Alzheimer Disease, Mild Cognitive Impairment
Conditions
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.
Interventions
BIOLOGICALABvac40
ABvac40 consists in a conjugate of Aβx-40 with a carrier protein (KLH) vehiculated in phosphate buffer containing 0.35% aluminum hydroxide as adjuvant.
BIOLOGICALPlacebo
Placebo consists in the vaccine's vehicle (phosphate buffer containing 0.35% aluminum hydroxide) without the conjugate.
Sponsors
Araclon Biotech S.L.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
A subject must meet all the following inclusion criteria: 1. Male or female between 55 and 80 years of age, both inclusive, at the time of signing informed consent. 2. 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). 3. Presence of a stable caregiver to attend the patient study visits. 4. Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), according to age and education level. 5. Clinical Dementia Rating (CDR) scale scoring 0.5. 6. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score on the Delayed Memory Index (DMI) of 85 or lower. 7. 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. 8. If the patient is receiving treatment for AD, must have been stable during the two months before the selection visit. 9. Treatment for concomitant diseases must be stable during the previous month before the treatment of the study. 10. Positive assessment of the candidate by the investigator for complying with the requirements and procedures of the study.
Exclusion criteria
A subject meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 withdrawn subjects due to treatment-emergent adverse events (TEAEs) during the whole study. |
| 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) | Clinically significant (CS) abnormalities in physical examination reported during the study. |
| 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) | Clinically significant (CS) abnormalities in neurological examination reported during the study. |
| 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) | Clinically significant (CS) abnormalities in hematology parameters reported during the study. |
| 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) | Clinically significant (CS) abnormalities in biochemistry parameters reported during the study. |
| 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) | Clinically significant (CS) abnormalities in coagulation parameters reported during the study. |
| Level of Anti-Aβ40 Antibodies in CSF | Part A (Week 50A and Week 104A) | The change in levels of anti-Aβ40 antibodies in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| 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) | The change in levels of anti-Aβ40 antibodies in plasma from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| 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) | The change in levels of antibody-secreting cells from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| 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) | The change in levels of anti-Aβ40 peptides in plasma (ABtest-IA) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| 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) | The change in levels of anti-Aβ42 peptides in plasma (ABtest-IA) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| 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) | The change in levels of anti-Aβ40 peptides in plasma (ABtest-MS) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| 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) | The change in levels of anti-Aβ42 peptides in plasma (ABtest-MS) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans | Part A (Week 50A and Week 104A) | The change in amyloid-PET (a-PET) standard centiloid global cortical area (reference Pons) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Percentage of Change in Brain Volume | Part A (Week 24A, Week 50A, and Week 104A) | The percent change in brain volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Percentage of Change in Hippocampal Volume | Part A (Week 24A, Week 50A, Week 104A) | The percent change in right and left hippocampal volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Percentage of Change in Ventricular Volume | Part A (Week 24A, Week 50A, and Week 104A) | The percent change in ventricular volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Level of Aβ42 Peptides in CSF | Part A (Week 50A and Week 104A) | The change in levels of Aβ42 peptides in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Level of Aβ40 Peptides in CSF | Part A (Week 50A and Week 104A) | The change in levels of Aβ40 peptides in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Aβ42/Aβ40 Ratio in CSF | Part A (Week 50A and Week 104A) | The change in Aβ42/Aβ40 ratio in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Level of Total Tau in CSF | Part A (Week 50A and Week 104A) | The change in levels of total Tau in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Level of p-Tau 181 in CSF | Part A (Week 50A and Week 104A) | The change in levels of p-Tau 181 in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Level of Neurofilament Light in CSF | Part A (Week 50A and Week 104A) | The change in levels of neurofilament light in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Level of Neurogranin in CSF | Part A (Week 50A and Week 104A) | The change in levels of neurogranin in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Mini Mental State Examination (MMSE) Score | Part A (baseline, and post-baseline at Week 24A, Week 50A, Week 77A, and Week 104A) | The change in MMSE score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a MMRM and the ITT analysis set. MMSE is an 11-question measure that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall, and language. MMSE score ranges: 0-30, with lower scores indicating worst cognition. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score | Part A (Week 24A, Week 50A, Week 77A, and Week 104A) | The change in CDR-SB score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a MMRM and the ITT analysis set. CDR-SB assesses 6 cognitive and functional domains: Memory, Orientation, Judgment \& Problem Solving, Community Affairs, Home \& Hobbies, Personal Care. CDR-SB score ranges: 0-18. The higher scores mean a worst outcome. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score | Part A (Week 24A, Week 50A, Week 77A, and Week 104A) | The change in RBANS total score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a MMRM and the ITT analysis set. RBANS assesses 5 cognitive domains: Immediate Memory, Visuospatial/constructional, Language, Attention, Delayed Memory. Total score (range 40-160) sums the 5 domain scores. The higher scores mean a better outcome. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI) Score | Part A (Week 24A, Week 50A, Week 77A, and Week 104A) | The change in ADCS-ADL MCI total score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a MMRM and the ITT analysis set. ADCS-ADL MCI is a 24-item scale that includes 6 basic activities of daily living (ADL) items and 16 instrumental ADL items that provide a total score: 0-78, with a lower score indicating greater severity. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Trail Making Test (TMT) Scores | Part A (Week 24A, Week 50A, Week 77A, and Week 104A) | Change in TMT score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a MMRM and the ITT analysis set. TMT has 2 parts in which the patient connects 25 dots in order as quickly as possible. In TMT-A, targets are numbers 1-25; in TMT-B, targets are numbers 1-13 interleaved with letters A-L. Lower timings indicate better outcome. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| Investigator Global Evaluation (IGE) Score | Part A (Week 24A, Week 50A, and Week 104A) | Change in IGE from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using MMRM and ITT analysis set. IGE at baseline:1-Good general status;2-Slight deterioration;3-Moderate deterioration;4-Bad general status. IGE after baseline:1-Marked improvement;2-Moderate improvement;3-Slight improvement;4-No change;5-Slight worsening;6-Moderate worsening;7-Marked worsening. MMRM included IGE after baseline as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix is used. Following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly significantly associated with response measure (p \< 0.15). |
| Columbia Suicide Severity Rating Scale | Part A (Week 24A, Week 50A, Week 77A, and Week 104A) | Subjects with suicidal ideation or suicidal behavior since last visit. |
| EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Overall Severity Index Score | Part A (Week 50A and Week 104A) | Change in EQ-5D-5L overall severity index from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using MMRM and ITT analysis set. EQ-5D-5L has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression; rated: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
| EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale (EQ-5D-5L - VAS) Score | Part A (Week 50A and Week 104A) | The change in EQ-5D-5L - VAS score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. VAS records the patient's self-rated health on a vertical scale, ranging from 100 = 'Best imaginable health state' down to 0 = 'Worst imaginable health state'. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have been included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15). |
Countries
France, Italy, Spain, Sweden
Participant flow
Recruitment details
A total of 23 centers in Spain (n=18), France (n=3), Italy (n=1) and Sweden (n=1) recruited subjects in this study. The subjects' recruitment was competitive until the required number of subjects was completed.
