Efficacy and Safety of T-817MA in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD

Study Overview
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Brief Summary
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Primary objective is to evaluate the neuroprotective effect of T-817MA on Tau protein phosphorylated at threonine 181 (p-tau 181) in cerebrospinal fluid (CSF) compared with placebo in patients with a diagnosis of MCI due to AD or mild AD. Secondary objectives are: To evaluate in patients on T-817MA and placebo: cognitive function measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and working memory and attention domain as measured by the Cognitive Functional Composite (CFC). AD-related biomarkers in CSF and plasma imaging analysis using volumetric magnetic resonance imaging (vMRI) alpha/theta ratio of the electroencephalogram (EEG) To evaluate the safety of T-817MA by clinical laboratory tests and adverse events (AEs). To evaluate the pharmacokinetics of T-817MA

Official Title
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A Phase 2 Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of T-817MA in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease or Mild Alzheimer's Disease

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Drug: T-817MA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Female of non-childbearing potential or male, ages 50 to 80 years (inclusive) MCI due to AD or mild AD per NIA-AA diagnostic criteria (Jack et al., 2018), with MMSE 24 to 30 (inclusive) CSF results at Screening consistent with the presence of Aß and p-tau181 abnormality (≤1000 pg/ml for Aß, ≥19 pg/ml for p-tau181). Taking stable dose of AChE Inhibitor (donepezil, galantamine or rivastigmine) at least for 3 months prior to randomization, or not taking any AChE Inhibitors. Key Exclusion Criteria: MRI of the brain within the previous 2 years that showed pathology that would be inconsistent with a diagnosis of AD Taking memantine Any contraindications to lumbar puncture Any contraindications to MRI

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-817MA (448 mg)<br> | Drug: T-817MA<br>* 224mg T-817MA orally once daily for first 4 weeks, and then 448mg T-817MA orally once daily for the following weeks.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in the CSF p-tau181 from Baseline to Week 78 |  | Baseline to Week 78 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in the CSF p-tau181 from Baseline to Week 52 |  | Baseline to Week 52 | 
| The change in the CSF p-tau217 from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the CSF total tau from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the CSF Aβ1-42 from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the CSF Aβ1-40 from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the CSF neurofilament light (NFL) from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the CSF neurogranin from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the CSF YKL-40 from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the CSF Aβ1-42/Aβ1-40 ratio from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the plasma Aβ1-42 from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the plasma Aβ1-40 from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in the plasma NFL from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in cognitive function assessed by CDR-sb and working memory and attention domain as measured by the CFC from Baseline to Weeks 28, 52 and 78 |  | Baseline to Weeks 28, 52 and 78 | 
| The change in brain volume (total brain volume (TBV), ventricular volume and hippocampal volume) and cortical thickness measured by vMRI from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| The change in alpha/theta ratio measured by the EEG from Baseline to Weeks 52 and 78 |  | Baseline to Weeks 52 and 78 | 
| Safety as assessed by the occurrence of AEs, clinical laboratory tests, vital signs, physical examinations, ECGs |  | Screening to Week 82 | 
| Population PK analysis of T-817MA with assessment of maximum plasma concentration (Cmax) |  | Weeks 16, 28, 40, and 65 | 
| Population PK analysis of T-817MA with assessment of minimum plasma concentration (Cmin) |  | Weeks 16, 28, 40, and 65 | 
| Population PK analysis of T-817MA with assessment of total daily exposure (AUC0-24h) |  | Weeks 16, 28, 40, and 65 |