Alzheimer Disease, Preclinical Alzheimer's Disease
Conditions
Keywords
Tau protein, Immunotherapy, Vaccine, Preclinical Alzheimer's Disease, Alzheimer's Disease, secondary prevention, Neurodegeneration, Preventive Alzheimer's
Brief summary
This is a Phase 1, multicenter, randomized, double-blind, placebo-controlled, multiple-dose-escalation study evaluating the safety, tolerability, and immunogenicity of AV-1980R, an investigational vaccine targeting pathological tau, in participants with preclinical Alzheimer's disease. Up to 48 cognitively unimpaired adults aged 65 to 80 years with biomarker evidence of preclinical Alzheimer's disease will be enrolled into three ascending-dose cohorts.
Detailed description
This study will evaluate AV-1980R, a MultiTEP-based active immunotherapy formulated with Advax-CpG55.2 adjuvant, in participants with preclinical Alzheimer's disease. Up to 48 participants aged 65 to 80 years will be randomized in a 3:1 ratio to receive AV-1980R or placebo in three ascending-dose cohorts of 20 µg, 60 µg, and 180 µg. Participants will receive three intramuscular injections at Weeks 0, 4, and 38, with follow-up visits through Week 58. The primary objective is to evaluate safety and tolerability. Secondary objectives include evaluation of anti-tau antibody responses and T-cell responses. Exploratory assessments include plasma Alzheimer's disease biomarkers, tau PET imaging, immune-response characteristics, and cognitive measures.
Interventions
BIOLOGICALAV-1980R 20 µg
AV-1980R is an investigational recombinant protein tau vaccine based on the MultiTEP platform. Participants receive 20 µg of AV-1980R formulated with Advax-CpG55.2, consisting of Advax and CpG55.2, by intramuscular injection at Weeks 0, 4, and 38.
BIOLOGICALAV-1980R 60 µg
AV-1980R is an investigational recombinant protein tau vaccine based on the MultiTEP platform. Participants receive 60 µg of AV-1980R formulated with Advax-CpG55.2, consisting of Advax and CpG55.2, by intramuscular injection at Weeks 0, 4, and 38.
BIOLOGICALAV-1980R 180 µg
AV-1980R is an investigational recombinant protein tau vaccine based on the MultiTEP platform. Participants receive 180 µg of AV-1980R formulated with Advax-CpG55.2, consisting of Advax and CpG55.2, by intramuscular injection at Weeks 0, 4, and 38.
OTHERPlacebo
The placebo consists of 10 mM phosphate buffer without active AV-1980R, formulated with Advax-CpG55.2, consisting of Advax and CpG55.2. It is administered by intramuscular injection at Weeks 0, 4, and 38.
Sponsors
Institute for Molecular Medicine
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study is double-blind. Participants and clinical staff administering the investigational product will not know whether AV-1980R or placebo was assigned. The randomization schedule will be maintained in the interactive response technology system, and the AV-1980R and placebo vials will be masked to maintain the blind. Emergency unblinding is permitted only when treatment assignment is necessary for the participant's medical care.
Intervention model description
Participants are randomized in a 3:1 ratio to receive AV-1980R or placebo across three ascending dose cohorts. Each participant gets one assigned intervention in parallel with others.
Eligibility
Sex/Gender
ALL
Age
65 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Male or postmenopausal or surgically sterile female, 65 to 80 years of age, inclusive. Cognitively unimpaired participant with preclinical Alzheimer's disease who meets all of the following: Clinical Dementia Rating global score of 0 at Screening. Mini-Mental State Examination score ≥26, with education adjustment at Screening. Plasma p-tau217/Aβ42 ratio ≥0.00738 measured using Lumipulse (Fujirebio). A prior positive result obtained within 12 months before Screening may be accepted but must be confirmed by the central laboratory. Sight and hearing, including use of a hearing aid, sufficient to comply with study procedures. Stable concomitant medications. Participants receiving fluctuating medication or treatment may be considered if the underlying condition is controlled. Signed informed consent before any study-related procedure. Ability, in the Investigator's opinion, to understand the study and comply with protocol requirements.
Exclusion criteria
Screening MRI showing any of the following: More than one noncortical lacunar infarct greater than 1.5 cm. Any territorial infarct greater than 1.5 cm. Combined microbleeds and areas of leptomeningeal hemosiderosis greater than 5, or disseminated leptomeningeal hemosiderosis. Any other significant cerebral abnormality, including ARIA-E. Contraindication to MRI, including non-MRI-safe implanted metallic devices or clinically significant claustrophobia. Serious illness requiring systemic treatment or hospitalization within 4 weeks before study entry. Clinically relevant cardiovascular, respiratory, gastrointestinal, endocrine, immunologic, hematologic, systemic disease, or major surgery that could interfere with participation or follow-up. Insulin-dependent diabetes. Clinically relevant cardiac arrhythmia, palpitation, conduction abnormality, prolonged QT interval, or bundle branch block. Pre-existing autoimmune disease. C-SSRS score of 3 or higher. History of seizure disorder, except permitted stable use of certain antiepileptic medications for chronic pain. Any medical, psychological, or social condition that could interfere with participation, compliance, or participant safety. Participation in another investigational drug study or use of an investigational drug within 30 days or 5 half-lives, whichever is longer, before dosing. Prior tau or amyloid-beta immunotherapy within 1 year before Screening. Use of specified immunomodulatory or growth-stimulating treatments within 30 days before study entry. Chronic use for more than 3 months of warfarin, other coumarin derivatives, anticoagulants, or an antiplatelet agent such as clopidogrel. Parenteral immunoglobulin preparations, blood products, or plasma derivatives. History of severe local or systemic vaccination reactions or significant allergic reactions. Clinically significant laboratory abnormalities at Screening, including ALT or AST greater than 1.5 times the upper limit of normal. Positive testing for HIV-1 or HIV-2, hepatitis B surface antigen, or hepatitis C.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Treatment-Emergent Adverse Events and Serious Adverse Events | Baseline through Week 58 | Number of participants who experience one or more treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs), summarized by severity and relationship to study intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Clinically Significant Changes in Vital Signs | Baseline through Week 58 | Number of participants with clinically significant abnormalities or changes in blood pressure, heart rate, respiratory rate, or body temperature. |
| Number of Participants with Clinically Significant Changes in ECG Results | Baseline through Week 58 | Number of participants with new or worsening clinically significant ECG abnormalities. |
| Number of Participants with Clinically Significant Changes in Laboratory Tests | Baseline through Week 58 | Number of participants with new or worsening abnormalities in hematology, serum chemistry, coagulation, or urinalysis results. |
| Number of Participants with Clinically Significant Changes in Physical Examinations | Screening through Week 58 | Number of participants with new or worsening abnormal findings on physical examination. |
| Number of Participants with Clinically Significant Changes in Neurological Examinations | Screening through Week 58 | Number of participants with new or worsening abnormal neurological findings. |
| Number of Participants with New MRI Abnormalities, Including ARIA-E and ARIA-H | Screening and Weeks 6, 40, and 58 | Number of participants with new MRI findings of vasogenic edema or sulcal effusion (ARIA-E), cerebral microhemorrhage, macrohemorrhage, or superficial siderosis (ARIA-H), or new ischemic findings. |
| Change from Baseline in Columbia-Suicide Severity Rating Scale Assessment | Baseline and Weeks 38, 40, 50, and 58 | Change from baseline in suicidal ideation and behavior assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS). |
| Change from Baseline in Serum Anti-Tau Antibody Titers | Baseline through Week 58 | Serum anti-tau antibody titers measured using a validated enzyme-linked immunosorbent assay. |
| Change from Baseline in MultiTEP-Specific T-Helper Cell Responses | Baseline through Week 58 | MultiTEP-specific interferon-gamma-producing T-helper cells detected in peripheral blood mononuclear cells using an ELISPOT assay after stimulation with MultiTEP T-helper peptides. |
| Change from Baseline in Tau-Specific Autoreactive T-Helper Cell Responses | Baseline through Week 58 | Tau-specific interferon-gamma-producing T-helper cells detected in peripheral blood mononuclear cells using an ELISPOT assay after stimulation with the Tau2-18 peptide. |
Countries
United States
Contacts
CONTACTRoman Kniazev
CONTACTAnahit Ghochikyan
PRINCIPAL_INVESTIGATORMichael Agadjanyan, PhD
Institute MM
STUDY_DIRECTORRoman Kniazev
Institute MM
Outcome results
None listed