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    Summary
    EudraCT Number:2017-000852-24
    Sponsor's Protocol Code Number:15/0552
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-18
    Trial results View 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 number2017-000852-24
    A.3Full title of the trial
    A Phase I/II, Open label, Multicentre, Ascending Single Dose, Safety Study of a Novel Adeno-associated Viral Vector (FLT180a) in Patients With Haemophilia B
    Studio di sicurezza, di fase I/II, in aperto, multicentrico, a incremento di dose singola su un nuovo vettore virale adeno-associato (FLT180a) in pazienti affetti da emofilia B
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Factor IX Gene Therapy Study (FIX-GT)
    Studio Teraopia genica actor IX (FIX-GT)
    A.3.2Name or abbreviated title of the trial where available
    A Factor IX Gene Therapy Study (FIX-GT)
    Studio Terapia Genica Factor IX (FIX-GT)
    A.4.1Sponsor's protocol code number15/0552
    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 SponsorUNIVERSITY COLLEGE LONDON
    B.1.3.4CountryUnited Kingdom
    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 supportFreeline Therapeutics Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London
    B.5.2Functional name of contact pointRegulatory Manager
    B.5.3 Address:
    B.5.3.1Street AddressJoint Research Office, UCL, Gower
    B.5.3.2Town/ cityLondra
    B.5.3.3Post codeWC1E 6BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number000000000
    B.5.5Fax number000000000
    B.5.6E-mailCTIMPS@ucl.ac.uk
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFTL180a
    D.3.2Product code FTL180a
    D.3.4Pharmaceutical form Concentrate for 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 codeFLT180A
    D.3.9.3Other descriptive nameFLT180A
    D.3.9.4EV Substance CodeSUB187364
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number2 to 4
    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
    Haemophilia B
    Emofilia B
    E.1.1.1Medical condition in easily understood language
    hereditary bleeding disorder caused by a lack of blood clotting factor
    Disordine ereditario emorragico causato da una carenza del fattore di coagulazione
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10018939
    E.1.2Term Haemophilia B (Factor IX)
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Safety
    To assess the safety of systemic administration of FLT180a in adults with haemophilia
    B (HB) at up to 3 different dose cohorts.
    Efficacy
    To assess Factor IX (FIX) levels following systemic administration of FLT180a, at the
    terminal dose level.
    Sicurezza
    Valutare la sicurezza della somministrazione sistemica di FLT180a negli adulti con
    emofilia B (HB) fino a 3 diverse coorti di dose.
    Efficacia
    Valutare i livelli di Fattore IX (FIX) in seguito alla somministrazione sistemica di
    FLT180a, al livello di dose terminale
    E.2.2Secondary objectives of the trial
    To investigate the endogenous production of FIX following systemic administration of
    FLT180a at up to 3 different dose cohorts.
    To investigate the effectiveness of a single administration of FLT180a on annualised
    bleeding rate and exogenous FIX consumption.
    To assess the immune response to the FIX transgene product following systemic
    administration of FLT180a.
    To assess viral shedding in various body fluids after systemic administration of
    FLT180a.
    Studiare la produzione endogena di FIX seguendo la somministrazione sistemica di
    FLT180a fino a 3 diversi coorti di dose.
    Studiare l'efficacia di una singola somministrazione di FLT180a sul tasso di
    sanguinamento annualizzato e sul consumo di FIX esogeno.
    Valutare la risposta immunitaria al prodotto transgenico FIX in seguito alla
    somministrazione sistemica di FLT180a.
    Valutare la dispersione virale in vari fluidi corporei dopo la somministrazione
    sistemica di FLT180a.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Adults males, = 18 years of age;
    2.Confirmed diagnosis of HB defined as one of the following:
    (a)Documented severe FIX deficiency with plasma FIX activity of <1% of normal or
    (b)moderately severe FIX deficiency with plasma FIX activity level between =1% and =2% and a severe bleeding phenotype defined by one of the following:
    (i) On prophylaxis for a history of bleeding, or
    (ii) On-demand therapy with a history of 4 or more bleeding episodes/year on average over the past 3 years, or
    (iii) Evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion).
    3.Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up;
    4.Willing to practice barrier contraception until at least two consecutive semen samples after vector administration are negative for vector sequences;
    5.Lack of neutralising anti-AAV-S3 antibodies using an in-vivo transduction inhibition assay within 4 weeks of vector administration;
    6.At least 150 exposure days to FIX concentrates.
