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    Clinical Trial Results:
    A prospective, open label, multicountry, efficacy and safety study of several infusions of HepaStem in Urea Cycle Disorders pediatric patients.

    Summary
    EudraCT number
    2014-000650-11
    Trial protocol
    BE   ES   FR   PL  
    Global end of trial date
    28 Sep 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)
    Efficacy
    Safety
    Conclusion

    Trial information

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    Trial identification
    Sponsor protocol code
    HEP002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02489292
    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
    04 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate the functional efficacy of HepaStem at 6 months after initiation of infusion in terms of ureagenesis improvement based on a functional test (13C tracer method).
    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. Recruitment was to be split into 2 periods. A first period was planned to confirm the benefit risk ratio in 5 patients before resuming recruitment (i.e., a stopping rule was introduced as a particular measure to protect pediatric patients: If the positive benefit risk ratio for the study was confirmed after the first five patients having completed follow-up (FU) visit 3 (6 months post first infusion), the study was to be continued). The decision to prematurely stop the study occurred before the end of the first recruitment period. All the appropriate measures were taken to minimize the known risks for the patient as well as pain and distress. A data safety monitoring board (DSMB) was appointed to review safety data periodically and determine whether subjects were exposed to unnecessary risks. A Data Review Committee (DRC) composed of external experts in metabolic diseases was appointed to evaluate whether there was a clinical improvement or not based on a complete blinded file of each patient after 6 and 12 months of initiation of HepaStem therapy.
    Background therapy
    Patients included in the study were pediatric patients with UCD, aged below 12 years prior to infusion, presenting one of the UCDs defined in the protocol (carbamoylphosphate synthetase I [CPS I] deficiency [CPSID], ornithine transcarbamylase [OTC] deficiency [OTCD], argininosuccinic acid synthetase [ASS] deficiency [ASSD], argininosuccinic acid lyase [ASL] deficiency [ASLD], arginase [ARG] deficiency [ARGD]). Patients had severe disease with impaired protein tolerance defined as: chronic protein restricted diet AND chronic treatment with at least one nitrogen scavenger and showed patency of the portal vein and its branches including mesenteric veins, with normal flow velocity as confirmed by Doppler US and accessibility of the portal vein and/ or affluent.
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    9 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 4
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    6
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    •Pediatric patient < 12 years prior to infusion. •Presenting with one of the Urea Cycle Disorders: CPSID, OTCD, ASSD, ASLD, ARGD •Having severe disease with impaired protein tolerance •Showing patency of the portal vein and its branches with normal flow velocity as confirmed by Doppler US and accessibility of the portal vein and/ or affluent

    Pre-assignment
    Screening details
    Participation to this study was voluntary. During the Screening period (1 to 4 weeks maximum), the patient eligibility was assessed and the investigator ensured that the chronic metabolic treatment was optimized for the patient’s metabolic condition (confirmed in writing).

    Period 1
    Period 1 title
    Screening period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    Single arm - Screening Visit
    Arm description
    During this period, the patient eligibility was assessed and the investigator ensured that the chronic metabolic treatment was optimised for the patient’s metabolic condition (confirmed in writing). The patient’s eligibility was thereafter confirmed by the sponsor’s medical monitor.
    Arm type
    Experimental

    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
    Planned daily dose: 12.5 x 10^6 cells/kg body weight (4 infusions foreseen). Planned total target dose: 50 x 10^6 cells/kg body weight.

    Number of subjects in period 1
    Single arm - Screening Visit
    Started
    6
    Completed
    6
    Period 2
    Period 2 title
    Baseline period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Single arm - Baseline Visit 1
    Arm description
    This period consisted of 3 visits (BL visit 1 to BL visit 3) during which the 13C tracer method tests were performed to assess the metabolic condition.
    Arm type
    Experimental

    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
    Planned daily dose: 12.5 x 10^6 cells/kg body weight (4 infusions foreseen). Planned total target dose: 50 x 10^6 cells/kg body weight.

    Arm title
    Single arm - Baseline Visit 2
    Arm description
    -
    Arm type
    Experimental

    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
    Planned daily dose: 12.5 x 10^6 cells/kg body weight (4 infusions foreseen). Planned total target dose: 50 x 10^6 cells/kg body weight.

