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    Clinical Trial Results:
    SAF 001: A long-term safety follow-up study of patients suffering from Urea Cycle disorders (UCD) or Crigler-Najjar Syndrome (CN) having received infusions of HepaStem.

    Summary
    EudraCT number
    		 2013-001045-14
    Trial protocol
    		 BE   PT   IT   GB  
    Global end of trial date
    20 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2022
    First version publication date
    27 Apr 2022
    Other versions
    Summary report(s)
    		 SAF001_Synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SAF001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02051049
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Promethera Therapeutics (formerly Promethera Biosciences)
    Sponsor organisation address
    Rue Granbonpré 11, Mont-Saint-Guibert, Belgium, 1435
    Public contact
    Welcome Desk, Promethera Therapeutics (formerly Promethera Biosciences), 32 10394300, regulatory@promethera.com
    Scientific contact
    Welcome Desk, Promethera Therapeutics (formerly Promethera Biosciences), 32 10394300, regulatory@promethera.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001155-PIP01-11
    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
    04 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to document the safety of HepaStem therapy during a period up to a maximum of 48 months (4 years (Y)) in the SAF001 study (SAF001 Y1+Y2+Y3+Y4). This long term safety follow-up study will start when the patient is ending the period of active surveillance post infusion of Hepastem in any former interventional study (Study A) conducted by Promethera Biosciences (PB). The safety will be assessed in terms of clinical status, biochemical parameters and morphology of the liver, detection of circulating anti-HLA antibodies specific for donor cells or other immune markers related to liver diseases as well as Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) related to HepaStem therapy.
    Protection of trial subjects
    The study was conducted in accordance with the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP), the ethical principles that have their origins in the revised Declaration of Helsinki and local regulations. The protocol, all amendments and the informed consent forms (ICFs) / patient information sheets (PIS) were reviewed and approved by the competent authorities (CA) and relevant ethics committee (EC) in each participating country. The safety monitoring was planned to last for a maximum of 4 years for each patient. However, for different reasons, patients could have been removed from this study: • In case of organ transplantation, if it was a liver transplantation, liver samples were to be collected from the exograft. An additional visit after orthotopic liver transplantation (OLT) including examinations and OLT questionnaire completion were also requested • In case of intake of other investigational treatments Nevertheless, whenever possible, Promethera Biosciences was to continue to collect safety data of these patients once a year in collaboration with the center where the patient was followed. If the patient terminated their participation prematurely, they were asked to have a last visit including the evaluation of all the study parameters, similar to those at 24- or 48-months, depending on the case.
    Background therapy
    		 No investigational medicinal product was administered during this trial. All UCD and CN patients included in the trial continued their disease-specific treatment based on usual metabolic monitoring under the responsibility of the investigator/treating physician. A low level of immunosuppression was maintained after a HepaStem infusion (in the initial investigational HEP001 study) to avoid a potential risk of developing an immunization against HepaStem, which would be detrimental for HepaStem or any other future treatment with cells or organ transplant (Kaneku 2013, O`Leary 2011). Thus, in the SAF001 study, a close monitoring was set up to follow the level of immunosuppression of the patients. Patients might have been maintained under immunosuppressive treatment based on investigator’s judgement and in some cases based on the results of functional 13C tests. For patients who received HepaStem 12 months ago, the recommended target through blood level for tacrolimus was 4 ± 2 ng/mL. However, immunosuppression could have been terminated at any time following the decision taken by the investigator/treating physician. Any termination was to be carefully documented.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    17 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Israel: 4
    Worldwide total number of subjects
    17
    EEA total number of subjects
    11
    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)
    11
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Ten centers were active in 5 countries (Belgium, France, the UK, Italy and Israel). Date of first patient screened: 17-APR-2013; date of first patient enrolled: 17-APR-2013.

    Pre-assignment
    Screening details
    		 A total of 17 patients (12 UCD and 5 CN) were enrolled. All received infusions of HepaStem during the former interventional clinical HEP001 study and had terminated their participation in that study. All signed an informed consent form. None received mature liver cell or stem cell transplantation other than HepaStem, or organ liver transplantation.

    Period 1
    Period 1 title
    Visit 0 Month
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 Crigler-Najar

    Investigational medicinal product name
    HepaStem
    Investigational medicinal product code
    Other name
    Heterologous human adult liver-derived progenitor cells (HHALPC)
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intraportal use
    Dosage and administration details
    HepaStem was administrated in the previous interventionnal trial HEP001

    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 UCD

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Started
    5
    12
    Completed
    5
    12
    Period 2
    Period 2 title
    Visit 6 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Started
    5
    12
    Completed
    5
    12
    Period 3
    Period 3 title
    Visit 12 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Started
    5
    12
    Completed
    5
    12
    Period 4
    Period 4 title
    Visit 18 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Started
    5
    12
    Completed
    3
    12
    Not completed
    2
    0
         Lost to follow-up
    1
    -
         Discovery of exclusion criteria
    1
    -
    Period 5
    Period 5 title
    Visit 24 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 5
    		Pediatric patients suffering from UCD Pediatric patients suffering from CN
    Started
    12
    3
    Completed
    9
    3
    Not completed
    3
    0
         Physician decision
    1
    -
         Lost to follow-up
    2
    -
    Period 6
    Period 6 title
    Visit 30 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 6
    		Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Started
    3
    9
    Completed
    1
    9
    Not completed
    2
    0
         Discovery of exclusion criteria
    1
    -
         Sponsor decision
    1
    -
    Period 7
    Period 7 title
    Visit 36 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 7
    		Pediatric patients suffering from UCD Pediatric patients suffering from CN
    Started
    9
    1
    Completed
    7
    1
    Not completed
    2
    0
         Sponsor decision
    2
    -
    Period 8
    Period 8 title
    Visit 42 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Pediatric patients suffering from CN
    Arm description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 8
    		Pediatric patients suffering from UCD Pediatric patients suffering from CN
    Started
    7
    1
    Completed
    2
    0
    Not completed
    5
    1
         Sponsor decision
    5
    1
    Period 9
    Period 9 title
    Visit 48 Months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Pediatric patients suffering from UCD
    Arm description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 9
    		Pediatric patients suffering from UCD
    Started
    2
    Completed
    1
    Not completed
    1
         Sponsor decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study

    Reporting group values
    		 Pediatric patients suffering from CN Pediatric patients suffering from UCD Total
    Number of subjects
    		 5 12 17
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 5 6 11
        Adolescents (12-17 years)
    		 0 6 6
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.7 ± 2.0 11.5 ± 6.1 -
    Gender categorical
    Units: Subjects
        Female
    		 3 6 9
        Male
    		 2 6 8
    Cognitive assessment (Wechsler scores)
    Units: Subjects
        WPPSI
    		 1 1 2
        WISC
    		 1 1 2
        WAIS
    		 3 10 13
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 22.64 ± 6.16 40.02 ± 23.85 -
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 116.40 ± 10.53 134.21 ± 30.35 -
    Head circumference
    Units: centimetre
        arithmetic mean (standard deviation)
    		 49.70 ± NA 49.00 ± 3.92 -
    Subject analysis sets

    Subject analysis set title
    Pediatric patients suffering from CN
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set: All patients included in this follow-up study were analyzed. The following subgroups have been considered for the analysis: • The study population includes 2 types of indication: o patients suffering from UCD with specific associated subtypes being UCD NAGS, UCD CPS I, UCD OTC, UCD ASS, UCD ASL and UCD Arginase o patients suffering from CN with specific associated subtypes being CN I and CN II Analyses were reported separately for each indication and some analyses were reported per indication (sub)type. Some analyses were performed according to cohorts that were defined in the previous HEP001 study and based on: • Theoretical assigned dose group: low dose cohort (12.5x10^6 cells/kg), intermediate dose (50x10^6 cells/kg) and high dose (200x10^6 cells/kg). • Weight: cohort > 20 kg, cohort ≥ 10 kg-20 kg and cohort < 10 kg. • Age at the time of the first treatment infusion: Age cohort ≤ 12 years and age cohort > 12 years