    1.Soggetti di sesso maschile di età pari o superiore a 18 anni
    2.Diagnosi confermata di HB definita da una delle seguenti condizioni:
    (a)Carenza FIX grave documentata con un'attività FIX nel plasma <1% del valore normale o
    (b) carenza FIX moderatamente grave con livelli di attività FIX nel plasma compresi tra =1% e =2% e un fenotipo emorragico grave definito da uno dei seguenti elementi:
    (i) profilassi in corso per precedenti emorragie oppure
    (ii) terapia al bisogno con anamnesi di 4 o più episodi emorragici/anno in media negli ultimi 3 anni oppure
    (iii) evidenza di artropatia emofilica cronica (dolore, distruzione articolare e perdita del range di movimento).
    3.Capacità di fornire il pieno consenso informato e di soddisfare tutti i requisiti dello studio, incluso il follow-up a lungo termine di 15 anni.
    4.Disponibilità a utilizzare un metodo contraccettivo a barriera fino a quando almeno due campioni di sperma consecutivi dopo la somministrazione del vettore siano negativi per le sequenze di vettori.
    5.Assenza di anticorpi neutralizzanti anti-AAV-S3 utilizzando un test di inibizione della trasduzione in-vivo entro 4 settimane dalla somministrazione del vettore.
    6.Almeno 150 giorni di esposizione a concentrati FIX.
    E.4Principal exclusion criteria
    1.Presence of neutralising anti-human FIX antibodies (inhibitor, determined by the
    Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX
    inhibitor;
    2.Patients at high risk of thromboembolic events (high risk patients would include those
    with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis,
    pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired
    thrombophilia including conditions such as atrial fibrilation);
    3.Use of investigational therapy for haemophilia within 30 days before enrolment;
    4.Patients with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity,
    respectively, or currently on antiviral therapy for hepatitis B or C. (Negative viral
    assays in 2 samples, collected at least 6 months apart, will be required to be
    considered negative. Both natural clearers and those who have cleared HCV on antiviral
    therapy are eligible.);
    5. Serological evidence of HIV-1
    6.Evidence of liver dysfunction (persistently elevated alanine aminotransaminase,
    aspartate aminotransferase, bilirubin >1.5 x upper limit of normal);
    7.Platelet count <50x109/L;
    8.Uncontrolled glaucoma, diabetes mellitus, or hypertension;
    9.Malignancy requiring treatment;
    10.Patients with uncontrolled cardiac failure or unstable angina or myocardial infaction
    in the past 6 months;
    11.Poor performance status (World Health Organization score >1);
    12.Prior treatment with any gene transfer medicinal product;
    13.Known or suspected intolerance hypersensitivity or contraindicationto the
    investigational product and non-investigational product or their excipients.
    14.Planned major elective surgery prior to the end of trial.
    15. Current or relevant history of a physical of psychiatric illness or any medical
    condition that in the opinion of the investigator could affect the patients safety or
    interfere with the study assessments.
    16. CMV IgG postive patients who are CMV PCR positive at screening
    1.Presenza di anticorpi anti-FIX umano neutralizzanti (inibitore, determinato dal test
    della presenza di inibitori secondo il metodo di Bethesda) al momento dell'arruolamento
    o precedente anamnesi di inibitore FIX.
    2.Pazienti ad alto rischio di eventi tromboembolici (pazienti ad alto rischio
    includerebbe quelli con una storia di tromboembolia arteriosa o venosa (es. Trombosi
    venosa profonda, embolia polmonare, ictus non emorragico, embolia arteriosa) e quelli
    con trombofilia acquisita incluse condizioni come fibrillazione atriale)
    3.Utilizzo di una terapia sperimentale per l'emofilia nei 30 giorni precedenti
    l'arruolamento.
    4.Pazienti con epatite B o C attiva, e HBsAg positivo o HCV RNA positivo,
    rispettivamente, o in terapia antivirale per epatite B o C al momento dello screening.
    Sono da considerarsi negativi i test virali negativi di 2 campioni prelevati ad almeno 6
    mesi di distanza. Sono idonei sia coloro che hanno eliminato l'HCV in modo spontaneo sia
    coloro che l'hanno eliminato con la terapia antivirale.
    5. Evidenza sierologica di HIV-1.
    6.Evidenza di disfunzione epatica (alanina aminotransaminasi elevata persistente,
    aspartato aminitransferasi, bilirubina>1,5 volte il limite superiore di normalità).
    7.Conta piastrinica <50x109/l.
