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 FTDGRN. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part B: • Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 80 years. Women who are of childbearing potential but on highly effective, low user dependent contraceptive methods will be allowed. • BMI of ≥ 18 to ≤ 32 kg/m² • Have a Clinical Dementia Rating® plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration global score ≥ 0.5 • Have confirmed granulin (GRN) mutation via genetic testing or historical records available for review by investigator • When engaging in sex with a woman of child bearing potential, both the male participant and his female partner must use highly effective contraception
Part C • All participants who completed Part B of this trial are eligible for an 18-month OLE if the participant has no unresolved clinically significant TEAEs, where continued dosing may represent a risk to participant safety.
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E.4 | Principal exclusion criteria |
Part B • Have any history of clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders • Have a history of malignancy, except fully resected basal cell carcinoma or other malignancies at low risk of recurrence • Have a clinically significant history of stroke, cognitive impairment due to causes other than FTD, seizure within 5 years of screening, or head trauma with loss of consciousness within 2 years of screening • Have a positive serum pregnancy test or are currently lactating or breastfeeding
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) |
1. Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs) 2. Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values 3. Change from baseline in vital sign measurements: systolic and diastolic blood pressure 4. Change from baseline in vital sign measurements: heart rate 5. Change from baseline in vital sign measurements: respiratory rate 6. Change from baseline in vital sign measurements: body temperature 7. Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals 8. Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings 9. Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. PK Parameter: Maximum concentration (Cmax) of DNL593 in serum 2. PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum 3. PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593 in serum 4. PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum 5. PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only) 6. PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only) 7. PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only) 8. PK Parameter: AUC from time 0 to the end of the dosing interval (AUCĪ) of DNL593 in serum (Parts B and C only) 9. Concentration of DNL593 in cerebrospinal fluid (CSF) 10. DNL593 CSF: serum concentration ratio |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Brazil |
Colombia |
United States |
Turkey |
Serbia |
Belgium |
Czechia |
France |
Italy |
Netherlands |
Portugal |
Spain |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |