A Multiple-dose, Steady-state, Double-blind, Ascending Dose, Safety, Tolerability, Pharmacokinetic Study of AL001 in Patients With Mild to Moderate Alzheimer's Disease and Healthy Adult Subjects ("MAD Study")
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 65
- 试验地点
- 2
- 主要终点
- Number of Participants With Serious AEs, TEAEs That Lead to Premature Discontinuation, Abnormal Laboratory Test Results, Abnormal ECG Readings.
研究概览
简要总结
This is a Phase 1/2a, multi-center, placebo-controlled, double-blinded, randomized, multiple ascending dose (MAD) clinical trial to determine the safety and maximum tolerated dose of AL001. Up to 72 participants will be randomly assigned to receive study drug (active AL001) or placebo. The study consists of a 4-week screening period, a 14-day treatment period, and a 42-day follow-up period.
详细描述
This is a Phase 1/2a, multi-center, placebo-controlled, double-blind, randomized, multiple ascending dose (MAD) clinical trial to determine the safety and maximum tolerated dose (MTD) of AL001, a crystal engineered lithium-salicylate-proline lithium delivery product that in nonclinical studies was shown to enhance and prolong the pharmacokinetic (PK) profile of lithium in the brain with enhanced efficacy potential in Alzheimer's models compared to lithium carbonate.
A maximum of approximately 72 participants will be enrolled. Participants will be randomly assigned to receive study drug (active AL001) or placebo in a ratio of 6:2, respectively, with 8 patients in each dosing cohort. Placebos will be pooled and regarded as a comparative cohort for safety.
Cohorts 2a, 3a, 4a and 5a will involve 1:1 healthy non-elderly and elderly subjects; cohorts 1, 2b, 3b, 4b and 5b will involve Alzheimer's subjects. The study will consist of a screening period (Days -28 to -2), a 14-day treatment period, and a 42-day follow-up period.
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)
盲法说明
double-blind
入排标准
- 年龄范围
- 50 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Multiple Ascending Doses of AL001 vs. Placebo - Cohorts 2b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 2b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID).
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 1
Participants will be randomized to receive AL001. When adequate safety data are available, a review will be done for all participants to make a dose-escalation or dose and/or regimen modification decision. This will be repeated for each cohort.
A total of 9 cohorts will receive 5 different dose levels of AL001 in multiple ascending doses under fasted conditions up to tolerability/safety limits.
Cohort 1 will include 8 AD subjects. In this cohort, 6 active and 2 placebo AD subjects (as per randomization code) will receive the following treatment or placebo:
• Cohort 1: 60% of 450 mg lithium carbonate equivalent of AL001 (1890 mg AL001 daily ×14 days, given as 3 × 210 mg AL001 capsules TID)
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 1
Participants will be randomized to receive AL001. When adequate safety data are available, a review will be done for all participants to make a dose-escalation or dose and/or regimen modification decision. This will be repeated for each cohort.
A total of 9 cohorts will receive 5 different dose levels of AL001 in multiple ascending doses under fasted conditions up to tolerability/safety limits.
Cohort 1 will include 8 AD subjects. In this cohort, 6 active and 2 placebo AD subjects (as per randomization code) will receive the following treatment or placebo:
• Cohort 1: 60% of 450 mg lithium carbonate equivalent of AL001 (1890 mg AL001 daily ×14 days, given as 3 × 210 mg AL001 capsules TID)
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohorts 2a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 2a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 2a: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID).
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohorts 2a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 2a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 2a: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID).
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 3 will be sub-divided into 2 cohorts: Cohort 3a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 3b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 3a and 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID)
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 3 will be sub-divided into 2 cohorts: Cohort 3a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 3b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 3a and 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID)
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 4a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID)
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 4a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID)
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 5a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 5a: 200% of 450 mg lithium carbonate equivalent of AL001 (6300 mg AL001 daily × 14 days - lithium dose equivalent to that used for bipolar/affective disorders, given as 10 × 210 mg AL001 capsules TID)
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5a
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 5a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 5a: 200% of 450 mg lithium carbonate equivalent of AL001 (6300 mg AL001 daily × 14 days - lithium dose equivalent to that used for bipolar/affective disorders, given as 10 × 210 mg AL001 capsules TID)
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohorts 2b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 2b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID).
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 3b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID)
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 3b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID)
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 4b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID)
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 4b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID)
干预措施: Placebo (Other)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 5b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 5b: 200% of 450 mg lithium carbonate equivalent of AL001 (6300 mg AL001 daily × 14 days - lithium dose equivalent to that used for bipolar/affective disorders, given as 10 × 210 mg AL001 capsules TID).
干预措施: AL001 (Drug)
Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5b
The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated.
Cohort 5b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort:
• Cohort 5b: 200% of 450 mg lithium carbonate equivalent of AL001 (6300 mg AL001 daily × 14 days - lithium dose equivalent to that used for bipolar/affective disorders, given as 10 × 210 mg AL001 capsules TID).
干预措施: Placebo (Other)
结局指标
主要结局
Number of Participants With Serious AEs, TEAEs That Lead to Premature Discontinuation, Abnormal Laboratory Test Results, Abnormal ECG Readings.
时间窗: 42 days with a 14-day treatment period
To evaluate the safety and tolerability of AL001 in healthy subjects and patients with adverse event(s), AD, descriptive statistics will be presented by treatment group for each cohort and overall, for the following: Proportion of participants with treatment-emergent adverse events (TEAEs) * Proportion of participants with serious AEs * Proportion of participants with TEAEs that lead to premature discontinuation * Proportion of participants with abnormal values for each safety laboratory test (change from baseline) * Proportion of participants with abnormal values for each Electrocardiogram (ECG) parameter (change from baseline in standard 12-lead ECG parameters) For all analyses, placebo-treated subjects from each Cohort were combined (pooled) to provide a composite placebo group for all comparisons. Adverse event profiles for all treated subjects were benign as were placebo-treated subjects. No further statistical analyses were therefore appropriate.
次要结局
- Maximum Tolerated Dose of AL001 (Lithium Component) in All Subjects Treated With AL001(42 days with a 14-day treatment period)
- Maximum Tolerated Dose of AL001 (Salicylate Component) in All AL001-treated Subjects(42 days with a 14-day treatment period)