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    Summary
    EudraCT Number:2021-001079-18
    Sponsor's Protocol Code Number:FLT180a-06
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-05-31
    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 ConcernedAustria - BASG
    A.2EudraCT number2021-001079-18
    A.3Full title of the trial
    A dose confirmation study of FLT180a (adeno-associated viral vector containing the Padua variant of a codon-optimized human Factor IX gene) in adult subjects with hemophilia B.
    Dosisbestätigungsstudie für FLT180a (Adeno-assoziierter viraler Vektor mit der PaduaVariante eines Codon-optimierten humanen Faktor-IX-Gens) bei erwachsenen Teilnehmern mit Hämophilie B
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to confirm the dose and safety of FLT180a in adult subjects with hemophilia B.
    Eine klinische Studie zur Bestätigung der Dosis und Sicherheit von FLT180a bei erwachsenen Patienten mit Hämophilie B.
    A.4.1Sponsor's protocol code numberFLT180a-06
    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 SponsorFreeline Therapeutics Ltd
    B.1.3.4CountryUnited Kingdom
    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 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 organisationFreeline Therapeutics Ltd
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressStevenage Bioscience Catalyst, Gunnels Wood Road
    B.5.3.2Town/ cityStevenage
    B.5.3.3Post codeSG1 2FX
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailcontact@freeline.life
    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/3/18/2080
    D.3 Description of the IMP
    D.3.1Product nameFLT180a
    D.3.2Product code FLT180a
    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.3.8INN - Proposed INNverbrinacogene setparvovec
    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 vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2,6 x 10^12
    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.
    E.1.1.1Medical condition in easily understood language
    Hereditary bleeding disorder caused by a lack of blood clotting factor.
    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
    • To assess the safety and tolerability of a single intravenous (IV) administration of FLT180a.
    • To confirm the dose of FLT180a for use in Phase 3.
    E.2.2Secondary objectives of the trial
    • To further assess the efficacy of a single IV administration of FLT180a.
    • To evaluate the effectiveness of the Clinical Immune Management Plan in controlling adeno-associated virus (AAV)S3 vector-associated transaminitis.
    • To describe the immune responses to the Factor IX (FIX) transgene product and AAVS3 capsid protein following a single IV administration of FLT180a.
    • To assess viral shedding in various body fluids following a single IV administration of FLT180a.
    • To investigate the impact of endogenous production of FIX following a single IV administration of FLT180a on quality of life.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult males ≥18 and ≤65 years of age.
    2. Subjects with hemophilia B with known severe or moderately severe FIX deficiency (≤2% of normal circulating FIX activity) for which the subject is on continuous, stable, and adequate FIX prophylaxis.
    3. Have acceptable laboratory values (per central laboratory): a. Hemoglobin ≥11g/dL; b. Platelets ≥100,000 cells/µL; c. AST, ALT and alkaline phosphatase (ALP) ≤ upper limit of normal (ULN); d. Serum albumin > lower limit of normal (LLN); e. Total bilirubin ≤1.5 x ULN (except if caused by Gilbert’s disease); f. Serum creatinine ≤2.0mg/dL.
    4. Willing to practice barrier contraception until at least three consecutive semen samples after vector administration are negative for vector sequences.
    5. Level of neutralizing anti-AAV-S3 antibodies below the limit of the pre-established clinical cutoff using an in vitro transduction inhibition assay within the 4 weeks prior to FLT180a administration.
    6. Has demonstrated ability to accurately, independently and in a timely manner enter bleed diary data during the lead-in study, as judged by the investigator.
    7. At least 150 exposure days to FIX concentrates.
    8. At least 6 months of satisfactory controlled prospective baseline data for bleeding events and FIX consumption from the FLT-01 lead-in study (ECLIPSE).
    E.4Principal exclusion criteria
    1. Any history of alcohol or drug dependence.
    2. Presence of neutralizing anti human FIX antibodies (inhibitor; determined by the Nijmegen modified Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor.
    3. Subjects at high risk of thromboembolic events.
    4. Evidence of advanced liver fibrosis.
    5. Prior treatment with a gene transfer medicinal product.
    6. Subjects with active hepatitis B or C.
    7. Serological evidence of HIV-1, not controlled with anti-viral therapy and as evidenced by cluster of differentiation 4 (CD4)+ counts ≤200 µL.
    8. Cytomegalovirus (CMV) immunoglobulin G positive subjects who are CMV polymerase chain reaction (PCR) positive at screening.
    9. Known coagulation disorder other than hemophilia B.
    10. History of uncontrolled cardiac failure, unstable angina, or myocardial infarction or other acute cardiac conditions requiring clinical management in the past 6 months.
    11. Planned surgical procedure within the next 12 months requiring prophylactic FIX treatment.
    12. Known active severe infection (including documented coronavirus (COVID)-19 infection), or any other significant concurrent, uncontrolled medical condition.
    E.5 End points
    E.5.1Primary end point(s)
    • Safety Endpoints assessed using treatment-emergent Adverse Events (AEs), AEs assessed by the investigator as related, Serious Adverse Events (SAE)s, SAEs assessed by the investigator as related, AEs leading to (early) study discontinuation, deaths, and AEs of special interest (AESI).
    • FIX activity levels.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety endpoints are assessed throughout the trial up to Week 52.

    FIX activity levels assessed at Day 21, Day 140 and Day 182.
    E.5.2Secondary end point(s)
    a. Change from baseline in annualized bleeding rate (ABR).
    b. Change from baseline in annualized FIX concentrate consumption.
    c. Proportion of subjects achieving FIX activity level above 40%.
    d. The proportion of subjects remaining free from continuous routine FIX prophylaxis.
    e. The proportion of subjects achieving a FIX activity level between 50-150% relative to baseline trough.
    f. Change from baseline in Haem-A-QOL scores.
    g. Joint bleeding rates.
    h. Spontaneous bleeding rates.
    i. Number of target joints.
    j. EQ-5D-5L utility scores.
    k. Anti-AAVS3 antibodies and neutralizing antibodies.
    l. Evaluation of AAVS3 capsid-specific T-cell reactions.
    m. Abnormal or change from baseline findings for liver ultrasound or serum alpha-fetoprotein (AFP) levels.
    n. FIX inhibitor levels.
    o. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and use of immunosuppressants for the prevention and treatment of increased ALT/AST levels.
    p. Clearance of vector genomes in plasma and semen.
    q. Clinically significant changes in 12-lead ECG.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Proportion of subjects achieving a FIX activity level above 40% will be assessed at Week 26. The remaining secondary endpoints will be measured at Week 52.
    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 No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose confirmation study
    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.8.2.4Number 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.8.5The trial involves multiple Member States No
    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
    Australia
    United States
    Austria
    United Kingdom
    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
    Last patient last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    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: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3
    F.4.2.2In the whole clinical trial 9
    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)
    All subjects treated in this study will enter a long-term follow-up period at the end of the trial, under a separate long-term follow-up protocol.
    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 Decision2021-09-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-05-31
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