Innate Immunity Stimulation Via TLR9 in Early AD

Study Overview
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Brief Summary
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This single-center, double-blind, placebo-controlled study will recruit in total 39 participants with either Mild Cognitive Impairment due to Alzheimer's disease (MCI) or Mild Alzheimer's disease dementia (mild AD). There will be 3 Dose levels. An initial cohort of 13 subjects will be randomized to a Dose level 1 (0.1 mg/kg vs. placebo) lasting 8 weeks. An additional 13 subjects will be recruited and randomized into Dose level 2 (0.25 mg/kg vs. placebo) for 8 weeks and 13 subjects for the last Dose level 3 (0.5 mg/kg vs. placebo) for 8 weeks. The primary objective will be to assess safety and tolerability of CpG 1018.

Official Title
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Phase 1 Clinical Trial of Innate Immunity Stimulation Via TLR9 in Early Alzheimer's Disease (AD)

Conditions
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Mild Cognitive Impairment, Alzheimer Dementia

Intervention / Treatment
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* Drug: CpG1018
* Drug: CpG1018
* Drug: CpG1018
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 65-85 years of age MCI due to AD or mild AD dementia per NIA-AA specified criteria published in 2018 Montreal Cognitive Assessment (MoCA) score ≥17 AND; Positive Florbetaben PET amyloid scan, or other positive PET amyloid scan performed within one year of study enrollment Must be able to provide consent or assent (If applicable). Must be willing and able to participate in all study related procedures. Must have a reliable study partner to provide information on the subject's cognitive and functional status. Study partner must have sufficient contact with the subject, as determined by the PI, and be available to accompany the subject to clinic visits or by phone. Exclusion Criteria: History of psychiatric illness (e.g. hallucinations, major depression, suicidal ideation or delusions) that could interfere with completion of study related procedures as determined by PI History of autoimmune disorders or antibody-mediated disease, severe asthma, or other serious infection or systemic illness, as determined by PI Use of corticosteroids or immunosuppressive drugs within 30 days of study entry History of splenectomy Renal impairment Use of chloroquine within 8 weeks of study entry Inability to undergo MRI imaging History of TIA, stroke or seizures within 12 months of screening Any neurological condition other than AD that could contribute to cognitive impairment (including related to possible long COVID) as determined by PI Participation in any other current AD investigational interventional trial Current use of an anti-coagulant Current use of drugs that are major substrates of cytochrome P450 (CYP) enzyme 1A2 Recent exposure to COVID-19 infection within 14 days or recent onset of symptoms within 14 days that may be related to COVID-19 infection