    8.Glaucoma, diabete mellito o ipertensione non controllati.
    9.Neoplasia che richiede un trattamento.
    10.Pazienti con insufficienza cardiaca o angina instabile non controllata o infarto del
    miocardio negli ultimi 6 mesi.
    11.Stato di validità insufficiente (punteggio >1 secondo l'Organizzazione Mondiale della
    Sanità).
    12.Precedente trattamento con un farmaco transgenico.
    13.Intolleranza ipersensibilità o controindicazioni note o sospette al farmaco
    sperimentale e al farmaco non sperimentale e o ai loro eccipienti.
    14.Pianificazione della chirurgia elettiva maggiore prima della fine del processo.
    15. Storia attuale o rilevante di una malattia psichiatrica fisica o di qualsiasi
    condizione medica che secondo il parere dello sperimentatore potrebbe influire sulla
    sicurezza dei pazienti o interferire con le valutazioni dello studio
    16. Pazienti con test postivo per IgG anti-CMV con PCR per CMVpositiva allo screening.
    E.5 End points
    E.5.1Primary end point(s)
    Safety
    Safety as assessed by the reporting of AEs according to Common Terminology Criteria
    for Adverse Events (CTCAE) v5.0.
    Efficacy
    The following primary endpoints will be analysed:
    1. The proportion of patients achieving clinical FIX response at Week 26, at the
    terminal dose level. A clinical FIX response is defined as achieving FIX activity of
    5% to 150%.
    2. The proportion of patients also achieving normalised FIX response at Week 26, at
    the terminal dose level. A normalised FIX response is defined as achieving FIX
    activity of in the normal range (50-150%).
    Sicurezza
    Sicurezza valutata in base agli AE segnalati in accordo ai criteri terminologici
    comuni per gli eventi avversi (Common Terminology Criteria for Adverse Events, CTCAE)
    versione 5.0.
    Efficacia
    Verranno analizzati i seguenti endpoint primari:
    1. La proporzione di pazienti che hanno ottenuto una risposta clinica FIX alla
    settimana 26, al livello di dose terminale. Una risposta FIX clinica è definita come
    il raggiungimento di un'attività FIX dal 5% al 150%.
    2. La percentuale di pazienti che ha ottenuto una risposta FIX normalizzata alla
    settimana 26, al livello di dose terminale. Una risposta FIX normalizzata è definita
    come il raggiungimento di un'attività FIX nell'intervallo normale (50-150%).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety
    Throughout the study
    Efficacy
    Week 26
    Sicurezza
    Durante lo studio
    Efficaia
    26 settimane
    E.5.2Secondary end point(s)
    Safety
    Safety as assessed by reporting of abnormal or change from baseline findings from safety assessments
    including, laboratory assessments, vital signs, ECG, physical exam and liver ultrasound.
    1. Produzione endogena di FIX (hFIX)
    2. Haemostatic effectiveness
    3. Immune response
    4. Shedding
    Sicurezza
    Sicurezza valutata mediante la segnalazione di anomalie o modifiche rispetto ai risultati di base delle valutazioni di sicurezza
    comprese valutazioni di laboratorio, segni vitali, ECG, esame fisico ed ecografia epaticaProduzione endogena di FIX (hFIX)
    1. Produzione endogena di FIX (hFIX)
    2. Efficacia emostatica
    2. Risposta immunitaria
    3. Dispersione
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Week 26
    2. Throughout study
    3. Throughout study
    4. Throughout study or until 2 consecutive samples test negative for
    vector sequences.
    1. durante lo studio
    2. durante lo studio
    3. durante lo studio
    4. durante lo studio o fino a quando 3 test consecutivi negativi per le sequenza del vettore
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    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 Yes
    E.8.2.3.1Comparator description
    Non applicabile : studio in aperto
    Not applicable: Open study
    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 EEA13
    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
    South Africa
    United States
    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
    LPLV
    LPLV
    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 months2
    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 months2
    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 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    F.2 Gender
    F.2.1Female No
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 19
    F.4.2.2In the whole clinical trial 24
    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)
    Treatment/care after study ends will be according to medical needs and local practice. Patients will be consented for a long-term follow-up trial, conducted under a separate extension protocol.
    Il trattamento / cura dopo la fine dello studio sar¿ a seconda delle esigenze mediche e la pratica locale. I pazienti saranno autorizzati per uno studio di follow-up a lungo termine, condotto con un protocollo di estensione separato.
    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 Decision2018-07-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-09
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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