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    Summary
    EudraCT Number:2016-002328-10
    Sponsor's Protocol Code Number:TIGEM1-MPSVI
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-17
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-002328-10
    A.3Full title of the trial
    A Phase I/II Open Label, Dose Escalation, Safety Study in Subjects with Mucopolysaccharidosis type VI (MPS VI) Using Adeno-Associated Viral Vector 8 to Deliver the human ARSB gene to Liver.
    Studio di fase I/II in aperto per valutare la sicurezza di una terapia genica in soggetti affetti da Mucopolisaccaridosi di tipo VI usando come vettore un virus Adeno-Associato di tipo 8 contenente il gene umano ARSB.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene Therapy in patients with Mucopolysaccharidosis disease
    Terapia genica in soggetti affetti da Mucopolissacaridosi
    A.3.2Name or abbreviated title of the trial where available
    TIGEM1-MPSVI
    TIGEM1-MPSVI
    A.4.1Sponsor's protocol code numberTIGEM1-MPSVI
    A.5.4Other Identifiers
    Name:TIGEM1-MPSVINumber:TIGEM1-MPSVI
    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 SponsorFONDAZIONE TELETHON
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportComunità Europea
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFONDAZIONE TELETHON
    B.5.2Functional name of contact pointSVILUPPO CLINICO
    B.5.3 Address:
    B.5.3.1Street AddressVIA POERIO 14
    B.5.3.2Town/ cityMILANO
    B.5.3.3Post code20129
    B.5.3.4CountryItaly
    B.5.4Telephone number3386337541
    B.5.5Fax number08119230650
    B.5.6E-mailSZancan@Telethon.it
    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/3/11/864
    D.3 Description of the IMP
    D.3.1Product nameAAV2/8.TBG.hARSB
    D.3.2Product code [AAV2/8.TBG.hARSB]
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAAV2/8.TBG.hARSB
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number259000000
    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 No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    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
    The clinical trial will be conducted on patients with Mucopolysaccharidosis Type VI. MPS VI is characterized by growth retardation, corneal clouding, cardiac valve disease, organomegaly, skeletal dysplasia, without central nervous system involvement
    La Sperimentazione verrà eseguita su pazienti affetti da Mucopolissacaridosi di tipo VI. La patologia è caratterizzata da ritardo nella crescita, opacità corneale, patologie relative alla valvola cardiaca, organomegalia, displasia scheletrica, senza il coinvolgimento del sistema nervoso centrale.
    E.1.1.1Medical condition in easily understood language
    Mucopolysaccharidosis type VI,Lysosomal Storage Disorder
    Mucopolisaccaridosi di tipo VI, malattia da accumulo lisosomiale
    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 PT
    E.1.2Classification code 10059318
    E.1.2Term Hepatic cancer stage I
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10054889
    E.1.2Term Transaminases increased
    E.1.2System Organ Class 10022891 - Investigations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10037933
    E.1.2Term Reaction anaphylactic anaphylactoid
    E.1.2System Organ Class 100000004870
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10019717
    E.1.2Term Hepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety of the three different doses of drug 2x10^11 gc/kg , 6x10^11 gc/kg , 2x10^12 gc/kg
    valutare la sicurezza di tre differenti dosi di farmaco 2x10^11 gc/kg , 6x10^11 gc/kg , 2x10^12 gc/kg
    E.2.2Secondary objectives of the trial
    to investigate the efficacy of the drug
    valutare l'efficacia del farmaco
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Subjects must have a documented biochemical and molecular diagnosis of MPS VI.
    2.Subjects must be 4 years old or older.
    3.Subjects should have received Enzyme Replacement Therapy (ERT) for at least 12 months before enrolment, and should continue to receive treatment until 7-14 days before IMP administration.
    4.Documented informed consent; willingness to adhere to protocol and required long-term follow-up as evidenced by written informed consent.
    1.I soggetti devono avere una diagnosi clinica, biochimica e molecolare di MPS VI.
    2.I soggetti dovranno avere un’età superiore ai 4 anni.
    3.I soggetti dovranno riceve la Terapia Enzimatica Sostitutiva (ERT) per almeno 12 mesi prima dell’arruolamento e dovranno continuare a ricevere il trattamento fino a 7-14 giorni prima della somministrazione del farmaco sperimentale.
    4.Consenso informato firmato. Volontà ad aderire al protocollo e ad un follow-up a lungo termine.
    E.4Principal exclusion criteria
    1.Subjects unable or unwilling to meet requirements of the study.
    2.History of severe anaphylactoid reaction to Naglazyme in subjects receiving ERT that could affect the safety (severe reaction is meant to be an event with respiratory impairment that is life-threatening).
    3.Serum AST or ALT above the upper limit of normal range at the baseline evaluations (Baseline 2, -5 days).
