Innate Immunity Stimulation Via TLR9 in Early AD

• ClinicalTrials.gov Identifier: NCT05606341
• Recruitment Status: Recruiting
• First Posted: November 4, 2022
• Last Update Posted: March 12, 2024
• Sponsor: NYU Langone Health
• Collaborator: Alzheimer's Association
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Mild Cognitive Impairment; Alzheimer Dementia	Drug: CpG1018; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention 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 (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 1 Clinical Trial of Innate Immunity Stimulation Via TLR9 in Early Alzheimer's Disease (AD)
• Actual Study Start Date: March 13, 2023
• Estimated Primary Completion Date: November 2025
• Estimated Study Completion Date: November 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: CpG 1018 0.1 mg/kg; 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; 0.1 mg/kg dose administered via subcutaneous injection. TLR9 agonist supplied by Dynavax Technologies Inc.
Experimental: CpG 1018 0.25 mg/kg; 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; 0.25 mg/kg dose administered via subcutaneous injection. TLR9 agonist supplied by Dynavax Technologies Inc.
Experimental: CpG 1018 0.5 mg/kg; 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; 0.5 mg/kg dose administered via subcutaneous injection. TLR9 agonist supplied by Dynavax Technologies Inc.
Placebo Comparator: Placebo; 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; Sterile saline injection supplied by the NYU Investigational Pharmacy.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change in AD Assessment Scale Cognitive Subscale (ADAS-Cog-13) Scores [ Time Frame: Baseline, Week 18 ]
   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.
2. Change in AD Cooperative Study-Activities of Daily Living Inventory, Mild Cognitive Impairment version (ADCS-ADL-MCI) Scores [ Time Frame: Baseline, Week 18 ]
   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.
3. Change in Columbia-Suicide Severity Rating Scale (C-SSRS) Scores [ Time Frame: Baseline, Week 18 ]
   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.
4. Change in Global Clinical Dementia Rating (CDR-Global) [ Time Frame: Baseline, Week 18 ]
   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.
5. Change in Montreal Cognitive Assessment (MoCa) Score [ Time Frame: Baseline, Week 18 ]
   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.
6. Change in Plasma Amyloid Biomarker Concentration [ Time Frame: Baseline, Week 18 ]
   Amyloid biomarker concentration detected via plasma analysis.
7. Change in Cerebral Spinal Fluid (CSF) Amyloid Biomarker Concentration [ Time Frame: Baseline, Week 18 ]
   Amyloid biomarker concentration detected via CSF analysis.
8. Change in Plasma Tau Biomarker Concentration [ Time Frame: Baseline, Week 18 ]
   Tau biomarker concentration detected via plasma analysis.
9. Change in CSF Tau Biomarker Concentration [ Time Frame: Baseline, Week 18 ]
   Tau biomarker concentration detected via CSF analysis.

Eligibility Criteria

• Ages Eligible for Study: 60 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 65-85 years of age
2. MCI due to AD or mild AD dementia per NIA-AA specified criteria published in 2018
3. Montreal Cognitive Assessment (MoCA) score ≥17 AND;
4. Positive Florbetaben PET amyloid scan, or other positive PET amyloid scan performed within one year of study enrollment
5. Must be able to provide consent or assent (If applicable).
6. Must be willing and able to participate in all study related procedures.
7. 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:

1. 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
2. History of autoimmune disorders or antibody-mediated disease, severe asthma, or other serious infection or systemic illness, as determined by PI
3. Use of corticosteroids or immunosuppressive drugs within 30 days of study entry
4. History of splenectomy
5. Renal impairment
6. Use of chloroquine within 8 weeks of study entry
7. Inability to undergo MRI imaging
8. History of TIA, stroke or seizures within 12 months of screening
9. Any neurological condition other than AD that could contribute to cognitive impairment (including related to possible "long COVID") as determined by PI
10. Participation in any other current AD investigational interventional trial
11. Current use of an anti-coagulant
12. Current use of drugs that are major substrates of cytochrome P450 (CYP) enzyme 1A2
13. 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

Contacts and Locations

Contacts

Contact: Alok Vedvyas; 212-263-2048; Alok.Vedvyas@nyulangone.org

Locations

United States, New York

NYU Langone Health; Recruiting

New York, New York, United States, 10016

Sponsors and Collaborators

NYU Langone Health

Alzheimer's Association

Investigators

• Principal Investigator: Arjun Masurkar, MD; NYU Langone Medical Center

More Information

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT05606341
• Other Study ID Numbers: 20-00267
• First Posted: November 4, 2022
• Last Update Posted: March 12, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The de-identified participant data from the final research dataset used in the published manuscript will be shared upon reasonable request beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research provided the investigator who proposes to use the data executes a data use agreement with NYU Langone Health. Requests may be directed to: Alok.Vedvyas@nyulangone.org. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• Access Criteria: The investigator who proposed to use the data will have access to the data upon reasonable request. Requests should be directed to Alok.Vedvyas@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alzheimer Disease; Cognitive Dysfunction; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Tauopathies; Neurodegenerative Diseases; 1018 oligonucleotide; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs