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    Summary
    EudraCT Number:2016-001446-25
    Sponsor's Protocol Code Number:FHGT002
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-12
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-001446-25
    A.3Full title of the trial
    AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects with Homozygous Familial Hypercholesterolemia (HoFH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a study to investigate if gene therapy is safe in people with homozygous familial hypercholesterolemia (also called HoFH).
    A.4.1Sponsor's protocol code numberFHGT002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02651675
    A.5.4Other Identifiers
    Name:IND #Number:16710
    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 of Pennsylvania
    B.1.3.4CountryUnited States
    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 supportDHHS
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportRegenXBio
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Pennsylvania
    B.5.2Functional name of contact pointMaria Caturla, Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address8046 Maloney Bldg. 3400 Spruce Street
    B.5.3.2Town/ cityPhiladelphia
    B.5.3.3Post code19104
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12156624618
    B.5.6E-mailcaturm@upenn.edu
    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 number11-3594
    D.3 Description of the IMP
    D.3.1Product nameAAV8.TBG.hLDLR
    D.3.2Product code AAV8.TBG.hLDLR
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) Yes
    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 Yes
    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
    Adults with homozygous familial hypercholesterolemia
    E.1.1.1Medical condition in easily understood language
    High cholesterol levels in subjects with homozygous familial hypercholesterolemia due to mutation in LDL receptor
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective will be to determine the safety of AAV8.TBG.hLDLR administration in this patient population.
    E.2.2Secondary objectives of the trial
    The secondary objective is to assess the efficacy of LDL-C reduction achieved with AAV8.TBG.hLDLR administration.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    AAV8-mediated Low Density Lipoprotein Receptor (LDLR)
    Gene Replacement in Subjects with Homozygous Familial
    Hypercholesterolemia (HoFH):
    Optional LDL Kinetics Substudy

    Version 2 – April 29, 2016

    Description: The purpose of this optional LDL Kinetics Substudy is to see if the study drug helps clear the LDL (the “bad” cholesterol) from circulation. To do this, LDL will be labeled with a “tracer” called deuterated leucine. LDL will be tagged with this tracer so we can use laboratory tests to look at how it behaves in your
    blood.
    E.3Principal inclusion criteria
    1. Age: 18 years or older;
    2. Molecularly defined LDLR mutations in both LDLR alleles and clinical
    presentation consistent with HoFH;
    3. No cardiovascular event or cardiovascular intervention within 12 weeks of
    enrollment;
    4. A baseline serum AAV8 neutralizing antibody titer ≤ 1:10.
    E.4Principal exclusion criteria
    1. Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period:
    niacin > 250 mg/day: within 4 weeks of baseline
    fibrates: within 4 weeks of baseline
    Lomitapide: within 6 weeks of baseline
    Mipomersen: within 24 weeks of baseline
    2. Heart failure defined by the NYHA classification as functional Class III with history of hospitalization(s) within 12 weeks of the baseline visit or functional Class IV.
    3. History within 12 weeks of the baseline visit of a myocardial infarction (MI), unstable angina leading to hospitalization, coronary artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI), uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid revascularization, endovascular procedure or surgical intervention.
    4. Uncontrolled hypertension defined as: systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg.
    5. History of cirrhosis or chronic liver disease based on documented histological evaluation or non- invasive imaging or testing.
    6. Documented diagnosis of any of the following liver diseases:
    Nonalcoholic steatohepatitis (biopsy-proven)
    Alcoholic liver disease
    Autoimmune hepatitis
    Liver cancer
    Primary biliary cirrhosis
    Primary sclerosing cholangitis
    Wilson’s disease
    Hemochromatosis
    α1 anti-trypsin deficiency
    7. Abnormal LFTs at screening (AST or ALT >2x upper limit of normal (ULN) and/or Total Bilirubin of
    >1.5x ULN unless patient has unconjugated hyperbilirubinemia due to Gilbert’s syndrome).
    8. Hepatitis B as defined by positive for HepB SAg, or Hep B Core Ab, and/or viral DNA
    9. Chronic active Hepatitis C as defined by positive for HCV Ab and viral RNA.
    10. History of alcohol abuse within 52 weeks.
    11. Certain prohibited medications known to be potentially hepatotoxic, especially those that can induce microvesicular or macrovesicular steatosis. These include but are not limited to: acutane, amiodarone, HAART medications, heavy acetaminophen use (2g/day more than 3 times a week), isoniazid, methotrexate, tetracyclines, tamoxifen, valproate.
    12. Current use of systemic corticosteroids or active tuberculosis, systemic fungal disease, or other chronic infection.
    13. History of immunodeficiency diseases, including a positive HIV test result.
    14. Chronic renal insufficiency defined as estimated GFR < 30 mL/min.
    15. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer.
    16. Previous organ transplantation.
    17. Administration of an investigational drug within 12 weeks or 5 half-lives of the drug (whichever is longer) prior to the screening visit and until 52 weeks after receiving AAV8.TBG.hLDLR.
    18. Any major surgical procedure occurring less than 3 months prior to the screening visit, or any planned future surgical procedure within 3 months of baseline.
    19. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject’s safety or successful participation in the study.
    20. A baseline serum AAV8 NAb titer > 1:10.
    21. Any other medical condition or finding that would make it not in the subject’s best interest to participate in the study
    22. Study staff member or any direct family member.
    E.5 End points
    E.5.1Primary end point(s)
    Safety assessments
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety visits take place at 24, 48 and 72 hours. Additional full safety visits will occur on days 7, 14, 28, and 56. Day 21, 35, 42,49,63,70,77 (± 3 days). Week 12 (±1 week). Weeks 24 and 36 (± 2 weeks) Week 52 (±2 weeks)
    E.5.2Secondary end point(s)
    - To assess the LDL-C reduction achieved with AAV8.TBG.hLDLR administration as defined by percent change in LDL-C at 12 weeks compared to baseline.
    - To assess changes in other lipid parameters at 12 weeks compared to baseline values, specifically percent change in total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C), HDL-C, fasting triglycerides (TG), very low density lipoprotein cholesterol (VLDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I).
    - To assess long term (up to 260 weeks) safety and efficacy after vector administration
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety Timepoints : Weeks 72, 96, 120, 144, 168, 192, 216, 260 (±4 weeks)

    Efficacy Timepoints: Day 1, 2 3,4,7,14,28,56
    (± 3 days) Day 21, 35,
    42,49,63,70,77 (± 3 days) Week 12 (±1
    week) Weeks 24 and 36 (± 2 weeks) Week 52
    (±2 weeks) Weeks 96, 144, 192, 260 (±4 weeks)
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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 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 trial2
    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 EEA4
    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
    Canada
    United States
    Italy
    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
    December 2022
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    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: 12
    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 Information not present in EudraCT
    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 8
    F.4.2.2In the whole clinical trial 12
    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 Decision2016-08-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-11-27
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