    4. Detectable serum neutralizing antibodies (NAB) against AAV8 vector.
    1.I soggetti che non sono in grado o che non vogliono soddisfare le esigenze dello studio.
    2.La prova di una reazione anafilattica grave al Naglazyme nei soggetti trattati con ERT che potrebbe incidere sulla sicurezza (grave reazione anafilattica potrebbe tradursi anche in un evento con insufficienza respiratoria)
    3.Livelli sierici di ALT e AST al di sopra del limite massino di normalità durante le valutazioni della Baseline (3-5 giorni)
    4.La presenza nel siero di anticorpi neutralizzanti (NAB) contro il vettore AVV8.
    E.5 End points
    E.5.1Primary end point(s)
    •Overall short-term and long-term safety and tolerability measured by recording of adverse events, physical examination including vital signs, laboratory tests and liver ultrasound.
    •Inflammation of the liver, as shown by an elevation in transaminases.
    •Urinary GAG excretion levels
    •Sicurezza generale a breve e lungo termine e tollerabilità misurata dalla registrazione di eventi avversi, esami fisici inclusi i parametri vitali , esami di laboratorio ed ecografia epatica
    •Infiammazioni epatiche determinate in base ad un aumento di transaminasi.
    •Livelli di GAG urinari
    E.5.1.1Timepoint(s) of evaluation of this end point
    The safety endpoints will be monitored in the days immediately following the infusion of the drug (short-term monitoring) and during the following weeks, months and years (monitoring long-term). L 'outcome of efficacy will be evaluated during the three days post treatment and at 4 and 9 months, a year, a year and a half, two years, two and a half years and three years.
    Gli end point di sicurezza saranno monitorati nei giorni immediatamente successivi l'infusione del farmaco (monitoraggio paramentri di sicurezza a breve termine) e durante le settimane, i mesi e gli anni successivi (monitoraggio paramentri di sicurezza a lungo termine). L' end point di efficacia verrà valutato nei tre giorni èpst trattamento e a 4 e 9 mesi, un anno, un anno e mezzo, due anni, due anni e mezzo e tre anni.
    E.5.2Secondary end point(s)
    •Leukocyte ARSB levels (enzyme activity),
    •Endurance measured by 6-minute walk test (6MWT) and 3-minute stair climb test (3MSCT),
    •Forced vital capacity (FVC) and forced expiratory volume at 1 minute (FEV1) in cooperative subjects.
    •Livelli di ARSB nei leucociti (attività enzimatica),
    •Livelli di durata in termini di resistenza misurati attraverso il 6-minute walking test (6MWT) e il 3-minute stairs climbing test (3MSCT),
    •Capacità vitale forzata (FVC) e del volume espiratorio in 1 minuto (FEV1) in soggetti cooperanti.
    E.5.2.1Timepoint(s) of evaluation of this end point
    •Leukocyte ARSB levels (enzyme activity) measured at screening; the day before treatment: 3 weeks post-treatment; 10 weeks post-treatment; 14 weeks post-treatment ; 4,9,12 months post-trattamento1.5, 2, 2.5, 3 years post-treatment
    •Endurance measured by 6-minute walk test (6MWT) and 3-minute stair climb test (3MSCT) measured at baseline1; 2 days pre-treatment; 4,9,12 months post-treatment; 1.5, 2, 2.5, 3 years post-trattamento,
    •Forced vital capacity (FVC) and forced expiratory volume at 1 minute (FEV1) in cooperative subjects measured at baseline1; 1 o 2 days pre-treatment; 4,9,12 months post-treatment; 1.5, 2, 2.5, 3 years post-treatment


    •Livelli di ARSB nei leucociti (attività enzimatica) misurata allo screening; il giorno prima del trattamento; 3 settimana post-trattamento; 10 settimane post-trattamento; 14 settimane post-trattamento; 4,9,12 mesi post-trattamento; 1.5, 2, 2.5, 3 anni post-trattamento
    •Livelli di durata in termini di resistenza misurati attraverso il 6-minute walking test (6MWT) e il 3-minute stairs climbing test (3MSCT) valutati alla baseline1; 2 giorni pre-trattamento; 4,9,12 mesi post-trattamento; 1.5, 2, 2.5, 3 anni post-trattamento
    •Capacità vitale forzata (FVC) e del volume espiratorio in 1 minuto (FEV1) in soggetti cooperanti misurati alla baseline1; 1 o 2 giorni pre-trattamento; 4,9,12 mesi post-trattamento; 1.5, 2, 2.5, 3 anni post-trattamento

    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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) No
    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 No
    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.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Turkey
    Netherlands
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 2
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 3
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    F.4.2.2In the whole clinical trial 10
    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)
    It is expected a period of follow up visits at he end of treatment
    E' previsto un programma di visite di follow up al termine del trattamento.
    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 Decision2017-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-17
    P. End of Trial
    P.End of Trial StatusOngoing
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