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    Summary
    EudraCT Number:2022-002568-62
    Sponsor's Protocol Code Number:AVB-PGRN-001
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2023-01-18
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2022-002568-62
    A.3Full title of the trial
    A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of AVB-101 Administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test whether AVB-101 is both safe and efficacious in a sub-population of genetically defined FTD patients that currently have no other treatment options
    A.3.2Name or abbreviated title of the trial where available
    Ph1/2 study of AVB-101 in Subjects with Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)
    A.4.1Sponsor's protocol code numberAVB-PGRN-001
    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 SponsorAviadoBio 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 supportAviadoBio Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace
    B.5.2Functional name of contact pointClinical Trial Management
    B.5.3 Address:
    B.5.3.1Street AddressVia Olona 2
    B.5.3.2Town/ cityMilan
    B.5.3.3Post code20123
    B.5.3.4CountryItaly
    B.5.4Telephone number39 0283413400
    B.5.6E-mailS.Zambruno@Medpace.com
    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 numberEMA/OD/0000068610
    D.3 Description of the IMP
    D.3.1Product nameRecombinant AAV-9 vector expressing the human progranulin protein
    D.3.2Product code AVB-101
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntracerebral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAVB-101
    D.3.9.3Other descriptive nameAVB-101
    D.3.9.4EV Substance CodeSUB296517
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0E13
    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
    Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
    E.1.1.1Medical condition in easily understood language
    Dementia
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    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
    To evaluate the safety and tolerability of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
    E.2.2Secondary objectives of the trial
    To evaluate the preliminary clinical and biomarker measures of efficacy of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects will be eligible to be included in the study if all of the following criteria apply:
    1. Are male or female, 30 to 75 years of age, inclusive, at Screening;
    2. Are carriers of a pathogenic granulin (GRN) mutation as confirmed by a Sponsor approved genetic test;
    3. Have frontotemporal dementia (FTD) as evidenced by Clinical Dementia Rating (CDR) + National Alzheimer's Coordinating Center (NACC) frontotemporal lobar degeneration (FTLD) global score of 0.5, 1.0, or 2.0;
    4. Have presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or primary progressive aphasia;
    5. Have a thalamic volume of 5.0 cm3 on each side on Screening magnetic resonance imaging (MRI);
    6. For women of childbearing potential, must have a negative serum pregnancy test at Screening, a negative urine dipstick, and not be breastfeeding within 2 weeks prior to treatment;
    7. Are willing to practice a highly effective birth control method as outlined in the Protocol if the subject or partner is of childbearing potential;
    8. Able and willing to comply with all procedures and the study visit schedule as outlined in the Protocol;
    9. Able and willing to give written informed consent prior to study participation, and agree to designate a legal representative to act on their wishes to continue participation should they lose capacity to consent at some point during the study; and
    10. Have an identified, informed study partner who is able and willing to support the subject's participation in the study and to provide assessments of the subject during the study (separate, written informed consent to be obtained from the study partner for their participation, where required to do so by the relevant country's competent authorities).
    E.4Principal exclusion criteria
    Subjects will be excluded from the study if any of the following criteria apply:
    1. Have a classification of the mutation in the GRN gene as "not pathogenic," "likely benign variant," or "benign variant";
    2. Have severe dementia, defined as CDR + NACC FTLD global score of 3.0, or other symptoms that preclude the ability to comply with study procedures and/or pose unacceptable safety risk to the subject;
    3. Have any concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency;
    4. Have a clinically significant abnormality on MRI at Screening considered to be a contraindication to intrathalamic infusion;
    5. Have a surgically significant pattern of brain atrophy on MRI at Screening that in the determination of the neurosurgeon interferes with planned neurosurgical trajectory;
    6. Have had previous treatment with any gene or cell therapy;
    7. Have had previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment;
    8. Have had a concomitant disease, any clinically significant laboratory abnormality, or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the subject or interfere with study conduct or the subject's ability to comply with study procedures;
    9. Have a malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated;
    10. Have any contraindications to MRI as per local guidelines;
    11. Have any contraindications to gadolinium-based contrast agents per local guidelines;
    12. Have any contraindications to general anesthesia for a period of up to 10 hours and/or cardiopulmonary disorders that would result in higher American Society of Anesthesiology risk classification;
    13. Have any contraindications to lumbar puncture as per local guidelines;
    14. Have been hospitalized for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned procedure during the study;
    15. Are using anticoagulants at Screening, or will have an anticipated need during the period of treatment. Antiplatelet therapies are acceptable concomitant medications if they can be stopped at least 48 hours prior to treatment;
    16. Have a history of previous serious or recent Coronavirus Disease 2019 (COVID-19) as defined by (1) any history of hospitalization for severe illness at any time, (2) any history of significant respiratory symptoms at any time, or (3) any pre-symptomatic or mildly symptomatic COVID 19 positivity within 12 weeks prior to planned treatment;
    17. Have a positive drug screen for drugs of abuse;
    18. Have a history of substance abuse disorder;
    19. Have the presence of an implanted deep brain stimulation device, ventriculoperitoneal or other cerebrospinal fluid shunt, or other implanted device;
    20. Have evidence of suicide risk, as assessed by the Columbia-Suicide Severity Rating Scale, defined as either a suicide attempt within 6 months prior to Screening or have a significant risk of suicide as judged by the Investigator; or
    21. Have a known or suspected intolerance or hypersensitivity to the study drug or any of the stated ingredients.
    E.5 End points
    E.5.1Primary end point(s)
    Over a 26-week initial and 5year total follow up period:
    • Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities;
    • Change from baseline in vital signs, ECG parameters, and physical and neurological examinations, and MMSEChange from baseline in mini-mental state
    examination (MMSE);;
    • Change from baseline in clinical chemistry and hematology safety laboratory tests;
    • Time to achieve clearance of vector genomes in plasma and semen (male only)
    • Incidence of treatment emergent suicidal ideation or behavior as measured using the C-SSRS.
    • Change from baseline in MRI including oedema, inflammation, asymptomatic/symptomatic hemorrhage and other structural changes
    E.5.1.1Timepoint(s) of evaluation of this end point
    26 weeks and 5 years
    E.5.2Secondary end point(s)
    Over a 26-week initial and 5-year total follow up period:
    • Change from baseline in PGRN protein levels in CSF and blood;
    Over a 26-week initial and 5-year total follow up period:
    • Change from baseline in NfL levels in CSF and blood
    Over a 5-year follow up period:
    • Change from baseline in CDR+NACC FTLD-SB score;
    • Change in CGI C, PGI-C, CaGI-C
    E.5.2.1Timepoint(s) of evaluation of this end point
    26 weeks and 5 years
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 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 Information not present in EudraCT
    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 EEA12
    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
    Belgium
    France
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    United Kingdom
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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 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: 5
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Participants will not be enrolled if they are unable to consent at initial screening/consent, but patients' disease may progress during the 5 year follow up period of the
    study, such that they will lack capacity to consent for themselves.
    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 6
    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)
    Participants will receive their usual standard of care.
    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 Decision2023-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-07-03
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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