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    Summary
    EudraCT Number:2021-005733-16
    Sponsor's Protocol Code Number:DNLI-H-0001
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-06-15
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2021-005733-16
    A.3Full title of the trial
    A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double-Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia Followed by an Open-Label Extension
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 3 Part first-in-human study of DNL593 in healthy volunteers and patients with frontotemporal dementia (FTD)
    A.3.2Name or abbreviated title of the trial where available
    Part B, C of first in human study of DNL593 in FTD patients
    A.4.1Sponsor's protocol code numberDNLI-H-0001
    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 SponsorDenali Therapeutics 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 supportDenali Therapeutics Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDenali Therapeutics Inc.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address161 Oyster Point Blvd.
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number1650238-4979
    B.5.6E-mailhuland@dnli.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 nameDNL593 Sterile Lyophilisate
    D.3.2Product code DNL593
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeDNL593
    D.3.9.3Other descriptive nameDNL593
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number37.00 to 43.00
    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 placeboLyophilisate for solution 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 (FTD)
    E.1.1.1Medical condition in easily understood language
    FTD - condition of the brain associated with loss of brain cells, affecting behaviour, judgement, language, memory
    and motor skills
    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
    Part B
    - To investigate the safety and tolerability of multiple doses of DNL593 in participants with FTD-GRN.
    Part C
    - To investigate the safety and tolerability of multiple doses of DNL593 in participants with FTD-GRN up to 18 months.
    E.2.2Secondary objectives of the trial
    Part B
    - To characterize the serum PK of DNL593 following multiple doses of DNL593 in participants with FTD-GRN.
    - To characterize the concentration of DNL593 in CSF following multiple doses in participants with FTD-GRN.
    Part C
    - To characterize the serum PK of DNL593 following multiple doses of DNL593 in participants with FTD-GRN.
    - To characterize the concentration of DNL593 in CSF following multiple doses of DNL593 in participants with FTDGRN.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part B
    1.Aged ≥ 18 to ≤ 80 years
    2.Have a BMI of ≥ 18 to ≤ 32 kg/m2
    3.Are willing and able to give informed consent for study participation or have a care partner or LAR who is willing and
    able to provide consent
    4.Have a study partner who is able to reliably complete the CDR plus NACC FTLD with participant and will accompany
    the participant to study visits or be available by telephone at designated times. Study partner must have frequent
    contact with participant (> 10 hours per week) and be able to reasonably participate in all CDR plus NACC FTLD
    assessments in the study period.
    Note: A second study partner may serve as backup, but it is preferred that one study partner be primarily responsible
    for the CDR plus NACC FTLD assessments.
    5.Are able to communicate with the investigator and staff either independently or through a caregiver
    6.Are willing and able to comply with the requirements of the study, including scheduled visits, study restrictions,
    laboratory tests, and all other study procedures. In the investigator’s opinion, both participant and caregiver are able to
    complete all required study procedures and visits during the Part B period of 24 weeks.
    7.Women of non-childbearing potential, defined as must have been surgically sterilized (hysterectomy, bilateral
    oophorectomy/salpingectomy, or bilateral tubal ligation; proper documentation required) > 3 months prior to dosing
    (Essure fallopian tube coil placement is not accepted as surgical sterilization because of the high failure rate), or be
    postmenopausal (amenorrheic for > 12 consecutive months before dosing, with a FSH level of > 40 IU/L at screening).
    Women who are of childbearing potential but on highly effective, low user dependent contraceptive methods will be
    allowed.
    8.For men: When engaging in sex with a WOCBP, both the male participant and his female partner must use highly
    effective contraception consisting of two forms of birth control, one of which must be a male barrier method (such as a
    latex or polyurethane condom), from the start of dosing, throughout the study period, and for 90 days after the final
    administration of study intervention.
    9.For men: The participant must not donate sperm at any time from the start of dosing, throughout the study period,
    and for 90 days after the final administration of study intervention.
    10.Have a diagnosis of FTD, including the probable bvFTD or PPA. Other diagnosis related to FTD syndrome,
    including, but not limited to, CBS or progressive supranuclear palsy (PSP) syndrome, are allowed pending Sponsor
    and investigator agreement.
    11.Have a CDR plus NACC FTLD global score ≥ 0.5
    12.Have confirmed GRN mutation via genetic testing or historical records available for review by investigator
    13.Doses of other chronic prescription medications that may affect cognition or behaviour at the determination of the
    investigator must be stable for ≥ 1 month prior to screening; participant is expected to stay on a stable regimen
    throughout the study. Participants who initiated or changed medication (described above) doses within 1 month prior
    to screening may be rescreened after dose stabilization.
