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    Summary
    EudraCT Number:2022-000933-18
    Sponsor's Protocol Code Number:HLSC-UCD-02
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-04-13
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2022-000933-18
    A.3Full title of the trial
    An Open-label, Non-controlled, Multi-center, Phase 2 Study to Assess the Efficacy and Safety of Allogeneic Human Liver Stem Cells (HLSCs) in the Treatment of Pediatric Patients with Early-onset Urea Cycle Disorder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of liver stem cells in children with urea cycle disorders
    A.4.1Sponsor's protocol code numberHLSC-UCD-02
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUnicyte AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUnicyte AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUnicyte AG
    B.5.2Functional name of contact pointChief Operating Officer
    B.5.3 Address:
    B.5.3.1Street AddressAawasserstrasse 2
    B.5.3.2Town/ cityOberdorf NW
    B.5.3.3Post code6370
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+49173366 9051
    B.5.6E-mailc.buck@unicyte.ch
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/11/904, EU/3/12/971, EU/3/22/2594
    D.3 Description of the IMP
    D.3.1Product nameAllogeneic human adult liver-derived stem cells
    D.3.2Product code HLSC-001
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrahepatic use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAllogeneic Human Liver Stem Cells
    D.3.9.2Current sponsor codeHLSC-001
    D.3.9.3Other descriptive nameAllogeneic adult liver-derived stem cells
    D.3.9.4EV Substance CodeSUB204176
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Urea cycle disorders
    E.1.1.1Medical condition in easily understood language
    Genetic disorder that results in a deficiency of one of the six enzymes in the urea cycle
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10013373
    E.1.2Term Disorders of urea cycle metabolism
    E.1.2System Organ Class 200000003094
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To investigate the effect of 500,000 HLSCs (IMP HLSC-001) per g liver weight (maximum dose 100 million cells, administered by a percutaneous intrahepatic injection) on the ureagenesis capacity in pediatric patients (neonates, infants, and toddlers up to 30 months of age) with a confirmed diagnosis of urea cycle disorder (UCD) as measured by a 15N-ammonium assay (15N- test).
    • To assess the safety and tolerability of the intrahepatic HLSC injection in neonates/infants with UCD
    E.2.2Secondary objectives of the trial
    • To examine the ureagenesis capacity before and under treatment as measured by repeated 15N-tests over time (time to first capacity increase, average increase over time, maximum effect, duration of effect).
    • To record the number and severity of hyperammonemia events before and during treatment
    • To examine the capability to increase the protein diet without clinically worrisome increase in ammonium blood levels. Worrisome is an increased ammonium blood level of at least medium severity, i.e., >250 µmol/L.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Has a genetically confirmed diagnosis of any of the following urea cycle disorders: Deficiency of argininosuccinate synthase (ASS), carbamoyl-phosphate synthase 1 (CPS1), argininosuccinate lyase (ASL), ornithine transcarbamylase (OTC) – or if exact genetic diagnosis is not available, confirmed by well accepted biochemical parameters.
    2.Early-onset of UCD symptoms within the first 28 days of life (the full genetic diagnosis can be available later). In patients with a family history of UCD, a diagnosis within the first 28 days after birth without clinical symptoms also qualifies for inclusion.
    3.Male and female patients, aged up to 30 completed months at inclusion.
    4.Body weight within the 5th to 95th percentile of the corresponding age with a minimum body weight of 2900 g.
    5.Stable clinical conditions (any acute condition needs to be stabilized before inclusion).
    6.Written informed consent signed by the parent(s) or legal representative(s).
    7.Statement from the parent(s) / caregiver(s) / legal representative(s) that they will be available during the scheduled study visits and that at least 1 of the parent(s)/caregiver(s)/legal representative(s) will join the transportation of their child to the study center.
