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    Clinical Trial Results:
    Human Liver Stem Cells (HLSCs) in patients suffering from liver-based inborn metabolic diseases causing life-threatening neonatal onset of hyperammonemic encephalopathy

    Summary
    EudraCT number
    2012-002120-33
    Trial protocol
    IT  
    Global end of trial date
    18 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Aug 2021
    First version publication date
    14 Aug 2021
    Other versions
    Summary report(s)
    Intrahepatic Administration of Human Liver Stem Cells in Infants with Inherited Neonatal-Onset Hyperammonemia: A Phase I Study

    Trial information

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    Trial identification
    Sponsor protocol code
    HLSCS01-11
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
    Sponsor organisation address
    Corso Bramante 88, Torino, Italy, 10126
    Public contact
    Dr. Marco Spada, Centro Malattie Metaboliche/ Presidio Ospedaliero Regina Margherita, 39 0113135857, marco.spada@unito.it
    Scientific contact
    Dr. Marco Spada, Centro Malattie Metaboliche/ Presidio Ospedaliero Regina Margherita, 39 0113135857, marco.spada@unito.it
    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
    18 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate hepatic and extra-hepatic complications after liver intraparenchymal HLSC injection in neonates suffering from inborn liver metabolic diseases causing life-threatening neonatal-onset of hyperammonemic encephalopathy
    Protection of trial subjects
    a total of two injections was administered, the first one as soon as the patient entered the study. The second admnistration had to be performed one week after the first, only in the absence of adverse events related to the first treatment. Each patient was regularly followed for clinical and laboratory aspects. Treatment was to be terminated in the following events: completion of 2 injections, unacceptable toxicity or withdrawal of consent.
    Background therapy
    Standard of care
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Oct 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    3
    EEA total number of subjects
    3
    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)
    3
    Children (2-11 years)
    0
    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
    start date 10 Feb 2014; end date 18 Jan 2017

    Pre-assignment
    Screening details
    Inclusion criteria: neonatal-onset hyperammonemic encephalopathy; formal biochemical diagnosis of one inborn metabolic disease (CPS1-, OTC-, ASS-, PCC-, MCM-, ASL-deficiency); formal evaluation for early OLT; be referred to OIRM, Centro Malattie Metaboliche, TO; Exclusion criteria: refusal of signing informed consent; uncontrolled coagulopathy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Baseline to dose level 1
    Arm description
    baseline to subjects treated with 125,000 HLSC cells x gram of liver
    Arm type
    Experimental

    Investigational medicinal product name
    HLSC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intrahepatic use
    Dosage and administration details
    two doses of 125,000 HLSC cells x gram of liver administered at two weeks interval

    Arm title
    Baseline to dose level 2
    Arm description
    baseline to subjects treated with 250,000 HLSC cells x gram of liver
    Arm type
    Experimental

    Investigational medicinal product name
    HLSC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intrahepatic use
    Dosage and administration details
    two doses of 250,000 HLSC cells x gram of liver administered at two weeks interval

    Number of subjects in period 1
    Baseline to dose level 1 Baseline to dose level 2
    Started
    1
    2
    Completed
    1
    2
    Period 2
    Period 2 title
    treatment
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    dose level 1
    Arm description
    subjects treated with 125,000 HLSC cells x gram of liver
    Arm type
    Experimental

    Investigational medicinal product name
    HLSC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intrahepatic use
    Dosage and administration details
    two doses of 125,000 HLSC cells x gram of liver administered at two weeks interval

    Arm title
    dose level 2
    Arm description
    subjects treated with 250,000 HLSC cells x gram of liver
    Arm type
    Experimental

    Investigational medicinal product name
    HLSC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intrahepatic use
    Dosage and administration details
    two doses of 250,000 HLSC cells x gram of liver administered at two weeks interval

    Number of subjects in period 2
    dose level 1 dose level 2
    Started
    1
    2
    Completed
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    baseline
    Reporting group description
    A total of 3 subjects were screened and entered into the study. No significant differences between subjects of the two treatment groups were observed with respect to age, height and body weight. Subjects underwent a physical examination, instrumental examinations and measurement of vital signs at the screening visit. Moreover a series of pathological values were examined in order to perform the diagnosis for metabolic disease. Of note, at physical examination all patients presented hypotonia. All reported positive history for at least one abnormality at the Hematological system (anemia) and at the Neurological system (commonly hyperammonemia / hyperammonemic comas). All abnormalities were continuing at the time of the study entry, except for the neonatal hyperammonemia / hyperammonemic comas, which were resolved before the signature of the informed consent.