    Arm title
    Single arm - Baseline Visit 3
    Arm description
    -
    Arm type
    Experimental

    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
    Planned daily dose: 12.5 x 10^6 cells/kg body weight (4 infusions foreseen). Planned total target dose: 50 x 10^6 cells/kg body weight.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: before baseline period is a screening period to verify inclusion/exclusion criteria
    Number of subjects in period 2
    Single arm - Baseline Visit 1 Single arm - Baseline Visit 2 Single arm - Baseline Visit 3
    Started
    6
    6
    6
    Completed
    6
    6
    6
    Period 3
    Period 3 title
    Active treatment period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    Single arm - Active treatment period
    Arm description
    This period was subdivided in a permanent mesenteric portal access and catheter (PAC) placement period and in an infusion period. During the infusion period, HepaStem was to be administered in addition to the conventional UCD treatment, with a total target dose of 50*10^6 cells/kg body weight (BW). Although 2 potential methods of HepaStem infusion were described in the protocol, HepaStem was administered through a PAC for all patients (therefore only this method is described in the present report). The patients were to receive a daily dose of 12.5*10^6 cells/kg BW of HepaStem on each infusion day. HepaStem was to be administered on 4 infusion days, spread over an 8-week period with an interval of 2 weeks (± 3 days) between infusion days. During the baseline and active treatment periods, the chronic metabolic treatment of the patient (adjusted to BW) was to remain stable according to medical practice unless changes were needed for safety reason.
    Arm type
    Experimental

    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
    Planned daily dose: 12.5 x 10^6 cells/kg body weight (4 infusions foreseen). Planned total target dose: 50 x 10^6 cells/kg body weight.

    Number of subjects in period 3
    Single arm - Active treatment period
    Started
    6
    Completed
    3
    Not completed
    3
         Physician decision
    1
         Comedication (bivalirudine) no longer available
    2
    Period 4
    Period 4 title
    Follow-up period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    Single arm - Follow-up Month 3
    Arm description
    Starting approximately 12 weeks after the first HepaStem infusion day, this period was to last about 9 months with study visits taking place every 6 weeks (FU visits 1 to 7). 13C tracer method tests were to be performed every 3 month post first infusion. After any change, an additional control visit was to be organized at least within 15 days for controlling the metabolic parameters of the patient. At each visit, the reasons for adapting or not the supportive treatment were documented in the eCRF. For each patient, the maximum duration of the study was foreseen to be ~17 months.
    Arm type
    Experimental

    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
    Planned daily dose: 12.5 x 10^6 cells/kg body weight (4 infusions foreseen). Planned total target dose: 50 x 10^6 cells/kg body weight.

    Number of subjects in period 4
    Single arm - Follow-up Month 3
    Started
    3
    Completed
    2
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    -

    Reporting group values
    Baseline period Total
    Number of subjects
    6 6
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    6 6
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    6.8 ± 3.4 -
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    3 3
    Weight
    Note: n=5 for Included Set
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    ± -
    Height
    Note: n=5 for Included Set
    Units: centimetre
        arithmetic mean (standard deviation)
    ± -
    Head circumference
    Note: n=3 for Included Set
    Units: centimetre
        arithmetic mean (standard deviation)
    ± -
    AUC 0-120 min for 13C Blood urea concentration
    Units: min*µmol/L
        median (full range (min-max))
    -
    Total protein intake
    Units: mg/kg/day
        median (full range (min-max))
    -
    Natural protein intake
    Units: mg/kg/day
        median (full range (min-max))
    -
    Subject analysis sets

    Subject analysis set title
    Included Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The included set (IS) consisted of all patients who signed an informed consent and performed at least one baseline (BL) visit.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Set (SS) included all patients from the Included Set (IS) who received at least one infusion of HepaStem.

    Subject analysis sets values
    Included Set Safety Set
    Number of subjects
    6
    3
    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)
    6
    3
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    6.8 ± 3.4
    5.7 ± 4.1
    Gender categorical
    Units: Subjects
        Female
    3
    0
        Male
    3
    3
    Weight
    Note: n=5 for Included Set
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    21.48 ± 7.64
    21.13 ± 10.36
    Height
    Note: n=5 for Included Set
    Units: centimetre
        arithmetic mean (standard deviation)
    111.2 ± 18.5
    107.1 ± 22.7
    Head circumference
    Note: n=3 for Included Set
    Units: centimetre
        arithmetic mean (standard deviation)
    50.67 ± 0.58
    50.67 ± 0.58
    AUC 0-120 min for 13C Blood urea concentration
    Units: min*µmol/L
        median (full range (min-max))
    33.39 (13.07 to 70.02)
    Total protein intake
    Units: mg/kg/day
        median (full range (min-max))
    1010.6 (470 to 1309)
    820.0 (470 to 987)
    Natural protein intake
    Units: mg/kg/day
        median (full range (min-max))
    743.4 (0 to 1160)
    600 (0 to 836)

