E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Frontotemporal Dementia (FTD) |
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E.1.1.1 | Medical condition in easily understood language |
FTD - condition of the brain associated with loss of brain cells, affecting behaviour, judgement, language, memory and motor skills |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068968 |
E.1.2 | Term | Frontotemporal dementia |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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 FTD-GRN. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary 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 |
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |