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    Summary
    EudraCT Number:2019-003159-12
    Sponsor's Protocol Code Number:PRV-FTD101
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-07-01
    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 ConcernedFrance - ANSM
    A.2EudraCT number2019-003159-12
    A.3Full title of the trial
    A Phase 1/2 Ascending Dose Study to Evaluate the Safety and Effects on Progranulin Levels of PR006A in Patients with Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN) (PROCLAIM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study with Ascending Dose in order to Evaluate the Safety and Effects on Progranulin Levels of investigational product under code PR006A in Patients with Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN) (PROCLAIM)
    A.3.2Name or abbreviated title of the trial where available
    PROCLAIM
    A.4.1Sponsor's protocol code numberPRV-FTD101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04408625
    A.5.4Other Identifiers
    Name:US INDNumber:019511
    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 SponsorPrevail Therapeutics, a wholly-owned subsidiary of Eli Lilly and Company
    B.1.3.4CountryUnited States
    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 supportPrevail Therapeutics, Eli Lilly and Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPrevail Therapeutics, Eli Lilly and Company
    B.5.2Functional name of contact pointRegulatory Department
    B.5.3 Address:
    B.5.3.1Street Address430 East 29th Street, Suite 1520
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10016
    B.5.3.4CountryUnited States
    B.5.4Telephone number0019173369310
    B.5.6E-mailpatients@prevailtherapeutics.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/0000037822
    D.3 Description of the IMP
    D.3.1Product namePR006A
    D.3.2Product code PR006A
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntracisternal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTBC
    D.3.9.2Current sponsor codePR006A
    D.3.9.3Other descriptive nameAdeno-associated viral vector serotype 9 expressing codon-optimized human GRN gene
    D.3.9.4EV Substance CodeSUB204195
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number14000000000000
    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 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
    Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN)
    E.1.1.1Medical condition in easily understood language
    Fronto-Temporal Dementia
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10068968
    E.1.2Term Frontotemporal dementia
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - Evaluate the safety, tolerability and immunogenicity of 3 dose levels of PR006A administered via suboccipital injection into the cisterna magna.
    - Quantify PGRN levels in blood and CSF.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of PR006A on:

    • Clinical Dementia Rating staging instrument plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains (CDR® plus NACC FTLD)
    • Neurofilament light chain (NfL) levels in blood and CSF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men or women aged 30 to 80 years (inclusive), at the time of informed consent.
    2. Body weight range of ≥40 kg (88 lbs) to ≤110 kg (242 lb) and a BMI of 18 to
    34 kg/m2.
    3. Has symptomatic FTD as per Investigator assessment (bvFTD, PPA-FTD, FTD with
    corticobasal syndrome, or a combination of syndromes are allowed for enrollment).
    4. Score ≥1 and ≤15 on CDR plus NACC FTLD SB.
    5. Stable use of background medications at least 8 weeks prior to PR006A
    dosing.
    6. Carrier of a pathogenic* GRN mutation confirmed by the central laboratory.
    *All null mutations including nonsense, frameshift, splice site mutations, and complete or
    partial (exonic) gene deletions:
    - All previously published pathogenic mutations, with proven functional deleterious effect
    (selected missense mutations may be included provided they are known to be pathogenic)
    - All pathogenic mutations listed in Molgen FTD database (http://www.molgen.ua.ac.be)
    - All new mutations with low plasma PGRN level (<70 ng/mL) based on central laboratory measurement.
    7. Negative screening test for mycobacterium tuberculosis (MTB) or documented negative MTB test within 1 year prior to Screening.
    8. Age- and gender-appropriate cancer screenings are up to date and completed as per the
    Investigator’s judgment and local standard of care prior to Screening.
    9. Patient and/or patient’s legally authorized representative (LAR) (where applicable by local regulation) has the ability to understand the purpose and risks of the study and provide written informed consent and authorization to use protected health information in accordance with national and local privacy regulations. The patient or LAR may also provide consent for future biomedical research in accordance with their national regulations; however, the patient may still participate in the study without providing consent for future biomedical research.
    10. Patient has a reliable study partner/informant (e.g., family member, friend) willing and able to participate in the study as a source of information on the patient’s health status and cognitive and functional abilities (including providing input into the rating scales). The study partner should have regular contact with the patient (in person or via phone/video communication). The study partner must sign a separate partner informed consent form (ICF) indicating that she/he understands the study requirements and is willing to participate and attend study visits requiring study partner input.
    11. Women of nonchildbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before Screening) or post-menopausal, defined as spontaneous amenorrhea for at least 2 years, with follicle-stimulating hormone level in the postmenopausal range at Screening based on the central laboratory’s range.
    12. Men and women of childbearing potential (i.e., ovulating, premenopausal, and not surgically sterile) must use a highly effective method of contraception consistently and correctly for the duration of the study including the long-term follow-up. Highly effective methods of contraception are those that, alone or in combination, result in a failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) and include the following for female participants of childbearing potential:
    a. Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormonal contraception associated with inhibition of ovulation
    b. Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation
    c. Intrauterine device
    d. Intrauterine hormone-releasing system
    e. Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior to Screening)
    f. Vasectomized partner (performed at least 3 months prior to Screening)
    g. Sexual abstinence (no sexual intercourse)

    Acceptable forms of contraception for male participants include:
    a. Sexual abstinence (no sexual intercourse)
    b. History of vasectomy (performed at least 3 months prior to Screening)
    c. Condom with spermicide used together with highly effective female contraceptive methods if the female partner(s) is of childbearing potential (see above for list of acceptable female contraceptive methods)
    13. Men must agree to abstain from sperm donation for the duration of the study, including long-term follow-up.
    14. Women must agree to abstain from egg donation for the duration of the study, including long-term follow-up.
    15. Women of childbearing potential cannot be pregnant or lactating/breastfeeding and must have a negative result for the serum pregnancy test (β-human chorionic gonadotropin) at Screening.
    16. Patient is generally ambulatory and not dependent on a walker or wheelchair.

