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    Summary
    EudraCT Number:2019-000138-20
    Sponsor's Protocol Code Number:AL001-2
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-05-21
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-000138-20
    A.3Full title of the trial
    A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in Heterozygous Carriers of Granulin or C9ORF72 Mutations Causative of Frontotemporal Dementia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label Study to Evaluate Safety of long-term AL001 dosing in FTD
    A.4.1Sponsor's protocol code numberAL001-2
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03987295
    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+16508269572
    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 N/A
    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
    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 safety and tolerability of intravenous (IV) administration of AL001 over 96 weeks in asymptomatic and symptomatic carriers of a granulin (GRN) mutation causative of frontotemporal dementia (FTD) and in symptomatic carriers of a C9orf72 mutation causative of FTD.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate the effect of IV
    administration of AL001 over 96 weeks in asymptomatic and
    symptomatic carriers of a GRN mutation causative of FTD and in
    symptomatic carriers of a C9orf72 mutation causative of FTD on the
    following:
    •Pharmacokinetics (PK)
    •Longitudinal plasma and CSF PGRN concentration levels
    •Longitudinal levels of Sortilin in WBCs
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants must meet all of the criteria specific to their applicable participant category.
    1) Participant completed Study AL001-1 through the Day 57 visit and did not experience AEs that the investigator deems would prevent safe participation in Study AL001-2
    2) Participant meets 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible behavioral variant frontotemporal dementia (bvFTD; Rascovsky 2011) or has diagnosis of primary progressive aphasia (PPA; Gorno Tempini 2011)
    3) Participant completed Study AL001-1 through the Day 43 visit and did not experience AEs that the investigator deems would prevent safe participation in Study AL001-2
    4) Participant is a carrier of a loss of function GRN mutation causative of FTD and knows their mutation status
    5) Participant has a CDR® plus NACC global score of 0.5, 1, or 2; and 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD (Rascovsky 2011) or a diagnosis of PPA (Gorno Tempini 2011)

