    6.39 ± 1.05
    High density lipoprotein
    Units: mmol/L
        arithmetic mean (standard deviation)
    1.06 ± 0.23
    Low density lipoprotein
    Units: mmol/L
        arithmetic mean (standard deviation)
    2.86 ± 1.25
    Triglyceride
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.00 ± 1.83
    Total cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.67 ± 1.36
    Uric acid
    Units: µmol/L
        arithmetic mean (standard deviation)
    347.9 ± 86.8
    Hyaluronic acid
    Units: µg/L
        median (full range (min-max))
    64.0 (12.0 to 329.0)
    Tissue inhibitor of metalloproteinase-1
    Units: ng/L
        median (full range (min-max))
    139.3 (63.7 to 243.3)
    N-terminal propeptide of Type III collagen
    Units: U/mL
        median (full range (min-max))
    0.94 (0.51 to 1.47)
    C-reactive protein
    Units: mg/L
        median (full range (min-max))
    2.80 (0.00 to 21.10)
    Interleukin-6
    Units: pg/mL
        median (full range (min-max))
    2.70 (0.93 to 7.88)
    Adiponectin
    Units: µg/mL
        median (full range (min-max))
    5.20 (2.52 to 10.47)
    MELD-Na
    Units: score
        arithmetic mean (standard deviation)
    7.78 ± 1.62
    Child-Pugh
    Units: score
        arithmetic mean (standard deviation)
    5.13 ± 0.34
    CLIF-C AD
    Units: score
        arithmetic mean (standard deviation)
    43.0 ± 4.3
    APRI
    Aspartate aminotransferase to platelet ratio index
    Units: score
        arithmetic mean (standard deviation)
    0.64 ± 0.31
    FIB-4
    Fibrosis-4 (score)
    Units: score
        arithmetic mean (standard deviation)
    -0.10 ± 1.22

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4
    Reporting group title
    Single arm - Dose Cohort 1
    Reporting group description
    		 Dose Cohort 1

    Reporting group title
    Single arm - Dose Cohort 2
    Reporting group description
    		 Dose Cohort 2

    Reporting group title
    Single arm - Dose Cohort 3
    Reporting group description
    		 Dose Cohort 3

    Reporting group title
    Single arm - Dose Cohort 4
    Reporting group description
    		 Dose Cohort 4

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety analysis set (SAF) included all patients entered in the study who received at least one dose of the IMP.

    Primary: Adverse events reported up to Day 28 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure

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    End point title
    		 Adverse events reported up to Day 28 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure [1]
    End point description
    Safety assessments from the time of signing the ICF through the Day 28 Visit included: • Adverse events/Treatment-emergent adverse events • Physical examination • Imaging • Vital signs • Local laboratory measurements
    End point type
    Primary
    End point timeframe
    Up to Day 28
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics. The study was not powered with respect to any specific hypothesis. Incidence of specific AEs and SAEs are tabulated as count and percentage, broken down by dose level.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    23
    Units: Number of cases
    28
    Attachments
    		 Untitled (Filename: HEP201_Primary Safety Endpoint_20231121_AEs up to D28.pdf)
    Untitled (Filename: HEP201_Primary Safety Endpoint_20231121_AEs up to D28_T.pdf)
    No statistical analyses for this end point

    Secondary: AEs reported up to Month 6 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure

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    End point title
    		 AEs reported up to Month 6 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure
    End point description
    Secondary safety assessments included: • AEs reported up to Month 6 post infusion assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    End point values
    		 Safety analysis set
    Number of subjects analysed
    23
    Units: Number of cases
    48
    Attachments
    		 Untitled (Filename: HEP201_Secondary Safety Endpoint_20231121_3_TEAEs up to M6.pdf)
    Untitled (Filename: HEP201_Secondary Safety Endpoint_20231121_3_TEAEs up to M6_T.pdf)
    No statistical analyses for this end point

    Secondary: Presence of anti-HLA antibodies (Abs) and identification of donor HLA specificity

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    End point title
    		 Presence of anti-HLA antibodies (Abs) and identification of donor HLA specificity
    End point description
    To understand better the effects HepaStem on immunogenicity development, anti-HLA Abs (class I and II) were assessed (specificity identification and quantification) in serum samples collected before infusion as well as on Day 28, Month 3, and Month 6 by Luminex method in a Central laboratory. The threshold for detection was set at a mean Fluorescence intensity (MFI) > 1500. MFI > 5000 was considered as clinically significant level.
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    End point values
    		 Safety analysis set
    Number of subjects analysed
    23
    Units: Number of patients with anti-HLA Abs
    7
    Attachments
    		 Untitled (Filename: HEP201_Secondary Safety Endpoint_20231121_1_HLA.pdf)
    No statistical analyses for this end point

    Secondary: Coagulation tests up to 24 hours post infusion

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    End point title
    		 Coagulation tests up to 24 hours post infusion
    End point description
    Local laboratory measurements included platelet counts, and levels of fibrinogen, INR, aPTT, D-dimer, TT, protein C, and protein S. Central laboratory measurements included plasminogen activator inhibitor-1 (PAI-1) activity. Laboratory measurements were carried out by standard, validated, and widely used methods. All blood samples for the safety laboratory tests had to be taken in a fasting state. Concentrations are expressed in mg/L (D-dimers), mg/dL (fibrinogen). G/L (platelet counts), % (Protein C and Protein S), seconds (TT and aPTT), UA/mL (PAI-1). INR has no unit.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours post infusion
    End point values
    		 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Number of subjects analysed
    6
    6
    7
    4
    6
    6
    7
    4
    7
    4
    6
    4
    7
    4
    7
    3
    Units: concentration or ratio
    arithmetic mean (standard deviation)
        D-dimers
    0.37 ± 0.17
    0.35 ± 0.15
    0.26 ± 0.15
    0.34 ± 0.38
    0.43 ± 0.17
    0.67 ± 0.49
    0.45 ± 0.32
    0.63 ± 0.53
    0.40 ± 0.32
    0.36 ± 0.32
    0.63 ± 0.61
    0.90 ± 0.48
    2.06 ± 4.53
    0.57 ± 0.40
    2.18 ± 3.73
    1.06 ± 0.82
        Fibrinogen
    375.3 ± 58.1
    369.8 ± 145.5
    409.7 ± 57.3
    316.1 ± 75.2
    334.3 ± 61.5
    359.5 ± 125.1
    392.1 ± 57.7
    323.7 ± 80.1
    423.6 ± 86.2
    349.0 ± 92.3
    398.3 ± 80.2
    360.9 ± 131.0
    407.1 ± 71.3
    344.9 ± 73.3
    413.0 ± 46.1
    369.0 ± 140.1
        INR
    1.01 ± 0.05
    1.10 ± 0.11
    1.02 ± 0.10
    1.17 ± 0.08
    1.05 ± 0.06
    1.10 ± 0.13
    1.03 ± 0.06
    1.18 ± 0.08
    1.02 ± 0.08
    1.015 ± 0.13
    1.05 ± 0.10
    1.15 ± 0.09
    1.00 ± 0.07
    1.15 ± 0.14
    1.05 ± 0.06
    1.15 ± 0.11
        Platelet count
    189.0 ± 65.8
    174.7 ± 63.0
    206.3 ± 45.9
    174.6 ± 70.8
    183.2 ± 66.2
    172.8 ± 64.9
    212.6 ± 53.7
    174.7 ± 81.0
    220.1 ± 44.1
    175.3 ± 90.1
    194.0 ± 49.4
    149.0 ± 56.7
    242.4 ± 49.3
    174.5 ± 93.1
    219.0 ± 52.6
    204.7 ± 112.6
        Protein C
    113.8 ± 27.0
    89.4 ± 25.1
    105.8 ± 6.4
    105.8 ± 41.1
    113.2 ± 25.7
    83.6 ± 18.3
    106.5 ± 8.6
    104.5 ± 50.9
    104.6 ± 14.2
    107.2 ± 37.0
    103.2 ± 14.7
    107.0 ± 35.1
    107.0 ± 13.5
    107.1 ± 33.5
    101.6 ± 11.6
    107.9 ± 39.2
        Protein S
    97.3 ± 27.4
    101.4 ± 13.0
    92.0 ± 20.2
    90.4 ± 15.3
    98.0 ± 22.1
    96.2 ± 6.5
    87.6 ± 21.2
    88.9 ± 17.9
    94.0 ± 37.6
    90.2 ± 19.0
    78.1 ± 18.9
    88.8 ± 24.5
    98.1 ± 11.2
    81.3 ± 6.9
    92.3 ± 12.5
    91.6 ± 18.1
        TT
    18.2 ± 2.6
    17.4 ± 3.7
    14.9 ± 3.0
    15.9 ± 1.2
    18.6 ± 2.4
    16.7 ± 2.5
    16.7 ± 4.5
    17.1 ± 1.2
    15.7 ± 3.3
    18.3 ± 3.4
    13.1 ± 4.2
    17.4 ± 1.8
    17.8 ± 4.7
    16.8 ± 1.0
    18.0 ± 4.4
    16.4 ± 1.7
        PAI-1
    26.0 ± 5.7
    18.8 ± 7.7
    25.8 ± 11.3
    24.7 ± 7.0
    19.8 ± 7.6
    17.2 ± 9.5
    22.1 ± 7.5
    21.1 ± 14.3
    25.8 ± 11.0
    26.0 ± 7.0
    17.3 ± 4.5
    20.7 ± 6.4
    25.7 ± 10.0
    24.5 ± 7.4
    21.4 ± 5.9
    20.1 ± 5.8
        aPTT
    28.5 ± 2.1
    28.9 ± 3.8
    27.2 ± 13.0
    27.8 ± 3.5
    27.9 ± 2.1
    27.5 ± 3.2
    25.8 ± 12.0
    26.6 ± 2.8
    25.3 ± 12.1
    28.5 ± 2.7
    25.8 ± 13.0
    26.9 ± 4.0
    26.7 ± 12.9
    27.8 ± 2.9
    24.7 ± 11.8
    27.2 ± 4.3
    Attachments
    		 Untitled (Filename: HEP201_Secondary Safety Endpoint_20231121_2_Coagulation.pdf)
    No statistical analyses for this end point

