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    Summary
    EudraCT Number:2019-004066-18
    Sponsor's Protocol Code Number:AL001-3
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-30
    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 number2019-004066-18
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of AL001 in Individuals at Risk for or With Frontotemporal Dementia Due to Heterozygous Mutations in the Progranulin Gene
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Double-Blind, Placebo-Controlled Study to Evaluate Efficacy and Safety of AL001 in FTD
    A.4.1Sponsor's protocol code numberAL001-3
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04374136
    A.5.4Other Identifiers
    Name:IND numberNumber:135892
    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 SponsorAlector Inc.
    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 supportAlector Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlector Inc.
    B.5.2Functional name of contact pointKristina Vlaovic
    B.5.3 Address:
    B.5.3.1Street Address131 Oyster Point Boulevard, Suite 600
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16508370384
    B.5.6E-mailkristina.vloavic@alector.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAL001
    D.3.2Product code AL001
    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 INNnot available
    D.3.9.1CAS number 2376132-27-1
    D.3.9.2Current sponsor codeAL001
    D.3.9.3Other descriptive nameAL001
    D.3.9.4EV Substance CodeSUB193428
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Frontotemporal Dementia
    E.1.1.1Medical condition in easily understood language
    A type of dementia that causes problems with behaviour and language
    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
    To evaluate the efficacy of AL001 compared with placebo in carriers of progranulin gene (GRN) mutations causative of frontotemporal dementia (FTD) as measured by the Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease Coordinating Center frontotemporal lobar degeneration Behavior & Language Domains Sum of Boxes (CDR® plus NACC FTLD-SB).
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate the clinical effects, safety, and tolerability of AL001 compared with placebo in carriers of GRN mutations causative of FTD as measured by:

    Secondary Objective:
    Clinical outcome assessments (COAs)

    Secondary Pharmacodynamic (PD) Objective:
    Disease pathology biomarkers

    Secondary Safety Objective:
    Safety assessments and antidrug antibodies (ADAs)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each participant must meet all of the following criteria to be enrolled in this study.
    Key Inclusion Criteria:
    •Participant is a known carrier of a heterozygous loss-of-function GRN mutation causative of FTD, with either:
    •A global CDR® plus NACC FTLD score of 0 and an elevated level of serum NfL as measured on the Simoa NF-Light Advantage Kit assay (pre-symptomatic participants) or,
    • A global CDR® plus NACC FTLD score of 0.5, 1, or 2; and 1 or more of the
    6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD, or a diagnosis of PPA (symptomatic participants).

    General Inclusion Criteria:
    2. Presymptomatic participants (with a global CDR® plus NACC FTLD score of 0) are 45 to 85 years of age, inclusive, at screening, or symptomatic participants (with a global CDR® plus NACC FTLD score of 0.5,1, or 2) are 25 to 85 years of age, inclusive, at screening
    3. At screening, female participants must be nonpregnant and nonlactating, and 1 of the following conditions must apply:
    a. Participant is not a woman of childbearing potential (WOCBP) (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1-year postmenopausal [amenorrhea duration of 12 consecutive months with no identified cause other than menopause]).
    b. Participant is a WOCBP and agrees to use an acceptable contraceptive method from screening until 10 weeks after the last dose of study treatment. Acceptable contraception is defined as using hormonal contraceptives (e.g. combined oral contraceptive pill) or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. In addition, total abstinence, in accordance with the lifestyle of the participant, is acceptable.
    A WOCBP must have a serum pregnancy test conducted at screening. Additional requirements for pregnancy testing during and after study intervention are described in the Schedules of Assessments.
    4. Male participants must agree to use acceptable contraception and not donate sperm from Day 0 until 10 weeks after the last dose of study treatment. Acceptable contraception for the male participant when having sexual intercourse with a WOCBP who is not currently pregnant is defined as using a condom. In addition, WOCBP partners must use hormonal contraceptives (e.g. combined oral contraceptive pill) or an intrauterine device.
    5. Participant agrees not to donate blood or blood products for transfusion for the duration of the study and for 1 year after the final dose of study treatment.
    6. Participant is willing to and can comply with the study protocol requirements, in the opinion of the investigator.
    7. Participant is willing and able to give informed consent. If the study participant is not competent, a legally authorized representative must provide informed consent on their behalf, and the participant must provide assent, in accordance with the local regulations, guidelines, and institutional review board (IRB) or independent ethics committee (IEC).
    8. Participant has availability of a person (“study partner”) who has frequent and sufficient contact with the participant (at least 5 hours per week of in-person contact), can provide accurate information regarding the participant’s behavior, cognitive, and functional abilities as well as their health throughout the study, agrees to provide information at investigational site visits that require partner input for COA completion, and gives the necessary informed consent.
    a. Pre-symptomatic participants (global CDR® plus NACC FTLD score of 0) require
    the study partner at the COA visits only; symptomatic participants require the
    study partner at each visit. Pre-symptomatic participants who become symptomatic
    (global CDR® plus NACC FTLD score of 0.5 or greater) during the study treatment period require the study partner at each visit moving forward through Study Completion.
    b. The study partner must have sufficient cognitive capacity to accurately report upon the participant’s behavior, cognitive, and functional abilities in the opinion of the investigator. The study partner should be in sufficiently good general health to
    have a high likelihood of maintaining the same level of interaction with the participant and participation in study procedures throughout the study duration.
    c. The same study partner should participate throughout the duration of the study. If a change in study partner is necessary, the Medical Monitor must be contacted.