Pre-assignment details
238 subjects were screened and assessed for eligibility. 88 subjects were screening failures and an additional 16 subjects dropped out the study before being randomized. 134 subjects were randomized. Finally, 10 randomized subjects did not receive the allocated IMP. Accordingly, 124 subjects received any IMP dose, constituting the SAF analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Arm Part A Subjects who received Placebo during Part A. Six administrations: the first five administered once every 4 weeks (28±3 days) and the sixth at week 42 (Visit 18), 26 weeks after the fifth. Each administration consisted of 1 mL injection of ABvac40 vehicle without its active ingredient. | 62 |
| ABvac40 Arm Part A Subjects who received ABvac40 during Part A. Six administrations: the first five administered once every 4 weeks (28±3 days) and the sixth at week 42 (Visit 18), 26 weeks after the fifth. Each administration consisted of 1 mL injection of ABvac40 (containing 0.2 mg of Aβx-40). | 62 |
| Total | 124 |
Baseline characteristics
| Characteristic | Total | ABvac40 Arm Part A | Placebo Arm Part A |
|---|---|---|---|
| Age, Continuous | 70.4 years STANDARD_DEVIATION 5.71 | 70.6 years STANDARD_DEVIATION 5.95 | 70.1 years STANDARD_DEVIATION 5.49 |
| Amyloid-positron Emission Tomography (a-PET) Status Negative | 32 Participants | 15 Participants | 17 Participants |
| Amyloid-positron Emission Tomography (a-PET) Status Positive | 92 Participants | 47 Participants | 45 Participants |
| Apolipoprotein E (ApoE) Status Carriers (Heterozygous: E2/E4, E3/E4) | 62 Participants | 29 Participants | 33 Participants |
| Apolipoprotein E (ApoE) Status Carriers (Homozygous: E4/E4) | 14 Participants | 9 Participants | 5 Participants |
| Apolipoprotein E (ApoE) Status Noncarriers: E2/E2 and E2/E3, E3/E3 | 48 Participants | 24 Participants | 24 Participants |
| Race/Ethnicity, Customized Asian/Pacific islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 118 Participants | 58 Participants | 60 Participants |
| Race/Ethnicity, Customized Missing | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 74 Participants | 38 Participants | 36 Participants |
| Sex: Female, Male Male | 50 Participants | 24 Participants | 26 Participants |
| Study Disease amnestic Mild Cognitive Impairment (a-MCI) | 80 Participants | 38 Participants | 42 Participants |
| Study Disease Very Mild Alzheimer's disease (VMAD) | 44 Participants | 24 Participants | 20 Participants |
| Time from Disease Diagnosis to Informed Consent | 14.58 months STANDARD_DEVIATION 14.74 | 14.68 months STANDARD_DEVIATION 13.71 | 14.48 months STANDARD_DEVIATION 15.81 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 60 | 1 / 64 | 0 / 37 | 0 / 40 |
| other Total, other adverse events | 53 / 60 | 57 / 64 | 30 / 37 | 30 / 40 |
| serious Total, serious adverse events | 16 / 60 | 17 / 64 | 6 / 37 | 2 / 40 |
Outcome results
Primary
Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA)
Average maximal increment (MΔ) of plasma anti-Aβ40 antibody signal (optical density \[OD\] in ELISA) in each subject with regard to Baseline visit.
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)
Population: The Modified Intent-to-treat (mITT) analysis set comprised all subjects in the ITT analysis set who had a Baseline- and at least 1 post-Baseline anti-Aβ40 antibody assessment (optical density \[OD\] in ELISA without pre-adsorption).~Analysis of the primary efficacy endpoint was carried out using the mITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Arm Part A | Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA) | 0.12 OD | Standard Deviation 0.21 |
| ABvac40 Arm Part A | Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA) | 3.27 OD | Standard Deviation 0.75 |
Comparison: The trial was considered successfully confirmatory regarding efficacy (immunogenicity) of ABvac40 if the average MΔ of anti-Aβ40 antibody signal (OD in ELISA) in the ABvac40 group was significantly greater than the average MΔ of anti-Aβ40 antibody signal in the Placebo group. i.e.~* Null hypothesis: average MΔ anti-Aβ40 (ABvac40) ≤ average MΔ anti-Aβ40 (placebo).~* Alternative hypothesis: average MΔ anti-Aβ40 (ABvac40) \> average MΔ anti-Aβ40 (placebo).p-value: <0.0001t-test, 1 sided
p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: The average MΔ of anti-Aβ40 antibody signal between the two treatment groups was compared using an ANCOVA model, using the MΔ anti-Aβ40 antibody signal as the dependent variable, baseline anti-Aβ40 antibody signal (OD in ELISA) as covariate and treatment group and amyloid positivity as fixed effects.p-value: <0.000195% CI: [2.96, 3.34]ANCOVA
Comparison: 1-sided t-test to compare the ABvac40 and placebo groups.~The primary analysis (t-test) was repeated, using the mITT Analysis Set to test the hypothesis:~* Null hypothesis: average MΔ anti-Aβ40 (ABvac40) - average MΔ anti-Aβ40 (placebo) ≤ 1.778~* Alternative hypothesis: average MΔ anti-Aβ40 (ABvac40) - average MΔ anti-Aβ40 (placebo) \> 1.778 The alternative hypothesis was confirmed.p-value: <0.0001t-test, 1 sided
Comparison: The change in anti-Aβ40 antibody signal from baseline to each post-baseline efficacy visit was analyzed using a Mixed-Model Repeated Measures (MMRM), using the mITT Analysis Set.~Dependent variable: change from baseline in anti-Aβ40 antibody signal. Fixed effects: treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity. Covariates: baseline anti-Aβ40 antibody signal and baseline age; Repeated measure: measures within-patient at each visit.p-value: <0.05Mixed Models Analysis
Secondary
Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score
The change in Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI) total score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. ADCS-ADL MCI is a 24-item scale that includes 6 basic activities of daily living (BADL) items and 16 instrumental activities of daily living (IADL) items that provide a total score from 0-78, with a lower score indicating greater severity.
Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 24A | -0.99 score on a scale | Standard Error 0.834 |
| Placebo Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 50A | -4.15 score on a scale | Standard Error 1.124 |
| Placebo Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 77A | -6.33 score on a scale | Standard Error 1.399 |
| Placebo Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 104A | -9.87 score on a scale | Standard Error 2.002 |
| ABvac40 Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 104A | -10.02 score on a scale | Standard Error 1.982 |
| ABvac40 Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 24A | -2.08 score on a scale | Standard Error 0.844 |
| ABvac40 Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 77A | -6.54 score on a scale | Standard Error 1.38 |
| ABvac40 Arm Part A | Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score | Week 50A | -3.78 score on a scale | Standard Error 1.112 |
Comparison: MMRM - Week 24Ap-value: =0.3246Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.8047Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.916Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.9582Mixed Models Analysis
Secondary
Aβ42/Aβ40 Ratio in CSF
The change in Aβ42/Aβ40 ratio in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Aβ42/Aβ40 Ratio in CSF | Week 50A | 0.0005 Ratio | Standard Error 0.00135 |
| Placebo Arm Part A | Aβ42/Aβ40 Ratio in CSF | Week 104A | 0.0016 Ratio | Standard Error 0.00183 |
| ABvac40 Arm Part A | Aβ42/Aβ40 Ratio in CSF | Week 50A | 0.0009 Ratio | Standard Error 0.00129 |
| ABvac40 Arm Part A | Aβ42/Aβ40 Ratio in CSF | Week 104A | 0.0020 Ratio | Standard Error 0.00205 |
Comparison: MMRM - Week 50Ap-value: =0.7977Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.8828Mixed Models Analysis
Secondary
Clinical Dementia Rating-Sum of Boxes Score
The change in clinical dementia rating-sum of boxes (CDR-SB) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. CDR-SB is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. CDR-SB, derived as the sum of the six individual domain scores and can range from 0 to 18. The higher scores mean a worst outcome.
Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 24A | 0.75 score on a scale | Standard Error 0.152 |
| Placebo Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 50A | 1.41 score on a scale | Standard Error 0.222 |
| Placebo Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 77A | 2.12 score on a scale | Standard Error 0.328 |
| Placebo Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 104A | 3.21 score on a scale | Standard Error 0.463 |
| ABvac40 Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 104A | 2.90 score on a scale | Standard Error 0.462 |
| ABvac40 Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 24A | 0.73 score on a scale | Standard Error 0.156 |
| ABvac40 Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 77A | 2.05 score on a scale | Standard Error 0.325 |
| ABvac40 Arm Part A | Clinical Dementia Rating-Sum of Boxes Score | Week 50A | 1.36 score on a scale | Standard Error 0.221 |
Comparison: MMRM - Week 24Ap-value: =0.8949Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.8712Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.8748Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.6402Mixed Models Analysis
Secondary
Columbia Suicide Severity Rating Scale
Subjects with suicidal ideation or suicidal behavior since last visit.
Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.~Number of participants entered in each row differs from the overall number of participants because data from all participants were not available at each visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 24A - suicidal ideation | 1 Participants |
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 24A - suicidal behavior | 0 Participants |
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 50A - suicidal ideation | 1 Participants |
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 50A - suicidal behavior | 0 Participants |
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 77A - suicidal ideation | 1 Participants |
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 77A - suicidal behavior | 0 Participants |
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 104A - suicidal ideation | 0 Participants |
| Placebo Arm Part A | Columbia Suicide Severity Rating Scale | Week 104A - suicidal behavior | 0 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 104A - suicidal behavior | 0 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 24A - suicidal ideation | 1 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 77A - suicidal ideation | 4 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 24A - suicidal behavior | 0 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 104A - suicidal ideation | 0 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 50A - suicidal ideation | 2 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 77A - suicidal behavior | 0 Participants |
| ABvac40 Arm Part A | Columbia Suicide Severity Rating Scale | Week 50A - suicidal behavior | 0 Participants |
Secondary
Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans
The change in amyloid-PET (a-PET) standard centiloid global cortical area (reference Pons) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans | Week 50A | 1.411 Centiloids | Standard Error 1.1203 |
| Placebo Arm Part A | Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans | Week 104A | 4.461 Centiloids | Standard Error 1.3841 |
| ABvac40 Arm Part A | Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans | Week 50A | 3.561 Centiloids | Standard Error 1.0918 |
| ABvac40 Arm Part A | Cortical Fibrillary Amyloid Deposition Assessed by a-PET Scans | Week 104A | 1.241 Centiloids | Standard Error 1.5403 |
Comparison: MMRM - Week 50Ap-value: =0.1058Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.0922Mixed Models Analysis
Secondary
EuroQol 5 Dimensions 5 Levels Overall Severity Index Score
The change in Euroqol 5 Dimensions 5 Levels (EQ-5D-5L) - overall severity index score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The EQ-5D-5L descriptive system comprises of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), with each dimension measured on the following increasing scale of severity: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems.
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | EuroQol 5 Dimensions 5 Levels Overall Severity Index Score | Week 50A | -0.99 score on a scale | Standard Error 1.204 |
| Placebo Arm Part A | EuroQol 5 Dimensions 5 Levels Overall Severity Index Score | Week 104A | -3.06 score on a scale | Standard Error 1.74 |
| ABvac40 Arm Part A | EuroQol 5 Dimensions 5 Levels Overall Severity Index Score | Week 50A | -2.71 score on a scale | Standard Error 1.196 |
| ABvac40 Arm Part A | EuroQol 5 Dimensions 5 Levels Overall Severity Index Score | Week 104A | -0.92 score on a scale | Standard Error 1.725 |
Comparison: MMRM - Week 50Ap-value: =0.2863Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.3703Mixed Models Analysis
Secondary
EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score
The change in Euroqol 5 Dimensions 5 levels (EQ-5D-5L) - visual analogue scale (VAS) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. VAS records the patient's self-rated health on a vertical scale, ranging from 100 = 'Best imaginable health state' down to 0 = 'Worst imaginable health state'.
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score | Week 50A | -5.20 score on a scale | Standard Error 2.335 |
| Placebo Arm Part A | EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score | Week 104A | -5.55 score on a scale | Standard Error 3.109 |
| ABvac40 Arm Part A | EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score | Week 50A | -5.07 score on a scale | Standard Error 2.289 |
| ABvac40 Arm Part A | EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score | Week 104A | -1.84 score on a scale | Standard Error 3.111 |
Comparison: MMRM - Week 50Ap-value: =0.9663Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.3843Mixed Models Analysis
Secondary
Investigator Global Evaluation Score
The change in Investigator Global Evaluation (IGE) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. IGE score range at baseline: 1-Good general status; 2-Slight deterioration; 3-Moderate deterioration; 4-Bad general status. IGE score range after baseline: 1-Marked improvement; 2-Moderate improvement; 3-Slight improvement; 4-No change; 5-Slight worsening; 6-Moderate worsening; 7-Marked worsening.
Time frame: Part A (Week 24A, Week 50A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Investigator Global Evaluation Score | Week 24A | 4.02 score on a scale | Standard Error 0.075 |
| Placebo Arm Part A | Investigator Global Evaluation Score | Week 50A | 4.26 score on a scale | Standard Error 0.101 |
| Placebo Arm Part A | Investigator Global Evaluation Score | Week 104A | 4.55 score on a scale | Standard Error 0.18 |
| ABvac40 Arm Part A | Investigator Global Evaluation Score | Week 24A | 4.07 score on a scale | Standard Error 0.077 |
| ABvac40 Arm Part A | Investigator Global Evaluation Score | Week 50A | 4.21 score on a scale | Standard Error 0.101 |
| ABvac40 Arm Part A | Investigator Global Evaluation Score | Week 104A | 4.45 score on a scale | Standard Error 0.184 |
Comparison: MMRM - Week 24Ap-value: =0.6189Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.6937Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.6981Mixed Models Analysis
Secondary
Level of Anti-Aβ40 Antibodies in CSF
The change in levels of anti-Aβ40 antibodies in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment.~assignment, regardless of the treatment received
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in CSF | Week 50A | 0.1654 ng/mL | Standard Error 3.86502 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in CSF | Week 104A | 0.2014 ng/mL | Standard Error 0.36753 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in CSF | Week 50A | 30.1826 ng/mL | Standard Error 3.90756 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in CSF | Week 104A | 1.2437 ng/mL | Standard Error 0.41902 |
Comparison: MMRM - Week 50Ap-value: <0.001Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.047Mixed Models Analysis
Secondary
Level of Anti-Aβ40 Antibodies in Plasma
The change in levels of anti-Aβ40 antibodies in plasma from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: 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)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 14A | 1.5479 μg/mL | Standard Error 4.24276 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 40A | 1.6027 μg/mL | Standard Error 4.33264 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 10A | 1.6172 μg/mL | Standard Error 4.24276 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 44A | 1.5463 μg/mL | Standard Error 4.35267 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 18A | 1.5789 μg/mL | Standard Error 4.30746 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 50A | 1.5993 μg/mL | Standard Error 4.35363 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 6A | 1.5580 μg/mL | Standard Error 4.221 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 77A | 1.5232 μg/mL | Standard Error 4.37735 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 24A | 1.5926 μg/mL | Standard Error 4.26432 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 104A | 1.7400 μg/mL | Standard Error 5.57743 |
| Placebo Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 2A | 1.5580 μg/mL | Standard Error 4.221 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 104A | 10.8365 μg/mL | Standard Error 5.82224 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 2A | 1.5112 μg/mL | Standard Error 4.40221 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 6A | 13.7052 μg/mL | Standard Error 4.44801 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 10A | 44.3187 μg/mL | Standard Error 4.41509 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 14A | 62.1946 μg/mL | Standard Error 4.43781 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 18A | 69.8861 μg/mL | Standard Error 4.43781 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 24A | 39.9483 μg/mL | Standard Error 4.44151 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 40A | 14.6139 μg/mL | Standard Error 4.48526 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 44A | 57.5771 μg/mL | Standard Error 4.48568 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 50A | 33.5366 μg/mL | Standard Error 4.51418 |
| ABvac40 Arm Part A | Level of Anti-Aβ40 Antibodies in Plasma | Week 77A | 10.8197 μg/mL | Standard Error 4.571 |
Comparison: MMRM - Week 2Ap-value: =0.9936Mixed Models Analysis
Comparison: MMRM - Week 6Ap-value: =0.0391Mixed Models Analysis
Comparison: MMRM - Week 10Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 14Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 18Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 24Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 40Ap-value: =0.0299Mixed Models Analysis
Comparison: MMRM - Week 44Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.1267Mixed Models Analysis
p-value: =0.2477Mixed Models Analysis
Secondary
Level of Antibody-secreting Cells
The change in levels of antibody-secreting cells from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: 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)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 40A | -0.5201 SFU/0.5x10^6 PBMCs | Standard Error 0.41447 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 44A | -1.1915 SFU/0.5x10^6 PBMCs | Standard Error 2.4582 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 50A | -0.3489 SFU/0.5x10^6 PBMCs | Standard Error 1.07737 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 77A | -0.3969 SFU/0.5x10^6 PBMCs | Standard Error 0.52153 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 104A | 0.1732 SFU/0.5x10^6 PBMCs | Standard Error 0.40914 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 2A | -0.4365 SFU/0.5x10^6 PBMCs | Standard Error 0.37501 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 6A | -0.0906 SFU/0.5x10^6 PBMCs | Standard Error 0.72718 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 10A | 0.3092 SFU/0.5x10^6 PBMCs | Standard Error 0.79081 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 14A | -0.1484 SFU/0.5x10^6 PBMCs | Standard Error 1.44968 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 18A | 0.2873 SFU/0.5x10^6 PBMCs | Standard Error 1.02944 |
| Placebo Arm Part A | Level of Antibody-secreting Cells | Week 24A | 0.4827 SFU/0.5x10^6 PBMCs | Standard Error 0.74628 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 10A | 4.0397 SFU/0.5x10^6 PBMCs | Standard Error 0.73611 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 40A | 1.2117 SFU/0.5x10^6 PBMCs | Standard Error 0.37194 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 2A | 0.1868 SFU/0.5x10^6 PBMCs | Standard Error 0.34352 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 44A | 10.3597 SFU/0.5x10^6 PBMCs | Standard Error 2.23485 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 24A | 3.6323 SFU/0.5x10^6 PBMCs | Standard Error 0.68609 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 50A | 4.5496 SFU/0.5x10^6 PBMCs | Standard Error 1.00962 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 6A | 2.3144 SFU/0.5x10^6 PBMCs | Standard Error 0.67867 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 77A | 1.8382 SFU/0.5x10^6 PBMCs | Standard Error 0.47244 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 14A | 7.5119 SFU/0.5x10^6 PBMCs | Standard Error 1.36804 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 104A | 0.3638 SFU/0.5x10^6 PBMCs | Standard Error 0.40349 |
| ABvac40 Arm Part A | Level of Antibody-secreting Cells | Week 18A | 6.8827 SFU/0.5x10^6 PBMCs | Standard Error 0.93624 |
Comparison: MMRM - Week 2Ap-value: =0.2151Mixed Models Analysis
Comparison: MMRM - Week 6Ap-value: =0.0169Mixed Models Analysis
Comparison: MMRM - Week 10Ap-value: =0.0008Mixed Models Analysis
Comparison: MMRM - Week 14Ap-value: =0.0002Mixed Models Analysis
Comparison: MMRM - Week 18Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 24Ap-value: =0.0023Mixed Models Analysis
Comparison: MMRM - Week 40Ap-value: =0.0021Mixed Models Analysis
Comparison: MMRM - Week 44Ap-value: =0.0007Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.0012Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.0018Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.738Mixed Models Analysis
Secondary
Level of Aβ40 Peptides in CSF
The change in levels of Aβ40 peptides in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Aβ40 Peptides in CSF | Week 50A | -62.3 pg/mL | Standard Error 173.57 |
| Placebo Arm Part A | Level of Aβ40 Peptides in CSF | Week 104A | -652.4 pg/mL | Standard Error 227.08 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in CSF | Week 50A | -141.8 pg/mL | Standard Error 180.07 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in CSF | Week 104A | -192.5 pg/mL | Standard Error 260.67 |
Comparison: MMRM - Week 50Ap-value: =0.7324Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.1719Mixed Models Analysis
Secondary