    End points

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    End points reporting groups
    Reporting group title
    Single arm - Screening Visit
    Reporting group description
    During this period, the patient eligibility was assessed and the investigator ensured that the chronic metabolic treatment was optimised for the patient’s metabolic condition (confirmed in writing). The patient’s eligibility was thereafter confirmed by the sponsor’s medical monitor.
    Reporting group title
    Single arm - Baseline Visit 1
    Reporting group description
    This period consisted of 3 visits (BL visit 1 to BL visit 3) during which the 13C tracer method tests were performed to assess the metabolic condition.

    Reporting group title
    Single arm - Baseline Visit 2
    Reporting group description
    -

    Reporting group title
    Single arm - Baseline Visit 3
    Reporting group description
    -
    Reporting group title
    Single arm - Active treatment period
    Reporting group description
    This period was subdivided in a permanent mesenteric portal access and catheter (PAC) placement period and in an infusion period. During the infusion period, HepaStem was to be administered in addition to the conventional UCD treatment, with a total target dose of 50*10^6 cells/kg body weight (BW). Although 2 potential methods of HepaStem infusion were described in the protocol, HepaStem was administered through a PAC for all patients (therefore only this method is described in the present report). The patients were to receive a daily dose of 12.5*10^6 cells/kg BW of HepaStem on each infusion day. HepaStem was to be administered on 4 infusion days, spread over an 8-week period with an interval of 2 weeks (± 3 days) between infusion days. During the baseline and active treatment periods, the chronic metabolic treatment of the patient (adjusted to BW) was to remain stable according to medical practice unless changes were needed for safety reason.
    Reporting group title
    Single arm - Follow-up Month 3
    Reporting group description
    Starting approximately 12 weeks after the first HepaStem infusion day, this period was to last about 9 months with study visits taking place every 6 weeks (FU visits 1 to 7). 13C tracer method tests were to be performed every 3 month post first infusion. After any change, an additional control visit was to be organized at least within 15 days for controlling the metabolic parameters of the patient. At each visit, the reasons for adapting or not the supportive treatment were documented in the eCRF. For each patient, the maximum duration of the study was foreseen to be ~17 months.

    Subject analysis set title
    Included Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The included set (IS) consisted of all patients who signed an informed consent and performed at least one baseline (BL) visit.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Set (SS) included all patients from the Included Set (IS) who received at least one infusion of HepaStem.

    Primary: Ureagenesis improvement at 6 months post first infusion day (follow-up [FU] visit 3)

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    End point title
    Ureagenesis improvement at 6 months post first infusion day (follow-up [FU] visit 3) [1]
    End point description
    The primary endpoint was evaluated using the absolute 13C blood urea area under the drug concentration-time curve calculated between 0 and 120 minutes, AUC(0-120 min), quantified with the 13C tracer method at FU visit 3 and comparing it with baseline (BL) evaluations (measurements at the 3 visits occurring during the BL period). 13C blood urea concentration (C) was measured in plasma before and 30, 60, 90 and 120 minutes after ingestion of 27 mg/kg solution of [1-13C] sodium-acetate at each assessment visits. The AUC(0-120 min) was calculated by linear trapezoidal rule. AUC was considered as missing for a specific visit if any 13C blood urea concentration was not available at any time point. The 13C blood urea concentration at each time-point and the AUC(0-120 min) are summarized by study visit. Individual medians per study period for the AUC(0-120 min) are also summarized by study periods.
    End point type
    Primary
    End point timeframe
    At 6 months post first infusion day (FU visit 3)
    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 analysis only
    End point values
    Single arm - Baseline Visit 1 Single arm - Baseline Visit 2 Single arm - Baseline Visit 3
    Number of subjects analysed
    3
    3
    3
    Units: min*µmol/L
        median (full range (min-max))
    20.78 (11.96 to 70.02)
    33.39 (13.07 to 80.75)
    57.03 (38.78 to 65.37)
    Attachments
    Primary efficacy
    No statistical analyses for this end point

    Secondary: Ureagenesis improvement at 3, 9, and 12 months post first infusion day (FU visits 1, 5, and 7)