    Reporting group values
    baseline Total
    Number of subjects
    3 3
    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)
    3 3
        Children (2-11 years)
    0 0
        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
    A total of 3 subjects were screened. All entered into the study
    Units: months
        arithmetic mean (standard deviation)
    2.90 ± 1.62 -
    Gender categorical
    Units: Subjects
        Female
    2 2
        Male
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Baseline to dose level 1
    Reporting group description
    baseline to subjects treated with 125,000 HLSC cells x gram of liver

    Reporting group title
    Baseline to dose level 2
    Reporting group description
    baseline to subjects treated with 250,000 HLSC cells x gram of liver
    Reporting group title
    dose level 1
    Reporting group description
    subjects treated with 125,000 HLSC cells x gram of liver

    Reporting group title
    dose level 2
    Reporting group description
    subjects treated with 250,000 HLSC cells x gram of liver

    Primary: Hepatic complications

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    End point title
    Hepatic complications [1]
    End point description
    portal vein thrombosis, intrahepatic hematoma, injury of the hepatic artery, arterio-portal, portal-biliary and arterio-biliary fistula, acute hepatic cytolysis > 20 times normal, clinical and biochemical signs of liver failure (ascites, development of jaundice with conjugated bilirubin above 3 mg/dL, alterations in INR > 2.5), appearance of cancer-like liver nodular lesions
    End point type
    Primary
    End point timeframe
    from the administration of the first dose (V1) to 4 weeks after the administration of the second dose (V4).
    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: The total study population was 3 subjects. Descriptive statistics (e.g., mean, standard deviation, minimum, maximum for continuous data; frequency tables for categorical data) are provided per dose level and overall. Summary statistics were provided per dose level and overall. Summary statistics: quantitative parameters were summarized using descriptive statistics: N, Mean, Median, STD,Minimum, Maximum; qualitative parameters were summarized using frequency tables: N and percentage (%).
    End point values
    dose level 1 dose level 2
    Number of subjects analysed
    1
    2
    Units: number of events
    1
    2
    Attachments
    Untitled (Filename: Overall summary of Adverse Events.pdf)
    Untitled (Filename: Summary of Adverse Events, by patient and overall.pdf)
    Untitled (Filename: Category of Adverse Events, by patient and overall.pdf)
    No statistical analyses for this end point

    Primary: Extra-hepatic complications

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    End point title
    Extra-hepatic complications [2]
    End point description
    pulmonary embolism, significant extra-hepatic (abdominal and/or chest) haemorrhage (requiring blood transfusion and / or specific treatment), documented sepsis with bacteremia, adverse reactions to sedative drugs administered for interventional radiological procedure
    End point type
    Primary
    End point timeframe
    from the administration of the first dose (V1) to 4 weeks after the administration of the second dose (V4).
    Notes
    [2] - 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: The total study population was 3 subjects. Descriptive statistics (e.g., mean, standard deviation, minimum, maximum for continuous data; frequency tables for categorical data) are provided per dose level and overall. Summary statistics were provided per dose level and overall. Summary statistics: quantitative parameters were summarized using descriptive statistics: N, Mean, Median, STD,Minimum, Maximum; qualitative parameters were summarized using frequency tables: N and percentage (%).
    End point values
    dose level 1 dose level 2
    Number of subjects analysed
    1
    2
    Units: number of events
    1
    2
    Attachments
    Overall summary of Adverse Events
    Summary of Adverse Events, by patient and overall
    Category of Adverse Events, by patient and overall
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    adverse events assessment started at baseline (signature of Informed Consent) and ended at the last visit (V4), 4 weeks after the administration of last dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    dose level 1
    Reporting group description
    subjects with two doses of 125,000 HLSC cells x gram of liver, administered at 2 weeks interval

    Reporting group title
    dose level 2
    Reporting group description
    subjects with two doses of 250,000 HLSC cells x gram of liver, administered at 2 weeks interval

    Serious adverse events
    dose level 1 dose level 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    dose level 1 dose level 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 2 (100.00%)
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Agitation neonatal
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 2 (100.00%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2014
    n. 1 : to include into the study patients affected by Deficiency of argininosuccinate lyase (ASL) (protocol Version 1.2 26 aug 2014)
    08 Jun 2016
    n. 2: to extend product expiration date to 36 months (IMPD Quality Report HLSCs_Drug substance and drug product”, Vers. Final 1.1_17.02.16)

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/31792768
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