Segurança e Imunogenicidade de Doses Repetidas de ABvac40 em Pacientes com a-MCI ou Vm-AD

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

Incremento máximo médio (Mδ) do sinal de anticorpo anti-Aβ40 plasmático (densidade óptica [OD] em ELISA) em cada sujeito em relação à visita de linha de base.

Análises de sensibilidade no conjunto de análise PP (Parte A).