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    End point title
    Ureagenesis improvement at 3, 9, and 12 months post first infusion day (FU visits 1, 5, and 7)
    End point description
    End point type
    Secondary
    End point timeframe
    At 3, 9, and 12 months post first infusion day (FU visits 1, 5, and 7)
    End point values
    Single arm - Baseline Visit 1 Single arm - Baseline Visit 2 Single arm - Baseline Visit 3 Single arm - Follow-up Month 3
    Number of subjects analysed
    3
    3
    3
    2
    Units: min*µmol/L
        median (full range (min-max))
    20.78 (11.96 to 70.02)
    33.39 (13.07 to 80.75)
    57.03 (37.78 to 65.37)
    68.00 (61.71 to 74.28)
    Attachments
    Secondary efficacy
    No statistical analyses for this end point

    Secondary: Chronic protein intake

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    End point title
    Chronic protein intake
    End point description
    Chronic (total and natural) protein intake reported as compared to World health organization (WHO) safe level for age. Global energy balance was evaluated based on a diet evaluation performed at each visit of the baseline period and at each visit of the FU period. For the diet evaluation, parents were requested to fill-in diet sheets for 3 days before the visit, using paper forms. The dietician (or other qualified health care professional) evaluated the total protein intake and natural protein intake based on the weight of the patient measured at the study visit (“reported diet”). In parallel, the prescribed dose of protein (total protein and natural protein) was collected at each study visit (“prescribed diet”) in order to check compliance to treatment.
    End point type
    Secondary
    End point timeframe
    At study visits during BL period and at scheduled study visits during the FU period.
    End point values
    Single arm - Baseline Visit 1 Single arm - Baseline Visit 2 Single arm - Baseline Visit 3 Single arm - Follow-up Month 3
    Number of subjects analysed
    3
    3
    3
    3
    Units: mg/kg/day
    arithmetic mean (standard deviation)
        Total protein intake
    758.9 ± 263.8
    762.1 ± 297.4
    752.8 ± 141.7
    616.2 ± 107.8
        Natural protein intake
    478.5 ± 430.8
    478.5 ± 430.8
    422.2 ± 367.2
    273.1 ± 386.2
    No statistical analyses for this end point

    Secondary: Chronic nitrogen scavenger dose

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    End point title
    Chronic nitrogen scavenger dose
    End point description
    The dose of each nitrogen scavenger was collected at each study visit (expressed in mg/day).
    End point type
    Secondary
    End point timeframe
    At scheduled study visits during BL period and at scheduled study visits during the FU period
    End point values
    Single arm - Baseline Visit 1 Single arm - Baseline Visit 2 Single arm - Baseline Visit 3 Single arm - Active treatment period Single arm - Follow-up Month 3
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: mg/kg/day
        number (not applicable)
    318
    318
    318
    318
    318
    Attachments
    Nitrogen scavenger
    No statistical analyses for this end point

    Secondary: Blood ammonia

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    End point title
    Blood ammonia
    End point description
    Blood samples were taken to measure blood ammonia (fasting and 2 hours post-prandial NH3)
    End point type
    Secondary
    End point timeframe
    At scheduled study visits during screening and BL periods and at scheduled study visits during the FU period
    End point values
    Single arm - Screening Visit Single arm - Baseline Visit 1 Single arm - Baseline Visit 2 Single arm - Baseline Visit 3 Single arm - Active treatment period Single arm - Follow-up Month 3
    Number of subjects analysed
    3
    3
    6
    6
    3
    3
    Units: µmol/L
        number (not applicable)
    60.5
    55
    43.3
    45.6
    46
    52.5
    Attachments
    Blood ammonia
    No statistical analyses for this end point

    Secondary: Blood amino acids

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    End point title
    Blood amino acids
    End point description
    Blood samples were taken to measure amino acid values during screening, BL and FU periods. Aminoacidogram was performed in fasting condition.
    End point type
    Secondary
    End point timeframe
    At scheduled study visits during screening and BL periods and at scheduled study visits during the FU period
    End point values
    Single arm - Screening Visit Single arm - Baseline Visit 1 Single arm - Baseline Visit 2 Single arm - Baseline Visit 3 Single arm - Active treatment period Single arm - Follow-up Month 3
    Number of subjects analysed
    3
    3
    3
    3
    2
    2
    Units: µmol/L
    number (not applicable)
        Glutamine
    715.655
    571
    490
    531
    986
    892.55
        Alanine
    225.535
    339.5
    344.5
    302
    542.07
    329.965
        Citrulline
    123.425
    403.7
    216.9
    217.9
    296.515
    229.555
        Arginine
    60.35
    71.8
    84
    94
    161.415
    73.065
    Attachments
    Blood amino acids
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to one year after initiation of HepaStem infusion
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: described in the attachement

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Nov 2014
    Amendment A • Following the Paediatric Committee within the European Medicines Agency (PDCO) request and available results from the HEP001 study: o The evaluation of the primary objective was based on biochemical parameters rather than functional parameters (ammonia). The primary and secondary objectives and endpoints were updated accordingly as well as the procedures (laboratory assessments), the rationale for sample size and the planned statistical analysis. o The rational for the new schedule of administration (4 infusions spread over a 2-month period) was updated. • Based upon the results from the HEP001 study which suggested a better efficacy in younger patients, the inclusion was restricted to patients aged below 12 years old. • Following the ANSM (French national competent authority) comments, o The total dose to be administered was clarified. o The differences between the 2 possible methods to administer HepaStem (PAC and transient transhepatic catheter) were clarified in term of procedures and study duration. More specifically, the procedures for each method, including the specification of the catheter to be used were provided. o The study population was redefined (inclusion and exclusion criteria). o The laboratory tests to be performed as well as the time points at which they should be performed were have been updated. o The qualification and training to be followed by the investigators were specified. • The importance to accurately document the evolution of the UCD metabolic condition of each patient throughout the study duration, and to standardise documentation of evaluation was emphasised. • The definition of the pre and post-infusion time windows were clarified.
    21 Sep 2015
    Amendment B The amendment followed a consultation of the EMA Scientific Advice Committee (CHMP) where Promethera Biosciences was seeking advice on the development of HepaStem for paediatric patients with UCDs. Additionally, several physicians expert in metabolic disease were consulted. Main major changes are summarised below: • Although based on available data, the benefit risk of the study was positive; a stopping rule was introduced to protect the paediatric patients. The DSMB was to review the efficacy and safety data of the first 5 patients treated till FU visit 3 before recruiting the subsequent patients. • The primary and secondary objectives and, primary and secondary endpoints, were updated because ammonia has been shown not to be a robust primary endpoint. o The primary endpoint was thus defined as ureagenesis improvement at 6 months post first infusion and was evaluated using the absolute 13C blood urea AUC0-120 min quantified with the 13C tracer method. o The secondary objectives/endpoints were adapted following the changes in the primary endpoints. • A DRC was appointed in order to get an objective evaluation of the patients. The members of this committee reviewed the clinical and biological parameters related to the secondary objectives. • The study design was adapted and was divided in 4 periods. A screening period was defined to allow for screening of the patients and for optimising their treatment, if needed. A BL period was also defined. • BL procedures were updated. They included 3 visits (therefore 3 evaluation of the BL ureagenesis) and collect data in a prospective way over 3 months in order to assess intra-patient variability and get a robust BL evaluation. • The request to increase the daily total protein dose adjusted to BW at each visit as of FU visit 3 and the monitoring of diet was strengthened. This was to allow for assessing if the diet could be improved without worsening of the other clinical parameters.
    26 Apr 2016
    Amendment C • Stopping rules were adapted to take into account the possibility that some patients may not be eligible or would not complete the baseline period. • Some procedures were clarified: o Protein electrophoresis (following recurrent question raised by the study centres). o Use of the concomitant treatment related to study procedure (clarification of timepoints for tacrolimus and of procedures for ACT measurement in the context of bivalirudin use). o Time window for PAC placement and update regarding the choice of the catheter to be used. • The laboratory performing the 13C analyses was specified, included its localisation, in order to be compliant with ethical practice and EU directive on data privacy.
    04 Apr 2017
    This amendment was only submitted in Spain as study recruitment was stopped and only Spain still had patients participating in the study at that date. • The investigational product shipment procedure was updated. • The pharmacovigilance activities had been outsourced and the contact details for AE reporting were then updated. • A long-term safety registry had replaced the foreseen long-term FU study (SAF001) in the aim of unifying data collection with standardised outcome data across all indications targeted by HepaStem therapy. The protocol was updated accordingly.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Dec 2016
    In December 2016, the sponsor decided to prematurely stop the study in order to find a partner before resuming in the best conditions the development of HepaStem as indication for UCD. The decision to prematurely stop the study occurred before the end of the first recruitment period. A total of only 6 patients were enrolled in the study and 3 patients received HepaStem infusion. Of the 3 patients included in the Safety Set, 2 completed the infusion protocol Follow-Up period and one was prematurely discontinued. The planned interim analysis was cancelled following the premature stop of the study.
    -

    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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