Level of Aβ40 Peptides in Plasma - ABtest-IA
The change in levels of anti-Aβ40 peptides in plasma (ABtest-IA) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: 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)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 14A | 4.7946 pg/mL | Standard Error 4.75127 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 40A | 4.7336 pg/mL | Standard Error 4.73069 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 10A | 4.2669 pg/mL | Standard Error 3.43764 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 44A | 7.4722 pg/mL | Standard Error 5.4515 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 18A | 7.7216 pg/mL | Standard Error 4.68637 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 50A | 6.5136 pg/mL | Standard Error 5.56714 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 6A | 3.2541 pg/mL | Standard Error 2.66184 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 77A | 9.9852 pg/mL | Standard Error 5.15517 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 24A | 6.3608 pg/mL | Standard Error 4.06529 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 104A | 7.9352 pg/mL | Standard Error 7.65221 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 2A | 2.5948 pg/mL | Standard Error 2.2212 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 104A | -16.5218 pg/mL | Standard Error 7.67117 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 2A | 3.4620 pg/mL | Standard Error 2.16724 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 6A | 8.3468 pg/mL | Standard Error 2.6051 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 10A | -3.3200 pg/mL | Standard Error 3.38626 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 14A | -10.5837 pg/mL | Standard Error 4.71154 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 18A | -13.4213 pg/mL | Standard Error 4.61987 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 24A | -30.6595 pg/mL | Standard Error 4.00199 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 40A | -43.2898 pg/mL | Standard Error 4.62 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 44A | -36.7343 pg/mL | Standard Error 5.32882 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 50A | -36.9475 pg/mL | Standard Error 5.43416 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-IA | Week 77A | -31.8000 pg/mL | Standard Error 5.04184 |
Comparison: MMRM - Week 44Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 2Ap-value: =0.7623Mixed Models Analysis
Comparison: MMRM - Week 6Ap-value: =0.1506Mixed Models Analysis
Comparison: MMRM - Week 10Ap-value: =0.1071Mixed Models Analysis
Comparison: MMRM - Week 14Ap-value: =0.0212Mixed Models Analysis
Comparison: MMRM - Week 18Ap-value: =0.0014Mixed Models Analysis
Comparison: MMRM - Week 24Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 40Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.0251Mixed Models Analysis
Secondary
Level of Aβ40 Peptides in Plasma - ABtest-MS
The change in levels of anti-Aβ40 peptides in plasma (ABtest-MS) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: 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)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 14A | 10.1449 pg/mL | Standard Error 86.57079 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 40A | -26.9761 pg/mL | Standard Error 88.54373 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 10A | 10.8314 pg/mL | Standard Error 86.57079 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 44A | -28.4349 pg/mL | Standard Error 88.5069 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 18A | 10.1987 pg/mL | Standard Error 87.66045 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 50A | -34.2153 pg/mL | Standard Error 88.91637 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 6A | 12.9981 pg/mL | Standard Error 86.19364 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 77A | -30.9656 pg/mL | Standard Error 89.32946 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 24A | 31.0861 pg/mL | Standard Error 86.93514 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 104A | -37.3585 pg/mL | Standard Error 110.48329 |
| Placebo Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 2A | 15.0554 pg/mL | Standard Error 86.19364 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 104A | 85.9804 pg/mL | Standard Error 113.05734 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 2A | 7.2235 pg/mL | Standard Error 87.23687 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 6A | 26.8351 pg/mL | Standard Error 87.2429 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 10A | 123.0016 pg/mL | Standard Error 87.42725 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 14A | 277.9974 pg/mL | Standard Error 87.75818 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 18A | 397.6406 pg/mL | Standard Error 88.10607 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 24A | 453.1893 pg/mL | Standard Error 88.16061 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 40A | 377.7762 pg/mL | Standard Error 88.44661 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 44A | 846.1633 pg/mL | Standard Error 88.82717 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 50A | 628.9483 pg/mL | Standard Error 88.88059 |
| ABvac40 Arm Part A | Level of Aβ40 Peptides in Plasma - ABtest-MS | Week 77A | 155.5480 pg/mL | Standard Error 89.69327 |
Comparison: MMRM - Week 2Ap-value: =0.9469Mixed Models Analysis
Comparison: MMRM - Week 6Ap-value: =0.9063Mixed Models Analysis
Comparison: MMRM - Week 10Ap-value: =0.3418Mixed Models Analysis
Comparison: MMRM - Week 14Ap-value: =0.0236Mixed Models Analysis
Comparison: MMRM - Week 18Ap-value: =0.0012Mixed Models Analysis
Comparison: MMRM - Week 24Ap-value: =0.0004Mixed Models Analysis
Comparison: MMRM - Week 40Ap-value: =0.0008Mixed Models Analysis
Comparison: MMRM - Week 44Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: <0.0001Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.1255Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.4232Mixed Models Analysis
Secondary
Level of Aβ42 Peptides in CSF
The change in levels of Aβ42 peptides in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Aβ42 Peptides in CSF | Week 50A | 29.0 pg/mL | Standard Error 19.4 |
| Placebo Arm Part A | Level of Aβ42 Peptides in CSF | Week 104A | -15.3 pg/mL | Standard Error 22.51 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in CSF | Week 50A | -2.0 pg/mL | Standard Error 19.79 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in CSF | Week 104A | 4.0 pg/mL | Standard Error 25.82 |
Comparison: MMRM - Week 50Ap-value: =0.2193Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.5543Mixed Models Analysis
Secondary
Level of Aβ42 Peptides in Plasma - ABtest-IA
The change in levels of anti-Aβ42 peptides in plasma (ABtest-IA) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: 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)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 14A | 1.6433 pg/mL | Standard Error 0.73975 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 40A | 2.0361 pg/mL | Standard Error 0.84268 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 10A | 1.2091 pg/mL | Standard Error 0.88576 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 44A | 1.7850 pg/mL | Standard Error 1.00896 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 18A | 1.9821 pg/mL | Standard Error 0.55465 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 50A | 2.6958 pg/mL | Standard Error 1.2446 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 6A | 1.2776 pg/mL | Standard Error 0.77358 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 77A | 2.9304 pg/mL | Standard Error 1.15392 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 24A | 2.8599 pg/mL | Standard Error 0.72452 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 104A | 0.8402 pg/mL | Standard Error 1.36427 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 2A | 0.6745 pg/mL | Standard Error 0.4769 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 104A | 0.5027 pg/mL | Standard Error 1.34946 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 2A | 0.3868 pg/mL | Standard Error 0.47126 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 6A | 1.6248 pg/mL | Standard Error 0.76131 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 10A | 2.1331 pg/mL | Standard Error 0.87167 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 14A | 1.0209 pg/mL | Standard Error 0.72987 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 18A | 1.2815 pg/mL | Standard Error 0.54507 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 24A | 1.6125 pg/mL | Standard Error 0.71101 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 40A | -1.2781 pg/mL | Standard Error 0.81992 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 44A | -0.9785 pg/mL | Standard Error 0.9852 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 50A | 0.5563 pg/mL | Standard Error 1.21767 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-IA | Week 77A | 0.9045 pg/mL | Standard Error 1.13274 |
Comparison: MMRM - Week 2Ap-value: =0.6515Mixed Models Analysis
Comparison: MMRM - Week 6Ap-value: =0.7447Mixed Models Analysis
Comparison: MMRM - Week 10Ap-value: =0.4518Mixed Models Analysis
Comparison: MMRM - Week 14Ap-value: =0.5416Mixed Models Analysis
Comparison: MMRM - Week 18Ap-value: =0.3504Mixed Models Analysis
Comparison: MMRM - Week 24Ap-value: =0.2109Mixed Models Analysis
Comparison: MMRM - Week 40Ap-value: =0.0049Mixed Models Analysis
Comparison: MMRM - Week 44Ap-value: =0.0498Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.2181Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.2087Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.8599Mixed Models Analysis
Secondary
Level of Aβ42 Peptides in Plasma - ABtest-MS
The change in levels of anti-Aβ42 peptides in plasma (ABtest-MS) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: 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)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 14A | 0.1680 pg/mL | Standard Error 1.15553 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 40A | 2.9633 pg/mL | Standard Error 1.71207 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 10A | -1.0248 pg/mL | Standard Error 1.33166 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 44A | 1.6060 pg/mL | Standard Error 1.5212 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 18A | 0.6469 pg/mL | Standard Error 1.51683 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 50A | 0.2069 pg/mL | Standard Error 1.49045 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 6A | -0.1492 pg/mL | Standard Error 1.32406 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 77A | 1.4766 pg/mL | Standard Error 1.61328 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 24A | -0.0526 pg/mL | Standard Error 1.38574 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 104A | 4.7604 pg/mL | Standard Error 2.18825 |
| Placebo Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 2A | -0.1364 pg/mL | Standard Error 1.2336 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 104A | 2.6870 pg/mL | Standard Error 2.19551 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 2A | 0.0301 pg/mL | Standard Error 1.23242 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 6A | 1.8092 pg/mL | Standard Error 1.32222 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 10A | 0.8740 pg/mL | Standard Error 1.32527 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 14A | 0.4841 pg/mL | Standard Error 1.1569 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 18A | -0.9551 pg/mL | Standard Error 1.49962 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 24A | -1.6059 pg/mL | Standard Error 1.38522 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 40A | 3.3472 pg/mL | Standard Error 1.68092 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 44A | 1.9498 pg/mL | Standard Error 1.49737 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 50A | 2.7196 pg/mL | Standard Error 1.46044 |
| ABvac40 Arm Part A | Level of Aβ42 Peptides in Plasma - ABtest-MS | Week 77A | 4.7243 pg/mL | Standard Error 1.58567 |
Comparison: MMRM - Week 2Ap-value: =0.9211Mixed Models Analysis
Comparison: MMRM - Week 6Ap-value: =0.2817Mixed Models Analysis
Comparison: MMRM - Week 10Ap-value: =0.2984Mixed Models Analysis
Comparison: MMRM - Week 14Ap-value: =0.8402Mixed Models Analysis
Comparison: MMRM - Week 18Ap-value: =0.4428Mixed Models Analysis
Comparison: MMRM - Week 24Ap-value: =0.4156Mixed Models Analysis
Comparison: MMRM - Week 40Ap-value: =0.8706Mixed Models Analysis
Comparison: MMRM - Week 44Ap-value: =0.8691Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.2188Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.1448Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.5004Mixed Models Analysis
Secondary
Level of Neurofilament Light in CSF
The change in levels of neurofilament light in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Neurofilament Light in CSF | Week 50A | 59.36 pg/mL | Standard Error 76.513 |
| Placebo Arm Part A | Level of Neurofilament Light in CSF | Week 104A | 317.11 pg/mL | Standard Error 190.948 |
| ABvac40 Arm Part A | Level of Neurofilament Light in CSF | Week 50A | 181.20 pg/mL | Standard Error 78.606 |
| ABvac40 Arm Part A | Level of Neurofilament Light in CSF | Week 104A | 276.14 pg/mL | Standard Error 216.781 |
Comparison: MMRM - Week 50Ap-value: =0.2283Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.886Mixed Models Analysis
Secondary
Level of Neurogranin in CSF
The change in levels of neurogranin in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, and treatment-by-visit interaction as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Neurogranin in CSF | Week 50A | -4.69 pg/mL | Standard Error 8.023 |
| Placebo Arm Part A | Level of Neurogranin in CSF | Week 104A | -34.97 pg/mL | Standard Error 13.533 |
| ABvac40 Arm Part A | Level of Neurogranin in CSF | Week 50A | -5.93 pg/mL | Standard Error 8.328 |
| ABvac40 Arm Part A | Level of Neurogranin in CSF | Week 104A | -31.13 pg/mL | Standard Error 15.571 |
Comparison: MMRM - Week 50Ap-value: =0.909Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.8498Mixed Models Analysis
Secondary
Level of p-Tau 181 in CSF
The change in levels of p-Tau 181 in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of p-Tau 181 in CSF | Week 50A | 2.43 pg/mL | Standard Error 1.684 |
| Placebo Arm Part A | Level of p-Tau 181 in CSF | Week 104A | 1.55 pg/mL | Standard Error 2.387 |
| ABvac40 Arm Part A | Level of p-Tau 181 in CSF | Week 50A | 3.15 pg/mL | Standard Error 1.697 |
| ABvac40 Arm Part A | Level of p-Tau 181 in CSF | Week 104A | 0.82 pg/mL | Standard Error 2.634 |
Comparison: MMRM - Week 50Ap-value: =0.743Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.832Mixed Models Analysis
Secondary
Level of Total Tau in CSF
The change in levels of total Tau in cerebrospinal fluid (CSF) from baseline to each applicable postbaseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 50A and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Level of Total Tau in CSF | Week 50A | 23.4 pg/mL | Standard Error 12.2 |
| Placebo Arm Part A | Level of Total Tau in CSF | Week 104A | 25.9 pg/mL | Standard Error 14.2 |
| ABvac40 Arm Part A | Level of Total Tau in CSF | Week 50A | 27.6 pg/mL | Standard Error 12.39 |
| ABvac40 Arm Part A | Level of Total Tau in CSF | Week 104A | 14.7 pg/mL | Standard Error 16.38 |
Comparison: MMRM - Week 50Ap-value: =0.7954Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.5895Mixed Models Analysis
Secondary
Mini Mental State Examination Score
The change in Mini Mental State Examination score (MMSE) score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. MMSE is an 11-question measure that testes five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. MMSE score ranges from 0 to 30, with lower scores indicating worst cognition.
Time frame: Part A (baseline, and post-baseline at Week 24A, Week 50A, Week 77A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Mini Mental State Examination Score | Week 24A | -2.15 score on a scale | Standard Error 0.422 |
| Placebo Arm Part A | Mini Mental State Examination Score | Week 50A | -3.64 score on a scale | Standard Error 0.465 |
| Placebo Arm Part A | Mini Mental State Examination Score | Week 77A | -4.58 score on a scale | Standard Error 0.628 |
| Placebo Arm Part A | Mini Mental State Examination Score | Week 104A | -5.98 score on a scale | Standard Error 0.816 |
| ABvac40 Arm Part A | Mini Mental State Examination Score | Week 104A | -4.97 score on a scale | Standard Error 0.816 |
| ABvac40 Arm Part A | Mini Mental State Examination Score | Week 24A | -2.24 score on a scale | Standard Error 0.42 |
| ABvac40 Arm Part A | Mini Mental State Examination Score | Week 77A | -4.15 score on a scale | Standard Error 0.621 |
| ABvac40 Arm Part A | Mini Mental State Examination Score | Week 50A | -2.65 score on a scale | Standard Error 0.46 |
Comparison: MMRM - Week 24Ap-value: =0.8711Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.1098Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.6179Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.3715Mixed Models Analysis
Secondary
Number of Subjects With Clinically Significant Abnormalities in Analytical Biochemistry
Clinically significant (CS) abnormalities in biochemistry parameters reported during the study.
Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)
Population: The safety analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Analytical Biochemistry | 12 Participants |
| ABvac40 Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Analytical Biochemistry | 5 Participants |
| ABvac40 Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Analytical Biochemistry | 6 Participants |
| Placebo+Booster Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Analytical Biochemistry | 6 Participants |
Secondary
Number of Subjects With Clinically Significant Abnormalities in Analytical Hematology
Clinically significant (CS) abnormalities in hematology parameters reported during the study.
Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)
Population: The safety analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Analytical Hematology | 5 Participants |
| ABvac40 Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Analytical Hematology | 4 Participants |
| ABvac40 Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Analytical Hematology | 0 Participants |
| Placebo+Booster Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Analytical Hematology | 6 Participants |
Secondary
Number of Subjects With Clinically Significant Abnormalities in Coagulation
Clinically significant (CS) abnormalities in coagulation parameters reported during the study.
Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)
Population: The safety analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Coagulation | 4 Participants |
| ABvac40 Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Coagulation | 1 Participants |
| ABvac40 Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Coagulation | 3 Participants |
| Placebo+Booster Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Coagulation | 2 Participants |
Secondary
Number of Subjects With Clinically Significant Abnormalities in Neurological Examination
Clinically significant (CS) abnormalities in neurological examination reported during the study.
Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)
Population: The safety analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Neurological Examination | 6 Participants |
| ABvac40 Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Neurological Examination | 5 Participants |
| ABvac40 Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Neurological Examination | 2 Participants |
| Placebo+Booster Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Neurological Examination | 1 Participants |
Secondary
Number of Subjects With Clinically Significant Abnormalities in Physical Examination
Clinically significant (CS) abnormalities in physical examination reported during the study.
Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)
Population: The safety analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Physical Examination | 4 Participants |
| ABvac40 Arm Part A | Number of Subjects With Clinically Significant Abnormalities in Physical Examination | 1 Participants |
| ABvac40 Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Physical Examination | 4 Participants |
| Placebo+Booster Arm Part B | Number of Subjects With Clinically Significant Abnormalities in Physical Examination | 2 Participants |
Secondary
Percentage of Change in Brain Volume
The percent change in brain volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 24A, Week 50A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Percentage of Change in Brain Volume | Week 24A | -1.39 percent change | Standard Error 0.157 |
| Placebo Arm Part A | Percentage of Change in Brain Volume | Week 50A | -2.05 percent change | Standard Error 0.175 |
| Placebo Arm Part A | Percentage of Change in Brain Volume | Week 104A | -4.16 percent change | Standard Error 0.47 |
| ABvac40 Arm Part A | Percentage of Change in Brain Volume | Week 24A | -1.40 percent change | Standard Error 0.165 |
| ABvac40 Arm Part A | Percentage of Change in Brain Volume | Week 50A | -1.75 percent change | Standard Error 0.187 |
| ABvac40 Arm Part A | Percentage of Change in Brain Volume | Week 104A | -3.11 percent change | Standard Error 0.412 |
Comparison: MMRM - Week 24Ap-value: =0.9313Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.2243Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.0952Mixed Models Analysis
Secondary
Percentage of Change in Hippocampal Volume
The percent change in right and left hippocampal volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 24A, Week 50A, Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Percentage of Change in Hippocampal Volume | Week 24A - left | -1.60 percent change | Standard Error 0.454 |
| Placebo Arm Part A | Percentage of Change in Hippocampal Volume | Week 50A - left | -4.13 percent change | Standard Error 0.588 |
| Placebo Arm Part A | Percentage of Change in Hippocampal Volume | Week 104A - left | -7.13 percent change | Standard Error 1.06 |
| Placebo Arm Part A | Percentage of Change in Hippocampal Volume | Week 24A - right | -1.37 percent change | Standard Error 0.442 |
| Placebo Arm Part A | Percentage of Change in Hippocampal Volume | Week 50A - right | -3.34 percent change | Standard Error 0.513 |
| Placebo Arm Part A | Percentage of Change in Hippocampal Volume | Week 104A - right | -6.37 percent change | Standard Error 1.001 |
| ABvac40 Arm Part A | Percentage of Change in Hippocampal Volume | Week 50A - right | -3.23 percent change | Standard Error 0.506 |
| ABvac40 Arm Part A | Percentage of Change in Hippocampal Volume | Week 24A - left | -2.14 percent change | Standard Error 0.45 |
| ABvac40 Arm Part A | Percentage of Change in Hippocampal Volume | Week 24A - right | -1.44 percent change | Standard Error 0.439 |
| ABvac40 Arm Part A | Percentage of Change in Hippocampal Volume | Week 50A - left | -4.24 percent change | Standard Error 0.571 |
| ABvac40 Arm Part A | Percentage of Change in Hippocampal Volume | Week 104A - right | -6.49 percent change | Standard Error 0.901 |
| ABvac40 Arm Part A | Percentage of Change in Hippocampal Volume | Week 104A - left | -8.15 percent change | Standard Error 0.965 |
Comparison: MMRM - Week 24A - leftp-value: =0.3599Mixed Models Analysis
Comparison: MMRM - Week 50A - leftp-value: =0.8913Mixed Models Analysis
Comparison: MMRM - Week 104A - leftp-value: =0.4736Mixed Models Analysis
Comparison: MMRM - Week 24A - rightp-value: =0.9095Mixed Models Analysis
Comparison: MMRM - Week 50A - rightp-value: =0.8744Mixed Models Analysis
Comparison: MMRM - Week 104A - rightp-value: =0.9307Mixed Models Analysis
Secondary
Percentage of Change in Ventricular Volume
The percent change in ventricular volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors may also have be included in the model: ApoE carrier status, baseline use of AD symptomatic medication and clinical subgroup - MCI or vmAD, if found to be significantly associated with the response measure (p \< 0.15).
