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
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 85
- 试验地点
- 57
- 主要终点
- Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals
研究概览
简要总结
This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in two parts followed by an optional open-label extension (OLE) period.
Part A will evaluate the safety, tolerability, PK, and PD of single doses of DNL593 in healthy male and healthy female participants of nonchildbearing potential. Part B will evaluate the safety, tolerability, PK, and PD of multiple doses of DNL593 in participants with frontotemporal dementia (FTD) over 25 weeks. Part B will be followed by Part C, an optional 18-month OLE period available for all participants who complete Part B.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 55 years
- •BMI of ≥ 18 to ≤ 32 kg/m²
- •When engaging in sex with a woman of child bearing potential, two forms of birth control are required
- •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
- •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.
排除标准
- •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
研究组 & 干预措施
DNL593 (Healthy Participant)
干预措施: DNL593 (Drug)
Placebo (Healthy Participant)
干预措施: Placebo (Drug)
DNL593 (Participants with FTD)
干预措施: DNL593 (Drug)
Placebo (Participants with FTD)
干预措施: Placebo (Drug)
结局指标
主要结局
Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals
时间窗: up to 18 months
Change from baseline in vital sign measurements: body temperature
时间窗: up to 18 months
Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)
时间窗: up to 18 months
Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
时间窗: up to 18 months
Change from baseline in vital sign measurements: systolic and diastolic blood pressure
时间窗: up to 18 months
Change from baseline in vital sign measurements: respiratory rate
时间窗: up to 18 months
Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings
时间窗: up to 18 months
Change from baseline in vital sign measurements: heart rate
时间窗: up to 18 months
Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)
时间窗: up to 18 months
次要结局
- PK Parameter: Maximum concentration (Cmax) of DNL593 in serum(up to 18 months)
- PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum(up to 18 months)
- PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593 in serum(up to 18 months)
- PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum(up to 18 months)
- PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)(up to 84 days)
- PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)(up to 18 months)
- PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)(up to 18 months)
- PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only)(up to 18 months)
- Concentration of DNL593 in cerebrospinal fluid (CSF)(up to 18 months)
- DNL593 CSF:serum concentration ratio(up to 18 months)
- Percentage change from baseline in plasma NfL(up to 18 months)