    Secondary: Composite scores for disease stage: MELD, Child-Pugh and CLIF-C AD (for F4 decompensated) scores

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    End point title
    		 Composite scores for disease stage: MELD, Child-Pugh and CLIF-C AD (for F4 decompensated) scores
    End point description
    Original and new MELD(-Na) scores, Child-Pugh score, and chronic liver failure consortium acute decompensation (CLIF-C AD) score (for F4 decompensated) were calculated based on the various exams performed.
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    End point values
    		 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Number of subjects analysed
    6
    6
    7
    4
    6
    5
    7
    3
    6
    4
    6
    3
    Units: score
    arithmetic mean (standard deviation)
        New MELD (MELD-Na)
    7.3 ± 0.8
    8.3 ± 2.0
    7.0 ± 1.2
    9.0 ± 2.2
    7.7 ± 1.2
    8.4 ± 1.1
    6.9 ± 0.7
    7.3 ± 0.6
    7.3 ± 0.8
    6.8 ± 0.5
    6.7 ± 0.5
    7.3 ± 1.2
        Child-Pugh
    5.0 ± 0.0
    5.2 ± 0.4
    5.1 ± 0.4
    5.3 ± 0.5
    5.0 ± 0.0
    5.0 ± 0.0
    5.0 ± 0.0
    5.0 ± 0.0
    5.0 ± 0.0
    5.0 ± 0.0
    5.0 ± 0.0
    5.0 ± 0.0
        CLIF-C AD
    43.2 ± 6.4
    43.7 ± 3.1
    42.3 ± 3.0
    43.3 ± 5.4
    43.5 ± 4.8
    43.0 ± 3.1
    42.4 ± 2.6
    41.0 ± 5.3
    45.5 ± 4.5
    43.8 ± 1.5
    43.0 ± 2.4
    39.3 ± 5.1
    Attachments
    		 Untitled (Filename: HEP201_Secondary Efficacy Endpoint_20231121_1_Scores.pdf)
    No statistical analyses for this end point