Time frame: Part A (Week 24A, Week 50A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Percentage of Change in Ventricular Volume | Week 24A | 5.30 percent change | Standard Error 0.584 |
| Placebo Arm Part A | Percentage of Change in Ventricular Volume | Week 50A | 10.63 percent change | Standard Error 0.809 |
| Placebo Arm Part A | Percentage of Change in Ventricular Volume | Week 104A | 22.51 percent change | Standard Error 1.887 |
| ABvac40 Arm Part A | Percentage of Change in Ventricular Volume | Week 24A | 5.94 percent change | Standard Error 0.573 |
| ABvac40 Arm Part A | Percentage of Change in Ventricular Volume | Week 50A | 10.21 percent change | Standard Error 0.819 |
| ABvac40 Arm Part A | Percentage of Change in Ventricular Volume | Week 104A | 21.26 percent change | Standard Error 1.848 |
Comparison: MMRM - Week 24Ap-value: =0.3982Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.7035Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.6334Mixed Models Analysis
Secondary
Repeatable Battery for the Assessment of Neuropsychological Status Score
The change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. RBANS assesses five cognitive domains, i.e., Immediate Memory, Visuospatial/constructional, Language, Attention, and Delayed Memory. The test consists of 12 subtests and the score on each subtest contributes to one of the five domains. Total score, which can range from 40 to 160, derived as the sum of the five domain scores. The higher scores mean a better outcome.
Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 24A | -1.30 score on a scale | Standard Error 1.009 |
| Placebo Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 50A | -5.45 score on a scale | Standard Error 1.076 |
| Placebo Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 77A | -4.71 score on a scale | Standard Error 1.273 |
| Placebo Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 104A | -3.17 score on a scale | Standard Error 1.798 |
| ABvac40 Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 104A | -1.33 score on a scale | Standard Error 1.793 |
| ABvac40 Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 24A | -2.10 score on a scale | Standard Error 1.022 |
| ABvac40 Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 77A | -2.66 score on a scale | Standard Error 1.255 |
| ABvac40 Arm Part A | Repeatable Battery for the Assessment of Neuropsychological Status Score | Week 50A | -5.56 score on a scale | Standard Error 1.077 |
Comparison: MMRM - Week 24Ap-value: =0.552Mixed Models Analysis
Comparison: MMRM - Week 50Ap-value: =0.9371Mixed Models Analysis
Comparison: MMRM - Week 77Ap-value: =0.2354Mixed Models Analysis
Comparison: MMRM - Week 104Ap-value: =0.4608Mixed Models Analysis
Secondary
Subject Discontinuations Due to TEAEs
Number of withdrawn subjects due to treatment-emergent adverse events (TEAEs) during the whole study.
Time frame: Entire study duration (Week 0 to Week 104 in Part A, and Week 0 to Week 77 in Part B)
Population: The safety analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Arm Part A | Subject Discontinuations Due to TEAEs | 4 Participants |
| ABvac40 Arm Part A | Subject Discontinuations Due to TEAEs | 2 Participants |
| ABvac40 Arm Part B | Subject Discontinuations Due to TEAEs | 0 Participants |
| Placebo+Booster Arm Part B | Subject Discontinuations Due to TEAEs | 1 Participants |
Secondary
Trail Making Test Scores
The change in Trail Making Test (TMT) scores (Trail A and Trail B) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. TMT consists of two parts in which the patient is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first, the targets are all numbers from 1 to 25 and the test taker needs to connect them in sequential order; in the second part, the dots go from 1 to 13 and include letters from A to L. The lower timings mean a better outcome.
Time frame: Part A (Week 24A, Week 50A, Week 77A, and Week 104A)
Population: The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm Part A | Trail Making Test Scores | Week 24A - Trail A | 0.54 seconds | Standard Error 2.96 |
| Placebo Arm Part A | Trail Making Test Scores | Week 50A - Trail A | 11.34 seconds | Standard Error 4.186 |
| Placebo Arm Part A | Trail Making Test Scores | Week 77A - Trail A | 17.42 seconds | Standard Error 4.669 |
| Placebo Arm Part A | Trail Making Test Scores | Week 104A - Trail A | 20.09 seconds | Standard Error 7.253 |
| Placebo Arm Part A | Trail Making Test Scores | Week 24A - Trail B | 5.43 seconds | Standard Error 8.102 |
| Placebo Arm Part A | Trail Making Test Scores | Week 50A - Trail B | 18.83 seconds | Standard Error 8.503 |
| Placebo Arm Part A | Trail Making Test Scores | Week 77A - Trail B | 17.13 seconds | Standard Error 8.68 |
| Placebo Arm Part A | Trail Making Test Scores | Week 104A - Trail B | 20.81 seconds | Standard Error 10.715 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 104A - Trail B | -4.64 seconds | Standard Error 11.206 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 24A - Trail A | -0.59 seconds | Standard Error 2.939 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 24A - Trail B | -8.47 seconds | Standard Error 8.464 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 50A - Trail A | 3.59 seconds | Standard Error 4.023 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 77A - Trail B | 2.38 seconds | Standard Error 9.762 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 77A - Trail A | 2.79 seconds | Standard Error 4.425 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 50A - Trail B | 18.43 seconds | Standard Error 9.122 |
| ABvac40 Arm Part A | Trail Making Test Scores | Week 104A - Trail A | 9.24 seconds | Standard Error 6.967 |
Comparison: MMRM - Week 24A - Trail Ap-value: =0.777Mixed Models Analysis
Comparison: MMRM - Week 50A - Trail Ap-value: =0.1727Mixed Models Analysis
Comparison: MMRM - Week 77A - Trail Ap-value: =0.0218Mixed Models Analysis
Comparison: MMRM - Week 104A - Trail Ap-value: =0.2789Mixed Models Analysis
Comparison: MMRM - Week 24A - Trail Bp-value: =0.2261Mixed Models Analysis
Comparison: MMRM - Week 50A - Trail Bp-value: =0.9743Mixed Models Analysis
Comparison: MMRM - Week 77A - Trail Bp-value: =0.2556Mixed Models Analysis
Comparison: MMRM - Week 104A - Trail Bp-value: =0.1008Mixed Models Analysis
Other Pre-specified
Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA) - Sensitivity
Average maximal increment (MΔ) of plasma anti-Aβ40 antibody signal (optical density \[OD\] in ELISA) in each subject with regard to Baseline visit. Sensitivity analyses in the PP (Part A) analysis set.
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)
Population: The Per-Protocol analysis set comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1, V4, V7, V10, V13 and V18 in Part A), attended the safety visit after Booster (V20 in Part A) and had no major protocol deviations that could have affected the efficacy analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Arm Part A | Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA) - Sensitivity | 0.10 OD | Standard Deviation 0.13 |
| ABvac40 Arm Part A | Average Maximal Increment of Anti-Aβ40 Antibody Signal (Optical Density [OD] in ELISA) - Sensitivity | 3.29 OD | Standard Deviation 0.67 |
Comparison: The trial was considered successfully confirmatory regarding efficacy (immunogenicity) of ABvac40 if the average MΔ of anti-Aβ40 antibody signal (OD in ELISA) in the ABvac40 group was significantly greater than the average MΔ of anti-Aβ40 antibody signal in the Placebo group. i.e.~* Null hypothesis: average MΔ anti-Aβ40 (ABvac40) ≤ average MΔ anti-Aβ40 (placebo).~* Alternative hypothesis: average MΔ anti-Aβ40 (ABvac40) \> average MΔ anti-Aβ40 (placebo)p-value: <0.0001t-test, 1 sided
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.000195% CI: [3.02, 3.4]ANCOVA