Effect of 10 mg Xanamem on Dementia Due to Alzheimer's Disease

Study Overview
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Brief Summary
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Xanamem® is being developed as a potential treatment for symptomatic, early stages of Alzheimer's Disease (AD) and Major Depressive Disorder (MDD). This XanaMIA Phase 2b study is to investigate the safety, tolerability, and efficacy of Xanamem in in mild or moderate dementia due to AD. Trial participants will be randomized to either receive 10mg of Xanamem once daily or a placebo for 36 weeks at a 1:1 ratio in a double-blinded fashion.

Official Title
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A Phase 2b, Double-Blind, Placebo-Controlled, Parallel-Groups, 36-Week, 2-Arm Trial to Assess the Safety, Tolerability, and Efficacy of Xanamem® 10 mg Daily in Patients With Mild or Moderate Dementia Due to Alzheimer's Disease

Conditions
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Dementia Moderate, Dementia, Mild, Alzheimer Disease

Intervention / Treatment
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* Drug: Xanamem
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 50 years or older, inclusive at the time of Screening. Clinical syndrome of mild or moderate dementia, likely to be due to AD in the opinion of the Investigator, at Screening, including meeting the following criteria: Clinical Dementia Rating (CDR) global score of 0.5 to 1.0 Mini-mental state examination (MMSE) score of 18 to 26 Magnetic resonance imaging (MRI) or computerized tomography (CT) scan within 1 year prior to randomization that excludes alternative diagnoses for dementia such as large stroke, likely vascular dementia, brain tumor, subdural hematoma, or other non-AD dementia type findings Positive plasma AD biomarker signature at Pre-screening, comprising fasting levels of p-tau181 ≥ 6.7 pg/mL per the Quanterix Simoa assay or equivalent levels using a comparable immunoassay. Cognitive impairment on a symbol coding test of at least 0.5 standard deviations (SD) below the normative data at Screening. If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to Screening. Has a consenting trial partner who, in the Investigator's judgment, has frequent and sufficient contact with the participant to be able to provide accurate information as to the participant's cognitive and functional abilities. The trial partner must be available to provide information to the Investigator and trial site staff about the participant and agrees to attend all trial site visits in person for scale completion. A trial partner should be available for the duration of the trial. The measure of adequate availability will be at the Investigator's discretion. Participants must be able to comfortably abstain from caffeine intake for 4 hours prior to scheduled cognitive assessments. Smokers are eligible if they are able to comfortably abstain from nicotine / tobacco products for 2 hours prior to scheduled cognitive assessments. Must provide written informed consent to participate in the trial and be willing and able to participate for the maximum of 9 months of treatment and up to 11.5 months of site visits. Exclusion Criteria: Use of anti-amyloid or anti-tau antibody within 6 months. Diagnosis of a non-AD dementia including traumatic brain injury. Diagnosis of an active major mental illness of concern in the opinion in the Investigator, including major depressive disorder, bipolar illness, or schizophrenia. Participation in another clinical trial of a drug or device Has a body mass index or body weight that will interfere with participation in the trial, including inadequate venous access to complete the trial assessments, to be determined at the discretion of the Investigator. Previous clinically significant systemic illness or infection, including test positive COVID-19, within the past 4 weeks prior to Screening. Clinical diagnosis of Type I or Type II diabetes requiring insulin. Exhibit physical, cognitive, or language impairments, in the opinion of the Investigator, of such severity as to adversely affect the validity of the data derived from the neuropsychological tests. Trial participants with evidence of current infection with HIV, hepatitis B, or hepatitis C. Participants with a history of clinically significant drug abuse or addiction in the past 2 years Evidence or history of alcohol abuse

Ages Eligible for Study
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Minimum Age: 50 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: 10 mg Xanamem<br>10 mg Xanamem tablet, to be administered orally once every morning with or without food | Drug: Xanamem<br>* Xanamem drug product is formulated as an immediate-release film-coated tablet formulation for oral administration. Each Xanamem tablet contains 10 mg Xanamem (UE2343) drug substance and excipients.<br>* Other names: UE2343;|
| Placebo Comparator: Placebo<br>Placebo tablet, to be administered orally once every morning with or without food | Drug: Placebo<br>* Matching placebo which is identical in appearance to the test product (10 mg Xanamem once daily) except that it contains no active ingredient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of 10 mg Xanamem on cognition | Change from Baseline to end of treatment (EOT) in a custom global cognitive test battery (CTB). The global CTB is calculated as an average Z-score, with higher scores indicating improvement. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) [safety and tolerability of Xanamem] | Incidence and severity of TEAEs | 36 weeks (Baseline to Week 36 [EOT]) | 
| Incidence of SAEs and suspected unexpected serious adverse reactions (SUSARs) [safety and tolerability of Xanamem] | Incidence of SAEs and SUSARs | 36 weeks (Baseline to Week 36 [EOT]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of Xanamem on integrated cognitive and functional abilities | Change from Baseline to EOT in the Clinical Dementia Ratio - Sum of Boxes (CDR-SB) | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on early impairment of daily functioning due to cognitive decline | Change from Baseline to EOT on the Amsterdam Instrumental Activities of Daily Living Questionnaire - short version (A-IADL-Q-SV). Each question is given a score from 1 to 5, with higher scores indicating a better outcome. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on attention and working memory | Change from Baseline to EOT in an Attention Composite. Scores are calculated as an average Z-score, with higher scores indicating improvement. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on executive function | Change from Baseline to EOT in an Executive Function Composite. Scores are calculated as an average Z-score, with higher scores indicating improvement. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on episodic memory | Change from Baseline to EOT in an Episodic Memory Composite. Scores are calculated as an average Z-score, with higher scores indicating improvement. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on paper and pencil tests of cognition (visual attention and executive function) | Change from Baseline to EOT in Trail Making A and B Tests, measured as time taken to complete (seconds). Higher scores indicate a worse outcome. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on biomarkers of AD. | Change from Baseline to EOT in plasma AD biomarkers. Biomarkers to be assessed are: p-tau181, p-tau217, amyloid-beta 1-40, amyloid-beta 1-42, neurofilament light, glial fibrillary acidic protein (all pg/mL). | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on AD biomarker ratios | Change from Baseline to EOT in ratios of plasma AD biomarkers: amyloid-beta 1-42/1-40 and p-tau181/amyloid-beta 1-42. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem on neuropsychiatric symptoms of AD | Change from Baseline to EOT on the Neuropsychiatric Inventory (NPI) and its component scores. A total score is calculated from the frequency and severity of each behavior. Higher scores indicate a worse outcome. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem using clinicians' and participant/trial partner's global impression measures | Change from Baseline to EOT in the Clinician's Global Impression of Severity Scale (CGI-S). Assessment is made on a seven-point scale, with a higher score indicating a worse outcome. | 36 weeks (Baseline to Week 36 [EOT]) | 
| Effects of Xanamem using clinicians' and participant/trial partner's global impression measures | Change from Baseline to EOT in the participant/trial partner's scores in the Patient's Global Impression of Change (PGI-C). Assessment is made on a seven-point scale, with a higher score indicating a worse outcome. | 36 weeks (Baseline to Week 36 [EOT]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Xanamem, Actinogen, Alzheimer's Disease, Cortisol