    In addition, this is the list of the important inclusion criteria
    • Participants are 18 to 85 years of age
    • At screening, female participants must be nonpregnant and nonlactating, and at least one of the following conditions must apply
    - 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])
    - Participant is a WOCBP and using an acceptable contraceptive method from screening until 8 weeks after the last dose of study drug. Acceptable contraception is defined as using hormonal contraceptives 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 located in the Schedule of Assessments ( in the protocol)
    • Male participants, if not surgically sterilized, must agree to use acceptable contraception and not donate sperm from Day 1 until 8 weeks after the last dose of study drug. Acceptable contraception for the male participant (and his female partner) is defined as using hormonal contraceptives 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
    •Participant agrees not to donate blood or blood products for transfusion for the duration of the study and for 1 year after final dose of study drug
    •Participant is willing and has the ability to comply with the study protocol requirements, in the opinion of the investigator
    • 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)
    •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 cognitive and functional abilities as well as their health throughout the study, agrees to provide information at site visits that require partner input for COA completion, and signs the necessary consent form. (Note: asymptomatic participants require the study partner at the COA visits only; symptomatic participants require the study partner at each visit)
    Inclusion criteria applicable to those UK, US, or Canadian participants participating in the optional Winterlight Lab Speech Assessment (WLA) and Summerlight Lab Speech Assessment (SLA) only:
    -participant has available and willing study partner to administer the WLA
    -participant has WiFi access in their residence or WiFi access in a private area where the testing can take place
    -US, UK, or Canadian participants who are proficient in English in the investigator’s opinion
    E.4Principal exclusion criteria
    • Participant has a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.
    • Participant has history of substance use disorder (drug or alcohol) within the past 2 years, with the exception of nicotine, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria (American Psychiatric Association 2013).
    •Participant currently has or has had an acute illness or infection that requires oral or IV antibiotics within 30 days prior to study drug administration that may affect safety assessments.
    •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.
    •Participant has had any surgery or hospitalization during the 30 days prior to study drug administration
    • Participant has history of cancer
    • Participant has history or presence of intracranial tumor that is clinically relevant (e.g. glioma, cerebral metastasis).
    • Participant is positive for hepatitis B surface antigen, hepatitis C virus antibodies, or human immunodeficiency virus 1 and 2 antibodies or antigen, or history of spirochetal infection of the CNS.
    • Participant has significant kidney disease as indicated by a screening creatinine clearance <30 mL/min as calculated by the central laboratory using the Cockcroft Gault formula, which remains <30 mL/min if retested.
    • 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, which remains above either of these limits if retested or other abnormalities in synthetic function that are clinically significant.
    •Participant has had unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, New York Heart Association Class III or more cardiac failure) within the last 2 years.
    • Participant has uncontrolled hypertension.
    • Participant has history or presence of an abnormal ECG that is clinically significant including complete left bundle branch block, second- or third degree heart atrioventricular block, or evidence of prior acute or subacute myocardial infarction or ischemia.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Safety Endpoints:
    To assess the potential effect of cumulative exposure on the safety profile of AL001, the following will be evaluated by dose, such as by using tertiles of the actual dose (normalized to weight) received:
    • Incidence, nature, and severity of AEs and SAEs
    • Incidence of treatment discontinuations and study discontinuations due to AEs
    • Physical examination abnormalities
    • Neurological examination abnormalities
    • Changes in vital signs from baseline over time
    • Changes in ECGs from baseline over time
    • MRI abnormalities after dosing relative to baseline
    • Changes in clinical laboratory tests from baseline over time
    • Sheehan Suicidality Tracking Scale (Sheehan-STS)
    • Incidence of ADAs to AL001
    E.5.1.1Timepoint(s) of evaluation of this end point
    AEs: will be summarized if applicable
    Laboratory data: at base line and at scheduled timepoints
    Vital signs: at base line and at scheduled timepoints
    ECG: at baseline and at scheduled timepoints
    Physical examinations: at Screening and at scheduled timepoints or as clinically indicated
    Neurological examinations and Sheehan-STS: At Screening and at scheduled timepoints
    ADA: at baseline and at scheduled timepoints
    E.5.2Secondary end point(s)
    Secondary Pharmacokinetic (PK) Endpoints:
    • Serum concentration of AL001 at specified time
    points
    • AL001 PK parameters (if data permit)
    - Cmax
    - Ctrough
    - AUCss

    Secondary Pharmacodynamic (PD) Biomarker Endpoints:
    • The overall change from baseline in PGRN in CSF
    • The overall change from baseline in PGRN in plasma
    •The overall change from baseline in SORT1 in WBCs

    Exploratory PD Biomarker Endpoints:
    •The overall change from baseline in exploratory biomarkers of neurodegeneration, lysosomal function, and glial activity in blood, plasma, and CSF
    •Global and regional brain MRI atrophy measures
    •Neuroinflammation assessed by TSPO-PET (for UK participants who agree to participate in the optional imaging assessment only; see Appendix 3 [Section 14.3]
    •Correlations among exploratory fluid biomarkers, imaging measures, and COAs

    Exploratory Clinical Endpoints:
    The overall change from baseline on the scores of the instruments in the COAs
    •Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD)
    •Frontotemporal Dementia Rating Scale (FRS)
    •Clinical Global Impression-Improvement (CGI I)
    •Clinical Global Impression-Severity (CGI S)
    •Color Trails Test (CTT) Part 2
    •Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
    •Winterlight and Summerlight Lab Speech Assessments (WLA and SLA; for participants who agree to participate in these optional assessments only)
    E.5.2.1Timepoint(s) of evaluation of this end point
    For Pharmacokinetic (PK), at day 1, day 10, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, day 309, day 337 and at study completion.

    For Pharmacodynamic (PD), at day 1, day 10, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, day 309, day 337 and at study completion.
    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 No
    E.6.6Pharmacokinetic Yes
    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) 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.8.3 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 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
    Canada
    United States
    Germany
    Italy
    Netherlands
    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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days41
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days41
    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: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 40
    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)
    According to their 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 Decision2019-07-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-18
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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