    Part C
    Participants from Part B who complete the double-blind period through the SFU visit are eligible to enter the 18-month
    Part C OLE, at the discretion of the investigator and Sponsor. Each participant will be reconsented for the OLE.
    E.4Principal exclusion criteria
    Part B
    1.Have any history of unstable or poorly controlled psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal,
    hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders. Well
    controlled conditions are permitted if investigator and Sponsor agree.
    2.Have a history of malignancy within 5 years before screening, except fully resected basal cell carcinoma or other
    malignancies (such as prostate cancer) at low risk of recurrence, depending on investigator and medical monitor
    agreement
    3.Have a history of clinically significant neurologic disorders other than FTD (for Part B only), including stroke, cognitive
    impairment due to causes other than FTD, or seizure within 5 years of screening, or head trauma with loss of
    consciousness within 2 years of screening. Note: Single incidence of provoked seizure with a clear cause may be
    acceptable with Investigator and Sponsor approval.
    4.Have the presence of any contraindication to MRI of the brain
    5.Have a current significant psychiatric disorder, suicidal ideation in the previous 6 months as assessed by the
    Baseline/Screening version of the C-SSRS (for Part B only)
    6.Have evidence of hepatic impairment, including ALT or AST > 2 × ULN or bilirubin> 1.5 × ULN at screening or
    baseline.
    7.Have a history of clinically significant renal impairment or an eGFR < 45 mL/min/1.73 m2 at screening
    8.Have a history or presence of a clinically significant ECG abnormality
    9.Have donated or lost > 500 mL whole blood within 30 days before entry in the treatment period
    10.Received vaccination (including second dose or any booster shots) against SARS-CoV-2 within 4 weeks of the start
    of dosing.
    11.Have any other issue that, in the opinion of the investigator, would make the participant ineligible for study
    participation
    For full exclusion criterion for Part B, please refer to Section 5.1.2.2 of the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Part B
    - Incidence, severity, and seriousness of TEAEs during the 24-week double-blind period
    - Change from baseline in safety laboratory values, vital sign measurements, ECG results, Columbia-Suicide Severity
    Rating Scale (C-SSRS), and physical and neurological examination findings during the 24-week double-blind period
    Part C
    - Incidence, severity, and seriousness of TEAEs during the OLE period
    - Change from baseline in safety laboratory values, vital sign measurements, ECG results, C-SSRS, and
    physical/neurological examination findings during the OLE period
    E.5.1.1Timepoint(s) of evaluation of this end point
    AE
    - Part A, B & C - AEs will be recorded from the point of informed consent up to final post-study follow up visit in each
    part.
    The remaining primary endpoints will be evaluated at set timepoints in each study part within the following periods:
    Part B - Set timepoints from screening to Week 29
    Part C - Set timepoints from Week 29 to Week 109
    Please see full schedule of assessments within the study protocol for full details of timepoints for evaluation.
    E.5.2Secondary end point(s)
    The secondary outcome measures for this study are pharmacokinetic parameters for the analysis of serum
    concentrations of DNL593 and cerebrospinal fluid (CSF) concentrations of DNL593.
    Endpoints are defined as follows:
    Part B
    DNL593 serum PK parameters (when feasible):
    - Cmax
    - tmax
    - Trough concentration (Ctrough)
    - AUClast
    - AUC from time 0 to the end of the dosing interval (AUCτ)
    - t1/2
    - Accumulation ratio
    DNL593 CSF concentrations 24 hours post dose at Week 25
    - DNL593 CSF:serum concentration ratio at Week 25
    Part C
    DNL593 serum PK parameters (when feasible):
    - Cmax
    - tmax
    - Ctrough
    - AUClast
    - AUCτ
    - t1/2
    - Accumulation ratio
    DNL593 concentration 24 hours post dose at multiple time points
    - DNL593 CSF:serum concentration ratio at multiple time points
    E.5.2.1Timepoint(s) of evaluation of this end point
    Serum PK
    Part B - 41 samples from Day 1 pre-dose to Week 29
    Part C - 51 samples from Week 29 pre-dose to Week 109

    CSF
    Part B - Day -1, Week 13 & Week 25
    Part C - Screening (12 weeks before Week 29), Week 41 & Week 53
    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) 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 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 Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Argentina
    Brazil
    Colombia
    United States
    France
    Sweden
    Netherlands
    Spain
    Czechia
    Italy
    Belgium
    Hungary
    Portugal
    Serbia
    Turkey
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 17
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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
    Patients with FTD with appointed study partner as an authorized representative to provide consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 28
    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)
    Not applicable as this is an experimental therapy - following completion of the post-study follow up visit, all participants
    will be discharged from the study provided that the Investigator deems it appropriate to do so.
    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 Decision2023-01-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-02-03
    P. End of Trial
    P.End of Trial StatusOngoing
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