    Secondary: Quantitative assessment of liver function

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    End point title
    		 Quantitative assessment of liver function
    End point description
    Local laboratory measurements for liver function included levels of bilirubin, ALT, AST, GGT, ALP, and albumin. Laboratory measurements were carried out by standard, validated, and widely used methods. Total bilirubin is expressed in mg/dL, liver enzymes in U/L, albumin in g/L.
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    End point values
    		 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Number of subjects analysed
    6
    6
    7
    4
    6
    6
    7
    3
    6
    4
    7
    3
    Units: concentration
    arithmetic mean (standard deviation)
        Total bilirubin
    0.66 ± 0.26
    1.17 ± 0.59
    0.71 ± 0.42
    1.09 ± 0.87
    0.69 ± 0.31
    0.90 ± 0.39
    0.69 ± 0.35
    0.67 ± 0.15
    0.61 ± 0.16
    0.78 ± 0.15
    0.72 ± 0.30
    0.26 ± 0.13
        ALP
    76.0 ± 18.0
    83.3 ± 22.9
    97.4 ± 39.4
    87.5 ± 35.1
    75.7 ± 22.2
    93.5 ± 21.7
    92.6 ± 35.9
    70.0 ± 10.6
    85.0 ± 20.5
    85.8 ± 7.4
    92.6 ± 36.4
    82.3 ± 19.9
        ALT
    64.5 ± 29.9
    44.8 ± 34.4
    63.4 ± 26.9
    47.3 ± 28.6
    62.3 ± 23.7
    41.7 ± 33.3
    50.7 ± 22.1
    45.0 ± 21.6
    57.2 ± 38.4
    36.0 ± 14.7
    54.0 ± 31.6
    33.7 ± 1.5
        AST
    50.5 ± 23.0
    38.9 ± 15.6
    41.4 ± 12.3
    35.8 ± 15.5
    48.4 ± 13.8
    36.7 ± 14.7
    43.6 ± 22.6
    38.3 ± 16.9
    43.3 ± 20.0
    37.5 ± 8.7
    43.4 ± 23.6
    32.3 ± 8.1
        GGT
    72.4 ± 35.1
    84.9 ± 47.7
    64.1 ± 57.9
    76.0 ± 48.4
    69.7 ± 31.1
    89.3 ± 48.0
    59.6 ± 51.3
    46.3 ± 17.1
    74.5 ± 39.1
    74.0 ± 60.8
    62.0 ± 65.5
    92.7 ± 88.6
    Attachments
    		 Untitled (Filename: HEP201_Secondary Efficacy Endpoint_20231121_2_Liver function.pdf)
    No statistical analyses for this end point