    E.4Principal exclusion criteria
    1. Participant has dementia due to a condition other than FTD including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Huntington disease, or vascular dementia.
    2. Participant has a known mutation causative of neurodegenerative disorder(s) other than heterozygous loss-of-function GRN mutations causative of FTD.
    3. Participant has a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.
    4. Participant has a history of moderate or severe substance use disorder within the past
    2 years, with the exception of nicotine, as defined by the Diagnostic and Statistical
    Manual of Mental Disorders, fifth edition criteria
    5. Participant currently has or has had an acute illness that requires or required systemic antibiotics within 30 days prior to study treatment administration.
    6. Participant has clinically significant vitamin B12 or folate deficiency (if treated, must be on a stable regimen for at least 3 months prior to study treatment administration).
    7. Participant has untreated hypothyroidism (if treated, thyroid supplementation dose must be stable for at least 3 months with a normal thyroid-stimulating hormone level prior to study treatment administration).
    8. Participant has insufficiently controlled diabetes mellitus (e.g., hemoglobin A1C
    ≥8%).
    9. Participant has had any surgery (major or emergent) or hospitalization within 30 days prior to study treatment administration.
    10. Participant has a history of cancer except if it:
    a.Is considered likely to be cured; b.Is not being actively treated with anticancer therapy or radiation and in the opinion of the investigator, is not likely to require treatment in the ensuing
    3 years; c.Is considered to have low probability of recurrence (with supporting documentation from the treating oncologist if possible), including participants with ongoing antihormonal treatment (e.g., tamoxifen);d.For prostate cancer, has not had significant progression within the past 2 years.
    11. Participant is positive for hepatitis B surface antigen, human immunodeficiency
    virus-1 or -2 antibodies or antigen, or history of spirochetal infection of the CNS (e.g., syphilis, borreliosis, or Lyme disease). Participants with a positive hepatitis C virus antibody will be allowed if hepatitis C RNA is negative.
    12. Participant has significant kidney disease as indicated by either of the following:
    a. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, according to the re-expressed abbreviated (four-variable) MDRD Study equation
    b.Creatinine ≥2 mg/dL.
    13. Participant has impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 the upper limit of normal (ULN), or total bilirubin ≥2.0 × ULN. Note: Participants with Gilbert's syndrome are eligible to participate
    14. Participant has hematologic abnormalities as indicated by hemoglobin ≤9 g/dL; white blood cells (WBC) ≤3 000/mm3; absolute neutrophil count ≤1 500/mm3; or platelet count ≤100 000/mm3.
    15. Participant has or has had unstable or clinically significant cardiovascular disease within the past 2 years.
    16. Participant has uncontrolled hypertension (e.g., repeated supine diastolic blood pressure [BP] >95 mm Hg).
    17. Participant has a history or presence of an abnormal ECG that is clinically significant, or evidence of acute or subacute myocardial infarction or ischemia.
    18. Participant has history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease or clinically significant electrolyte abnormalities Note: Participants with premature ventricular contractions are eligible to participate.
    19. For participants who consent to lumbar puncture, participant has contraindication to lumbar dural puncture, including coagulopathy, concomitant anticoagulation medication (except for a platelet inhibitor such as aspirin), thrombocytopenia, or other factor(s) that precludes safe lumbar puncture.
    20. Participant has history or presence of clinically evident vascular disease potentially affecting the brain
    21. Participant has history of a clinically significant, persistent neurologic deficit, structural brain damage, or CNS trauma.
    22. Participant resides in a skilled nursing facility, convalescent home, or long-term care facility at screening; or requires continuous nursing care.
    23. Participant is unable to tolerate MRI procedures or has a contraindication to MRI
    24. Participant has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise their ability to comply with the protocol-required testing or procedures, or compromise the participant's well-being, safety, or clinical interpretability
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint:
    •The CDR® plus NACC FTLD-SB
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and weeks 16, 32 and 48 for symptomatic patients and baseline and weeks 16,32, 48, 64, 80 and 96 for pre symptomatic patients.
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    •Clinical Global Impression-Severity (CGI S)
    •Clinical Global Impression-Improvement (CGI I)
    •The changes from baseline in the scores of the following COAs:
    o Frontotemporal Dementia Rating Scale (FRS)
    o Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

    Secondary PD Endpoints:
    •The changes from baseline in the following:
    o Structural volumetric magnetic resonance imaging (MRI) whole and regional brain volume
    o Progranulin protein (PGRN) concentrations in plasma and optional cerebrospinal fluid
    (CSF) o Neurofilament-light chain (NfL)
    concentrations in serum and optional CSF

    Secondary Safety Endpoints:
    •Incidence, nature, and severity of adverse events and serious adverse events
    •Physical examination abnormalities
    •Neurological examination abnormalities
    •Changes in vital signs from baseline over time
    •Changes in electrocardiograms from baseline over time
    •MRI abnormalities
    •Changes in clinical laboratory tests from baseline over time
    •Sheehan-Suicidality Tracking Scale (Sheehan STS)
    •Incidence of ADAs to AL001
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints: every 16 weeks.

    PD endpoints: MRI every 24 weeks PGRN and NfL measurements every 8 weeks and safety assessments every 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 No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) No
    E.7.1.1First administration to humans No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA31
    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
    Canada
    United States
    Belgium
    France
    Germany
    Italy
    Netherlands
    Portugal
    Spain
    Sweden
    Switzerland
    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 years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    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: 144
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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
    If the study participant is not competent, a legally authorised representative must provide informed consent on their behalf, and the participant must provide assent, in accordance with the local regulations, guidelines, and ethics committees.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 116
    F.4.2.2In the whole clinical trial 180
    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)
    Upon completion of the double blind study treatment period, participants who qualify are planned to be offered an open label extension (OLE) study with AL001 (to be described in a separate 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 Decision2021-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-03
    P. End of Trial
    P.End of Trial StatusOngoing
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