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 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: Sequential Assignment
Interventional Model Description: Subjects will be randomly allocated in a blinded fashion to receive s.c. injection of either CpG ODN (dose level 1, 0.1 mg/kg) or placebo (saline). Dose escalation will occur after 10 weeks after the last injection in a new subject cohort, and will be based on the safety data and immunostimulatory assessments at previous dose level cohorts.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CpG 1018 0.1 mg/kg<br>3 injections at Day 1, Week 4, and Week 8. Treatment administered as morning injection of dose 0.1mg/kg, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions. | Drug: CpG1018<br>* 0.1 mg/kg dose administered via subcutaneous injection. TLR9 agonist supplied by Dynavax Technologies Inc.<br>|
| Experimental: CpG 1018 0.25 mg/kg<br>3 injections at Day 1, Week 4, and Week 8. Treatment administered as morning injection of dose 0.25 mg/kg, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions. | Drug: CpG1018<br>* 0.25 mg/kg dose administered via subcutaneous injection. TLR9 agonist supplied by Dynavax Technologies Inc.<br>|
| Experimental: CpG 1018 0.5 mg/kg<br>3 injections at Day 1, Week 4, and Week 8. Treatment administered as morning injection of dose 0.5 mg/kg, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions. | Drug: CpG1018<br>* 0.5 mg/kg dose administered via subcutaneous injection. TLR9 agonist supplied by Dynavax Technologies Inc.<br>|
| Placebo Comparator: Placebo<br>3 injections of sterile saline at Day 1, Week 4, and Week 8, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions. | Drug: Placebo<br>* Sterile saline injection supplied by the NYU Investigational Pharmacy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patient-Reported Adverse Events (AEs) | AEs defined as any symptom, sign, illness or experience that develops or worsens in severity during the course of the study. | Up to Week 18 | 
| Percentage of Participants with Rheumatoid Factor (RF) Confirmed by Autoimmunity Marker Screening Test Result | Evaluation of RF in patient blood samples at Baseline, Day 56, Week 14 and Week 18. | Up to Week 18 | 
| Percentage of Participants with Antinuclear Antibody (ANA) Confirmed by Autoimmunity Marker Screening Test Result | Evaluation of ANA in patient blood samples at Baseline, Day 56, Week 14 and Week 18. | Up to Week 18 | 
| Percentage of Participants with Antineutrophil Cytoplasmic Antibody (ANCA) Confirmed by Autoimmunity Marker Screening Test Result | Evaluation of ANCA in patient blood samples at Baseline, Day 56, Week 14 and Week 18. | Up to Week 18 | 
| Percentage of Participants with Amyloid-Related Imaging Abnormalities-Haemosiderin (ARIA-H) Confirmed by Magnetic Resonance Imaging (MRI) | Evaluation of ARIA-H at Baseline and Week 14 using 3T PET/MR Siemens Biograph system. | Up to Week 14 | 
| Percentage of Participants with Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) | Evaluation of ARIA-E at Baseline and Week 14 using 3T PET/MR Siemens Biograph system. | Up to Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in AD Assessment Scale Cognitive Subscale (ADAS-Cog-13) Scores | 13-item self-assessment measuring levels of cognitive and non-cognitive dysfunctions from mild to severe. Total scores range from 0 to 85. Lower scores indicate greater cognitive performance. A decrease in scores indicates cognitive performance improved during the observational period. | Baseline, Week 18 | 
| Change in AD Cooperative Study-Activities of Daily Living Inventory, Mild Cognitive Impairment version (ADCS-ADL-MCI) Scores | 18-item questionnaire measuring a participant's basic and instrumental activities of daily living over the previous month. Total scores range from 0-53, where higher scores indicate greater competence in performing activities. An increase in scores indicates competence increased during the observational period. | Baseline, Week 18 | 
| Change in Columbia-Suicide Severity Rating Scale (C-SSRS) Scores | C-SSRS systematically tracks suicidal ideation and behavior. The total score range is 0 (no ideation is present) to 5 (active suicidal ideation with specific plan and intent). A decrease in scores indicates suicidal ideation and behavior decreased during the observational period. | Baseline, Week 18 | 
| Change in Global Clinical Dementia Rating (CDR-Global) | 5-point questionnaire assessing six domains of cognitive and functional performance applicable to Alzheimer's disease and related dementias: Memory, Orientation; Judgement & Problem Solving; Community Affairs; Home & Hobbies; and Personal Care. Higher scores indicate greater severity of dementia: 0= Normal, 0.5=very mild dementia, 1=mild dementia, 2=moderate dementia, 3=severe dementia. | Baseline, Week 18 | 
| Change in Montreal Cognitive Assessment (MoCa) Score | 30-item assessment of global cognitive function. Total scores range from 0 to 30, with higher scores indicating greater cognitive function. Scores of 26 and higher are consider to be normal. An increase in scores indicates cognitive function increased during the observational period. | Baseline, Week 18 | 
| Change in Plasma Amyloid Biomarker Concentration | Amyloid biomarker concentration detected via plasma analysis. | Baseline, Week 18 | 
| Change in Cerebral Spinal Fluid (CSF) Amyloid Biomarker Concentration | Amyloid biomarker concentration detected via CSF analysis. | Baseline, Week 18 | 
| Change in Plasma Tau Biomarker Concentration | Tau biomarker concentration detected via plasma analysis. | Baseline, Week 18 | 
| Change in CSF Tau Biomarker Concentration | Tau biomarker concentration detected via CSF analysis. | Baseline, Week 18 |