    Secondary: Quantitative assessment of metabolic biomarkers and clinical signs

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    End point title
    		 Quantitative assessment of metabolic biomarkers and clinical signs
    End point description
    Local laboratory measurements for metabolic biomarkers included levels of glucose, insulin, total cholesterol, LDL, HDL, triglycerides, uric acid, and HbA1C. Waist circumference and BMI (except in decompensated patients with ascites) were also measured or calculated. Laboratory measurements were carried out by standard, validated, and widely used methods. Fasting glucose is expressed in mmol/L, fasting insulin in pmol/L, HDL, LDL, total cholesterol and triglycerides in mmol/L, uric acid in µmol/L, creatinine in mg.dL.
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    End point values
    		 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Number of subjects analysed
    6
    6
    7
    4
    6
    6
    7
    3
    6
    4
    7
    3
    Units: concentration or length
    arithmetic mean (standard deviation)
        Fasting glucose
    7.15 ± 1.76
    8.51 ± 2.67
    7.20 ± 1.48
    7.38 ± 1.36
    6.67 ± 1.70
    7.22 ± 1.62
    7.06 ± 2.93
    6.14 ± 1.21
    6.32 ± 1.09
    7.69 ± 2.25
    6.64 ± 0.87
    6.84 ± 1.68
        Fasting insulin
    349 ± 315
    201 ± 135
    153 ± 45
    338 ± 297
    274 ± 156
    142 ± 59
    233 ± 154
    301 ± 329
    214 ± 150
    313 ± 295
    246 ± 240
    277 ± 273
        HDL
    1.08 ± 0.22
    0.94 ± 0.24
    1.10 ± 0.22
    1.16 ± 0.24
    1.16 ± 0.18
    0.98 ± 0.26
    1.12 ± 0.21
    1.11 ± 0.24
    1.30 ± 0.29
    1.17 ± 0.22
    1.05 ± 0.18
    1.24 ± 0.23
        LDL
    3.26 ± 0.87
    1.98 ± 0.80
    2.46 ± 1.18
    4.28 ± 1.18
    2.89 ± 0.59
    2.06 ± 0.78
    2.51 ± 1.11
    3.89 ± 0.97
    3.51 ± 0.73
    2.55 ± 0.84
    2.55 ± 1.22
    3.67 ± 1.40
        Total cholesterol
    5.48 ± 1.06
    3.72 ± 0.85
    4.06 ± 1.23
    5.96 ± 1.16
    5.11 ± 1.20
    3.71 ± 0.82
    4.26 ± 1.15
    5.41 ± 0.34
    5.90 ± 1.14
    4.36 ± 0.82
    4.10 ± 1.18
    5.43 ± 1.31
        Triglycerides
    3.23 ± 2.23
    1.75 ± 0.84
    1.27 ± 0.44
    1.98 ± 1.3
    2.45 ± 1.96
    1.47 ± 0.56
    1.48 ± 0.33
    1.74 ± 0.77
    2.32 ± 1.09
    1.37 ± 0.34
    1.27 ± 0.28
    1.28 ± 0.18
        Uric acid
    394 ± 109
    323 ± 69
    304 ± 59
    393 ± 88
    376 ± 103
    302 ± 48
    315 ± 46
    408 ± 87
    346 ± 106
    322 ± 71
    308 ± 77
    352 ± 25
        Creatinine
    0.97 ± 0.21
    0.78 ± 0.22
    0.65 ± 0.10
    0.76 ± 0.09
    1.02 ± 0.22
    0.77 ± 0.26
    0.69 ± 0.09
    0.73 ± 0.13
    0.99 ± 0.14
    0.68 ± 0.09
    0.67 ± 0.10
    0.67 ± 0.17
    Attachments
    		 Untitled (Filename: HEP201_Secondary Efficacy Endpoint_20231121_3_Metabolism biomarkers and score.pdf)
    No statistical analyses for this end point

    Secondary: Quantitative assessment of liver fibrosis biomarkers and stiffness

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    End point title
    		 Quantitative assessment of liver fibrosis biomarkers and stiffness
    End point description
    Liver stiffness and liver steatosis were simultaneously evaluated using non-invasive ultrasound imaging Fibroscan® 530 Compact or 502 Touch (Echosens, Paris, France) or with the Logiq S8 XDclear 2.0 ultrasound system with Integrated Liver Package (GE Healthcare and Echosens). Liver stiffness measurement (LSM) was evaluated by vibration-controlled transient elastography (TE). Fibrosis scores as non-invasive tests based on serum markers have limited value for definitive diagnosis of liver fibrosis; however, they help to rule-in or rule-out advanced fibrosis especially iin combination with TE. Simple non-patented fibrosis scores were calculated.
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    End point values
    		 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4 Single arm - Dose Cohort 1 Single arm - Dose Cohort 2 Single arm - Dose Cohort 3 Single arm - Dose Cohort 4
    Number of subjects analysed
    6
    6
    7
    4
    6
    6
    7
    3
    6
    4
    7
    3
    Units: unit(s)
    arithmetic mean (standard deviation)
        NAFLD score
    -0.12 ± 1.35
    0.10 ± 1.26
    -0.43 ± 0.60
    0.23 ± 2.02
    -0.34 ± 1.62
    0.22 ± 1.14
    -0.61 ± 0.59
    -0.60 ± 2.19
    -0.37 ± 1.48
    0.04 ± 0.90
    -0.23 ± 0.64
    0.50 ± 2.60
        FIB-4
    2.03 ± 1.24
    2.01 ± 0.76
    1.60 ± 0.30
    2.16 ± 1.34
    1.83 ± 0.87
    1.95 ± 0.93
    1.70 ± 0.61
    1.65 ± 1.34
    1.74 ± 0.69
    1.81 ± 0.82
    1.83 ± 0.56
    3.06 ± 2.14
        APRI
    0.73 ± 0.50
    0.63 ± 0.26
    0.56 ± 0.17
    0.65 ± 0.30
    0.60 ± 0.36
    0.58 ± 0.21
    0.55 ± 0.30
    0.54 ± 0.27
    0.55 ± 0.34
    0.53 ± 0.20
    0.60 ± 0.33
    0.74 ± 0.43
    Attachments
    		 Untitled (Filename: HEP201_Secondary Efficacy Endpoint_20231121_4_Fibrosis biomarkers and score.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Month 6 post infusion
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Safety analysis set (SAF)
    Reporting group description
    		 -

    Serious adverse events
    		 Safety analysis set (SAF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 23 (17.39%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic mass
    Additional description: Since a lesion of undetermined nature was already present at the same location and with the same size in repeated ultrasound images before study participation, the Sponsor assessed the event as not related to the IMP.
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
    Additional description: The event of prostatic adenocarcinoma occurred 223 days after the single administration of the study drug. The temporal relationship regarding the IMP was considered implausible. The event was assessed as unlikely related to the IMP.
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Ischaemic stroke
    Additional description: Five days after the 2nd infusion, the patient experienced an ischemic stroke of mild severity that completely resolved 6 days after the event onset and that was assessed as possibly related to the pre-existing condition of arterial hypertension & T2D
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal colic
    Additional description: Forty-three days after the first infusion, the patient experienced reno-ureteral colic of mild severity that resolved with analgesic treatment on the day after the event onset. The temporal relationship with the IMP was considered implausible.
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety analysis set (SAF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 23 (78.26%)
    Investigations
    Fibrin D dimer increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Tremor
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Toothache
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2019
    Study protocol v2.0 dated 29-AUG-2019: • The denomination of the IMP was updated from Heterologous Human Adult Liver-Derived Progenitor Cells (HHALPC) to Human Allogenic Liver-Derived Progenitor Cells (HALPC) • The exclusion criterion relative to the use (rather than the refusal to use) of highly effective (rather than reliable) contraceptive methods (Exclusion criterion #30) was updated. • The total volume of blood collected during the study procedures was added • A summary of potential risks and benefits was added • The DLT definition was updated not to limit it to 2 identical serious events • A 4-day safety period between each patient was added for Dose Cohorts 1 and 2 • A safety period between each patient for sequential management was defined for Dose Cohorts 3 and 4 • A negative pregnancy test for female patients of childbearing potential was added as eligibility infusion criterion • It was clarified that the laboratory urine pregnancy test was only applicable for female patients of childbearing potential
    10 Dec 2019
    Study protocol v3.0 dated 10-DEC-2019: • Additional patients with more advanced cirrhotic F4 NASH were envisaged and 2 additional dose cohorts (5 and 6) were added; other sections in the protocol were adapted accordingly • Some exploratory endpoints were removed because they were already described elsewhere • Exclusion criterion #2 relative to alcohol consumption was updated • Exclusion criterion #17 and #18 were merged and the numbering of subsequent exclusion criteria was adapted accordingly • Exclusion criterion #29 relative to known hypersensitivity to some antibiotics was added • Switzerland was added as participating country • The recommendation to consult the Summary of product characteristics (SmPCs) of corticosteroids used as preventive pre-medication was added • A sub-section relative to the notification of new facts was added in Section 12.2.10 • The sub-section relative to interim analysis was clarified

    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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