    E.4Principal exclusion criteria
    1.Severe neurological or other concomitant disorder preventing the patient from participating in the trial, according to the Investigator’s discretion
    2.Premature neonate with < 37 completed gestation weeks or a body weight at birth < 2900 g or with ongoing significant post-natal weight loss (premature neonates can be included when they are in stable clinical condition and are at least 4 weeks after the calculated Week 40 birth date).
    3.Participation in another trial with another investigational drug and a wash out phase of less than 30 days, or 5 half-lives, whichever is longer.
    4.Systemically administered corticosteroids, valproic acid, haloperidol, and any other medication with a suspected effect on the urea cycle must be discontinued whenever medically possible 3 days prior to each 15N-test and can be continued after the last blood draw of the 15N-test protocol.
    5.At high risk of complications or unsuitable for percutaneous intrahepatic HLSC injection due to a small liver size or liver malformation or liver misposition or other structural liver disorder, e.g., liver fibrosis/bridging fibrosis.
    6.Clinically relevant coagulation disorder representing a contraindication for intrahepatic injections.
    7.Treated with prohibited medication as specified in the protocol
    8.Any other disorder that would interfere with ethical standards or medical practices during the conduct of the trial according to the Investigator’s discretion.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is defined as the change of ureagenesis capacity between Baseline and Endpoint after treatment with two HLSCs injections 1 week apart in the Main Cohort. This change is determined from the average of two 15N tests at / before Baseline and the average of two 15N tests after treatment at Weeks 8 and 12 using AUC0-2 hrs blood measurements.
    Safety Endpoints:
    •Frequency and severity of adverse events (AEs) and treatment-related (TEAEs).
    •Change from Baseline in vital signs (including heart rate, blood pressure, body weight, body temperature).
    •Change in treatment regimen (except HLSC-001).
    •Change from Baseline in developmental and nutritional status.
    •Number and type of intercurrent infections / illness.
    •Change in laboratory parameters (hematology, clinical chemistry, coagulation, and disease specific biomarkers).
    •Immunogenicity/antigenicity (tested by Luminex, a specific antibody assay).
    •Histological assessment of the explanted liver using quantitative polymerase chain reaction (qPCR).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoints: 8 weeks and 12 weeks after treatment
    Safety endpoints: per protocol
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoints:
    Clinical response to treatment defined as a patient having:
    • An increase from the mean of Screening and Baseline assessments to the mean of Week 8 and Week 12 assessments in the AUC0-2 hrs of the 15N-test; and
    • No events with blood ammonium > 100 µmol/L in infants (or >150 µmol/L in neonates) between Week 1 and Week 12 after the initial HLSC treatment (each catabolic event should be reported with as much detail as possible about the potential initiating factors to allow a retrospective causal assessment of the individual case); and
    • An increase in tolerated protein diet according to age and weight after HLSC treatment
    Other Secondary Efficacy Endpoints:
    •Change from Baseline of specific biochemical parameters indicating that the deficiency of the respective urea cycle enzymes could be overcome.
    •Ureagenesis capacity over time as measured by the 15N-test:
    -Increase of 15N-urea in blood over time as measured by AUC0-2 hrs
    -Time to first increase of 15N-urea
    -Maximum concentration of 15N-urea and time point of this maximum effect
    •Time to the first hyperammonemia event > 250 µmol/L blood ammonium and the number and severity of hyperammonemia events categorized by severities
    •Change of protein intake tolerance from Baseline to the end of the trial.
    •Detection of HLSCs residing in the explanted liver after OLT using qPCR analysis.
    •Change from Baseline to End of Trial in general parameters of child development
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key Secondary Efficacy Endpoints:
    • Between 8 weeks and 12 weeks after treatment
    • Between 1 week and 12 weeks after the initial treatment
    Other Secondary Efficacy Endpoints: per protocol
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    Saudi Arabia
    Turkey
    Austria
    Belgium
    France
    Germany
    Italy
    United Kingdom
    Spain
    Switzerland
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 15
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 1
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 11
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 3
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 15
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-09-12
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-02-13
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