A Multi-center, Randomized, Double-blind, Placebo-controlled, 24 Months Study in Patients With Amnestic Mild Cognitive Impairment or Very Mild Alzheimer's Disease to Investigate the Safety, Tolerability and Immune Response of Repeated Subcutaneous Injections of ABvac40
Overview
- Phase
- Phase 2
- Intervention
- ABvac40
- Conditions
- Mild Cognitive Impairment
- Sponsor
- Araclon Biotech S.L.
- Enrollment
- 134
- Locations
- 23
- Primary Endpoint
- Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
Alzheimer's disease (AD) is the most common type of dementia, accounting for 50-75% of the estimated 47 million people with dementia worldwide. The amyloid cascade hypothesis of AD proposes that amyloid-β (Aβ) peptide accumulation in the brain, caused by an imbalance between Aβ production and clearance, is the initiating factor of a cascade ultimately leading to dementia.
Aβ peptides are generated from sequential cleavage of the amyloid precursor protein (APP), including Aβ40 and Aβ42. Aβ40 is the predominant variant (90%) among the secreted Aβ forms and although Aβ42 is more hydrophobic and prone to aggregate, and Aβ42 oligomers are regarded to be the most neurotoxic species, Aβ40 can also produce highly toxic diffusible aggregates, which can be prevented in vitro by specific anti-Aβ40 antibodies.
Several studies have proposed that a high concentration of Aβ40 in the brain distinguishes patients with AD from those who have senile plaques but are cognitively normal, pointing to the importance of Aβ40 in the onset of dementia. In keeping with this, previous studies have demonstrated that specific anti-Aβ40 antibodies label NFTs in the entorhinal cortex and the hippocampus of AD brains, and that these do not co-localize with tau NFTs, suggesting the presence of degenerating neuronal populations filled with C-terminal fragments of Aβx-40. In addition, Aβ40 is the main component of amyloid deposition around cerebral arteries causing cerebral amyloid angiopathy (CAA), which has a prevalence of about 80-90% in patients with AD (for more information see Lacosta et al. Alzheimer's Research & Therapy (2018) 10:12 DOI 10.1186/s13195-018-0340-8).
Considering those previous results suggesting that strategies targeting Aβ40 could represent novel disease-modifying therapies, we have developed ABvac40, the first active vaccine targeting the C-terminal end of the Aβ40 peptide.
The purpose of this Phase II study is to confirm in patients with a-MCI or vm-AD the level of safety and tolerability obtained in the ABvac40 Phase I clinical trial in patients with mm-AD. In addition, the study is aimed to better characterize the immune response elicited by ABvac40 and to explore its effects on AD biomarkers.
Investigators
Eligibility Criteria
Inclusion Criteria
- •A subject must meet all the following inclusion criteria:
- •Male or female between 55 and 80 years of age, both inclusive, at the time of signing informed consent.
- •The patient (or legal representative, if applicable) and a close relative/caregiver must read the subject information sheet, agree to participate in the clinical trial and sign the informed consent form (the patient and a close relative/caregiver).
- •Presence of a stable caregiver to attend the patient study visits.
- •Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), according to age and education level.
- •Clinical Dementia Rating (CDR) scale scoring 0.
- •Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score on the Delayed Memory Index (DMI) of 85 or lower.
- •The results of the patient's MRI brain scan must be concordant with the diagnosis of clinical a-MCI or vm-AD according to the following criteria: Scheltens scale, and measurement of white matter and past haemorrhages.
- •If the patient is receiving treatment for AD, must have been stable during the two months before the selection visit.
- •Treatment for concomitant diseases must be stable during the previous month before the treatment of the study.
Exclusion Criteria
- •A subject meeting any of the following exclusion criteria is NOT eligible for participation in the study.
- •Known allergy to components of the vaccine or prior history of anaphylaxis, a severe allergic reaction or a history of hypersensitivity to any component of the formulation. Allergy to fish or shellfish.
- •Active infectious disease (i.e. hepatitis B, C). Positive syphilis serology.
- •History or presence of autoimmune disease, except mild eczema, rhinitis or psoriasis.
- •Presence or history of immunodeficiency (i.e. HIV).
- •Significant kidney and/or liver disease.
- •History of asthma or reactive airway disease with bronchospasm in the last 6 months, or currently on regular treatment.
- •Major uncontrolled systemic condition (e.g. diabetes, congestive heart failure, hypertension).
- •History of cancer (≤5 years since the last specific treatment). Exceptions: basocellular carcinoma.
- •Significant alterations in hematological, biochemical or urine analytical parameters, particularly those relating to levels of vitamin B12, folic acid or thyroid tests.
Arms & Interventions
ABvac40
Six administrations of ABvac40; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of ABvac40.
Intervention: ABvac40
Placebo
Six administrations of Placebo; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of the vaccine's vehicle buffer without the active component.
Intervention: Placebo
Outcomes
Primary Outcomes
Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA)
Time Frame: Part A (Baseline, and post-Baseline visits at Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A)
Average maximal increment (MΔ) of plasma anti-Aβ40 antibody signal (optical density \[OD\] in ELISA) in each subject with regard to Baseline visit.
Secondary Outcomes
- Level of Aβ42 Peptides in Plasma - ABtest-IA(Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A))
- Subject Discontinuations Due to TEAEs(Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B))
- Number of Subjects With Clinically Significant Abnormalities in Physical Examination(Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B))
- Number of Subjects With Clinically Significant Abnormalities in Neurological Examination(Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B))
- Number of Subjects With Clinically Significant Abnormalities in Analytical Hematology(Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B))
- Number of Subjects With Clinically Significant Abnormalities in Analytical Biochemistry(Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B))
- Number of Subjects With Clinically Significant Abnormalities in Coagulation(Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B))
- Level of Anti-Aβ40 Antibodies in CSF(Part A (Week 50A and Week 104A))
- Level of Anti-Aβ40 Antibodies in Plasma(Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A))
- Level of Antibody-secreting Cells(Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A))
- Level of Aβ40 Peptides in Plasma - ABtest-IA(Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A))
- Level of Aβ40 Peptides in Plasma - ABtest-MS(Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A))
- Level of Aβ42 Peptides in Plasma - ABtest-MS(Part A (Week 2A, Week 6A, Week 10A, Week 14A, Week 18A, Week 24A, Week 40A, Week 44A, Week 50A, Week 77A, and Week 104A))
- Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans(Part A (Week 50A and Week 104A))
- Percentage of Change in Brain Volume(Part A (Week 24A, Week 50A, and Week 104A))
- Percentage of Change in Hippocampal Volume(Part A (Week 24A, Week 50A, Week 104A))
- Percentage of Change in Ventricular Volume(Part A (Week 24A, Week 50A, and Week 104A))
- Level of Aβ42 Peptides in CSF(Part A (Week 50A and Week 104A))
- Level of Aβ40 Peptides in CSF(Part A (Week 50A and Week 104A))
- Aβ42/Aβ40 Ratio in CSF(Part A (Week 50A and Week 104A))
- Level of Total Tau in CSF(Part A (Week 50A and Week 104A))
- Level of p-Tau 181 in CSF(Part A (Week 50A and Week 104A))
- Level of Neurofilament Light in CSF(Part A (Week 50A and Week 104A))
- Level of Neurogranin in CSF(Part A (Week 50A and Week 104A))
- Mini Mental State Examination Score(Part A (baseline, and post-baseline at Week 24A, Week 50A, Week 77A, and Week 104A))
- Clinical Dementia Rating-Sum of Boxes Score(Part A (Week 24A, Week 50A, Week 77A, and Week 104A))
- Repeatable Battery for the Assessment of Neuropsychological Status Score(Part A (Week 24A, Week 50A, Week 77A, and Week 104A))
- Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score(Part A (Week 24A, Week 50A, Week 77A, and Week 104A))
- Trail Making Test Scores(Part A (Week 24A, Week 50A, Week 77A, and Week 104A))
- Investigator Global Evaluation Score(Part A (Week 24A, Week 50A, and Week 104A))
- Columbia Suicide Severity Rating Scale(Part A (Week 24A, Week 50A, Week 77A, and Week 104A))
- EuroQol 5 Dimensions 5 Levels Overall Severity Index Score(Part A (Week 50A and Week 104A))
- EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score(Part A (Week 50A and Week 104A))