frontotemporale dementie brain disease dementia
Conditions
Interventions
Study Interventions, Dose, and Mode of Administration
• Study interventions: DNL593 and DNL593 placebo, both provided as a sterile
lyophilisate. On the label, the drug product may be described as *ly
route of administration and dosing interval will be
selected based on emerging safety, PK, and PD data from previous cohorts.
Sponsors
Denali Therapeutics Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Part B: • Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged >=18 to = 18 to = 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.
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary objective part B: - To investigate the safety and tolerability of multiple doses of DNL593 in participants with FTD-GRN Primary endpoint: - 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 Primary objective part C: - To investigate the safety and tolerability of multiple doses of DNL593 in participants with FTD-GRN up to 18 months Primary endpoint: - 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objective 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 of DNL593 in participants with FTD-GRN Secondary endpoints: - DNL593 serum PK parameters (when feasible): o Cmax o tmax o Trough concentration (Ctrough) o AUClast o AUC from time 0 to the end of the dosing interval (AUC*) o t1/2 o Accumulation ratio - DNL593 CSF concentrations 24 hours postdose at Week 25 - DNL593 CSF:serum concentration ratio at Week 25 Secondary objective 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 Secondary endpoints: - DNL593 serum PK parameters (when feasible): o Cmax o tmax o Ctrough o AUClast o AUC* o t1/2 o Accumulation ratio - DNL593 concentration 24 hours postdose at multiple time points - DNL593 CSF:serum concentration ratio at multiple time points | — |
Countries
Netherlands
Outcome results
None listed