    Subject analysis set title
    Pediatric patients suffering from UCD
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set: All patients included in this follow-up study were analyzed. The following subgroups have been considered for the analysis: • The study population includes 2 types of indication: o patients suffering from UCD with specific associated subtypes being UCD NAGS, UCD CPS I, UCD OTC, UCD ASS, UCD ASL and UCD Arginase o patients suffering from CN with specific associated subtypes being CN I and CN II Analyses were reported separately for each indication and some analyses were reported per indication (sub)type. Some analyses were performed according to cohorts that were defined in the previous HEP001 study and based on: • Theoretical assigned dose group: low dose cohort (12.5x10^6 cells/kg), intermediate dose (50x10^6 cells/kg) and high dose (200x10^6 cells/kg). • Weight: cohort > 20 kg, cohort ≥ 10 kg-20 kg and cohort < 10 kg. • Age at the time of the first treatment infusion: Age cohort ≤ 12 years and age cohort > 12 years

    Subject analysis sets values
    		 Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Number of subjects
    5
    12
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
    11
        Adolescents (12-17 years)
    6
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.1 ± 5.6
    ±
    Gender categorical
    Units: Subjects
        Female
    9
        Male
    8
    Cognitive assessment (Wechsler scores)
    Units: Subjects
        WPPSI
    1
    1
        WISC
    1
    1
        WAIS
    0
    2
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    34.91 ± 21.62
    ±
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    128.97 ± 27.03
    ±
    Head circumference
    Units: centimetre
        arithmetic mean (standard deviation)
    49.14 ± 3.41
    ±

    End points

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    End points reporting groups
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study

    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    		 CN pediatric patients presenting with Crigler-Najjar syndrome type I or type II (poorly controlled under phenobarbital treatment or experiencing serious impairment in QoL) in the former interventional clinical HEP001 study
    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    		 UCD pediatric patients diagnosed with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD) in the former interventional clinical HEP001 study

    Subject analysis set title
    Pediatric patients suffering from CN
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set: All patients included in this follow-up study were analyzed. The following subgroups have been considered for the analysis: • The study population includes 2 types of indication: o patients suffering from UCD with specific associated subtypes being UCD NAGS, UCD CPS I, UCD OTC, UCD ASS, UCD ASL and UCD Arginase o patients suffering from CN with specific associated subtypes being CN I and CN II Analyses were reported separately for each indication and some analyses were reported per indication (sub)type. Some analyses were performed according to cohorts that were defined in the previous HEP001 study and based on: • Theoretical assigned dose group: low dose cohort (12.5x10^6 cells/kg), intermediate dose (50x10^6 cells/kg) and high dose (200x10^6 cells/kg). • Weight: cohort > 20 kg, cohort ≥ 10 kg-20 kg and cohort < 10 kg. • Age at the time of the first treatment infusion: Age cohort ≤ 12 years and age cohort > 12 years

    Subject analysis set title
    Pediatric patients suffering from UCD
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set: All patients included in this follow-up study were analyzed. The following subgroups have been considered for the analysis: • The study population includes 2 types of indication: o patients suffering from UCD with specific associated subtypes being UCD NAGS, UCD CPS I, UCD OTC, UCD ASS, UCD ASL and UCD Arginase o patients suffering from CN with specific associated subtypes being CN I and CN II Analyses were reported separately for each indication and some analyses were reported per indication (sub)type. Some analyses were performed according to cohorts that were defined in the previous HEP001 study and based on: • Theoretical assigned dose group: low dose cohort (12.5x10^6 cells/kg), intermediate dose (50x10^6 cells/kg) and high dose (200x10^6 cells/kg). • Weight: cohort > 20 kg, cohort ≥ 10 kg-20 kg and cohort < 10 kg. • Age at the time of the first treatment infusion: Age cohort ≤ 12 years and age cohort > 12 years

    Primary: Long-term safety profile of HepaStem

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    End point title
    		 Long-term safety profile of HepaStem [1]
    End point description
    The primary endpoint was to characterize the long-term safety profile of HepaStem. Safety was assessed by evaluating the following parameters: • Physical examination • Vital signs • Laboratory tests • Liver tumor marker • Autoimmune markers related to liver pathology • Anti-human leucocyte antigen (HLA) antibodies specific for donor cell haplotypes • Morphology of liver, bile ducts and portal system by ultrasound • Morphology of the kidneys by ultrasound • Non-serious or serious adverse events of special interest (AESI) and serious adverse events (SAEs) related to HepaStem therapy
    End point type
    Primary
    End point timeframe
    During a period up to a maximum of 48 months (4 years) in the SAF001 study (SAF001 Year 1 + Year 2 + Year 3 + Year 4)
    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: Only descriptive analysis has been done, not possible to enter descriptive analysis in system
    End point values
    		 Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Number of subjects analysed
    5
    12
    Units: Absolute (n) and relative (%) frequency
    5
    12
    No statistical analyses for this end point

    Secondary: Long-term disease evolution and general safety after having received HepaStem

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    End point title
    		 Long-term disease evolution and general safety after having received HepaStem
    End point description
    The secondary endpoints were to characterize the disease evolution and the general safety post HepaStem infusion through the evaluation of the report on cognitive skills, behavior, and health-related QoL indicators, and the frequency and severity of metabolic decompensation reported as AESI. The general safety was also evaluated based on the following parameters: For CN patients: •Metabolic parameters: serum total and unconjugated bilirubin levels •Report on supportive treatment and any adjustment of phototherapy and medication For UCD patients: •Metabolic parameters: ammonia values, amino acids in plasma (alanine, arginine, citrulline, glutamine and argininosuccinate acid for UCD ASL patients only), orotic acid in urine (for UCD OTC patients only), argininosuccinate acid in urine (for UCD ASL patients only) •Report on supportive treatment and any adjustment of diet (natural protein intake, total protein intake, amino acid supplements) and medication (e.g., nitrogen scavengers)
    End point type
    Secondary
    End point timeframe
    During a period up to a maximum of 60 months post HepaStem infusion (HEP001 study + SAF001 year 1 + year 2 + year 3 + year 4)
    End point values
    		 Pediatric patients suffering from CN
    Number of subjects analysed
    17 [2]
    Units: Absolute (n) and relative (%) frequency
    17
    Notes
    [2] - Descriptive analysis
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Each patient was to be followed up for a maximum of 48 months. For each patient, the entire period of follow-up post HepaStem infusion could then be up to a maximum of 60 months (HEP001 study + 4 years in SAF001).
    Adverse event reporting additional description
    Only SAEs or AESIs were reported in this study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Pediatric patients suffering from UCD or CN
    Reporting group description
    		 -

    Serious adverse events
    		 Pediatric patients suffering from UCD or CN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 17 (70.59%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mycosis fungoides
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Loss of consciousness
    Additional description: Mycosis fungoides
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperammonaemia
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences causally related to treatment / all
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pediatric patients suffering from UCD or CN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 17 (70.59%)
    Investigations
    Amino acid level increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    HLA marker study positive
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mycosis fungoides
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    5
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Infections and infestations
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Otitis externa
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Staphylococcal infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2013
    Amendment A (Protocol version 2.0 dated 05-Dec-2013): • To allow all patients who received HepaStem infusion to be included in the study (modification of study title, primary objective, inclusion criteria) • To justify more precisely the maintenance of a low level of immunosuppression following HepaStem therapy, and to define, on the request of ANSM (French regulatory authority), rules to stop or adapt the immunosuppressive regimen rules • To adapt the procedures: o use of a notebook to record relevant information in between visits in order to detect AE of special interest o specifications of physical examination and vital signs measurements o addition of 2 psychological assessments (WAIS for patients who turned 18 years old and the Leiter International Performance Scale for children and adult patients who are cognitively delayed, non-English speaking, hearing impaired, speech impaired, or autistic) and a behavioral psychological assessments for patients who turned 18 years old, o addition of a statement to allow collection of essential information in terms of cell engraftment (collection of liver samples from the exograft in case of premature discontinuation because of a liver transplantation) o addition of definitions for metabolic decompensation to clarify AESI o deletion of some information about efficacy parameters • To described in more details the primary objective in order to be in alignment with the assessments previously approved by the EC/Health Authority • To clarify the frequency of interim analyses • To update the number of pediatric patients (from 18 to 20 patients)
    14 Jul 2016
    Amendment B (Protocol version 3.0 dated 14-Jul-2016): • To clarify the procedure of consent for minors or adults legally incapable • To specify how the decision to maintain the immunosuppressive treatment should be taken (by the investigator, in agreement with the patient’s family, based on the clinical condition / evolution of the patient) • To clarify some procedures (identity of the proteins measured by serum protein electrophoresis was clarified; precision on the baseline visit in case of the patient was not enrolled within 4 weeks after the last visit of the former study) • To ensure that previous infusions of HepaStem do not impact in any way the outcome of OLT, a last visit after OLT including examinations and OLT questionnaire completion was added • To specify the outsourcing of monitoring activities

    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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