    Please refer to protocol page 58 for rest of the inclusion criteria.
    E.4Principal exclusion criteria
    1. Diagnosis of a significant CNS disease other than FTD that may be a cause for the patient’s FTD symptoms or may confound study objectives.
    2. Brain or cervical spine MRI/magnetic resonance angiography (MRA) imaging indicating clinically significant abnormality, including evidence of prior hemorrhage, infarct >1 cm3 or >3 lacunar infarcts, or a structural or vascular abnormality deemed a contraindication to intracisternal injection.
    3. Hypersensitivity or contraindications to corticosteroid, rituximab, and/or sirolimus use (including but not limited to osteoporosis with vertebral fractures within 1 year prior to Screening, poorly controlled diabetes [see Exclusion Criterion 5c], uncontrolled hypertension [see Exclusion Criterion 5f]), uncontrolled hyperlipidemia or hypercholesterolemia as per Investigator assessment, uncontrolled interstitial lung disease, or uncontrolled renal insufficiency).
    4. Clinical evidence of peripheral symmetric sensory polyneuropathy (stable sensory mononeuropathies and radiculopathies are not exclusionary).
    5. Concomitant disease or condition within 6 months of Screening that could interfere with, or treatment of which might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable safety risk to the patient or interfere with the patient's ability to comply with study procedures; including, but not limited to, the following:
    a. Evidence of clinically significant liver disease
    b. Unstable autoimmune disease requiring chronic immunosuppression
    c. Poorly controlled/not adequately managed diabetes (Screening hemoglobin A1c ≥7%)
    d. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening
    e. Clinically significant 12-lead ECG abnormalities at Screening, as determined by the Investigator
    f. Uncontrolled hypertension defined as: average of 3 systolic blood pressure [SBP]/diastolic blood pressure [DBP] readings >165/100 mm Hg at Screening, or persistent SBP/DBP readings >180/100 mm Hg within 3 months prior to Screening that, in the opinion of the Investigator, are indicative of chronic uncontrolled hypertension
    g. History of cancer, including B-cell cancers, within 5 years of Screening or current presence of pre cancer lesions, with the exception of fully excised nonmelanoma skin cancers and fully excised prostate carcinoma in situ that have been stable for at least 6 months
    h. History or current alcohol or drug abuse within 2 years of Screening
    i. Any current psychiatric diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, International Statistical Classification of Diseases and Related Health Problems Tenth Revision, or equivalent, that may interfere with the patient’s ability to perform study procedures and all assessments (e.g., psychosis, major depression, bipolar disorder, mental retardation, and schizophrenia). NOTE: Psychiatric manifestations of FTD are not exclusionary
    j. At imminent risk of self-harm, based on clinical interview and responses on the C-SSRS. Patient must be excluded if they report ideation with intent, with or without a plan or method (i.e., positive response to item 4 or 5 on the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months
    k. Any medical disorders that, in the opinion of the Investigator, could interfere with study-related procedures (including safe performance of lumbar puncture (LP) or intracisternal injection), such as prohibitive spinal diseases, bleeding diathesis, clinically significant coagulopathy, thrombocytopenia, or increased intracranial pressure
    l. Documented stroke or transient ischemic attack within 1 year prior to Screening
    m. History of seizure or unexplained blackouts, with the exception of seizure due to known, transient cause (e.g., medication, electrolyte disturbance), within 10 years prior to Screening
    n. Currently active infection or severe infection (e.g., pneumonia, septicemia, CNS infections [e.g., meningitis, encephalitis]) within 12 weeks prior to Screening
    o. History of severe allergic or anaphylactic reactions. History of hypersensitivity to any inactive ingredient of PR006A (refer to the IB) or protocol required immunosuppressant medications
    p. Clinical evidence of vitamin B12 deficiency or vitamin B12 level less than the lower limit of normal if deemed clinically significant as per Investigator’s assessment at Screening
    q. History of neurosyphilis or history of syphilis infection without documentation of adequate treatment.

    Please refer to Protocol page 61 for full exclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    - Change from baseline in PGRN levels in blood at Months 1, 2, 3, 6, 9, and 12
    - Change from baseline in PGRN levels in CSF at Months 2, 6 and 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1, 2, 3, 6, 9, and 12 Months
    E.5.2Secondary end point(s)
    - Change from baseline in CDR plus NACC FTLD SB at Months 6 and 12
    - Change from baseline in NFL levels in plasma and serum at Months 2, 6, 9, and 12
    - Change from baseline in NFL levels in CSF at Months 2, 6 and 12
    E.5.2.1Timepoint(s) of evaluation of this end point
    3, 6, 9, and 12 Months
    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 Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    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 Yes
    E.8.1.7.1Other trial design description
    Ascending dose
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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
    Belgium
    France
    Spain
    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
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    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: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 15
    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)
    Following conclusion of trial participation the subjects will be released to the local 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 Decision2022-03-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-01-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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