Safety and Immunogenicity of Repeated Doses of ABvac40 in Patients With a-MCI or Vm-AD

Phase 2

Completed

Conditions: Mild Cognitive Impairment
Alzheimer Disease

Interventions: Biological: ABvac40
Biological: Placebo

Registration Number: NCT03461276

Lead Sponsor: Araclon Biotech S.L.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 134

Inclusion Criteria

A subject must meet all the following inclusion criteria:

Male or female between 55 and 80 years of age, both inclusive, at the time of signing informed consent.
The patient (or legal representative, if applicable) and a close relative/caregiver must read the subject information sheet, agree to participate in the clinical trial and sign the informed consent form (the patient and a close relative/caregiver).
Presence of a stable caregiver to attend the patient study visits.
Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), according to age and education level.
Clinical Dementia Rating (CDR) scale scoring 0.5.
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score on the Delayed Memory Index (DMI) of 85 or lower.
The results of the patient's MRI brain scan must be concordant with the diagnosis of clinical a-MCI or vm-AD according to the following criteria: Scheltens scale, and measurement of white matter and past haemorrhages.
If the patient is receiving treatment for AD, must have been stable during the two months before the selection visit.
Treatment for concomitant diseases must be stable during the previous month before the treatment of the study.
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 exclusion criteria is NOT eligible for participation in the study.

Known allergy to components of the vaccine or prior history of anaphylaxis, a severe allergic reaction or a history of hypersensitivity to any component of the formulation. Allergy to fish or shellfish.
Active infectious disease (i.e. hepatitis B, C). Positive syphilis serology.
History or presence of autoimmune disease, except mild eczema, rhinitis or psoriasis.
Presence or history of immunodeficiency (i.e. HIV).
Significant kidney and/or liver disease.
History of asthma or reactive airway disease with bronchospasm in the last 6 months, or currently on regular treatment.
Major uncontrolled systemic condition (e.g. diabetes, congestive heart failure, hypertension).
History of cancer (≤5 years since the last specific treatment). Exceptions: basocellular carcinoma.
Significant alterations in hematological, biochemical or urine analytical parameters, particularly those relating to levels of vitamin B12, folic acid or thyroid tests.
History of any other central nervous system disorder, degenerative or non-degenerative neurological or psychiatric condition that, in the investigator's opinion could be the cause of the dementia, or could explain the cognitive impairment, or that might interfere with cognitive function directly or by its treatment.
Geriatric Depression Scale (GDS; abbreviated version), score >5
Has a "yes" answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.
History or signs of cerebrovascular disease (ischemic or haemorrhagic stroke, transient ischemic attack), or diagnosis of possible, probable or clear vascular dementia according to NINDS-AIREN criteria.
Presence on MRI of a relevant pattern of microvascular disease (Leukoaraiosis, Fazekas score ≥2 in the deep white matter scale or ≥4 in the global score) or more than one lacunar or territorial infarcts. Any other MRI finding that, in the opinion of the investigator, might be a relevant contributing cause of subject´s cognitive impairment. Presence of up to 3 microhemorrhages will be acceptable.
History of bleeding disorder or predisposing conditions, blood clotting or clinically significant abnormal results on coagulation profile at Screening, as determined by the Investigator.
Patients being treated with anticoagulants or antiaggregant therapy (aspirin at a prophylactic dose ≤ 325 mg daily or clopidogrel at a dose ≤75 mg daily are allowed) should not be recruited in the study.
Modified Hachinski Ischemic Scale, score higher than 4.
Surgery (with general anaesthetic) within the previous three months to be included in the trial or programed during the study period.
Treatment within 30 days prior to visit 0 with systemic corticosteroids or other immunosuppressant's.
Vaccination against influenza or any other vaccination within 2 months before first IMP dose.
Patients, who have previously been randomized in this trial.
Participation in another clinical trial within the previous 1 month to screening visit, or within the previous 12 months after the last dose to the screening visit in the case of subjects who participated in trials with a study drug whose intention was to modify the progression AD unless documentation of receipt of placebo is available. The patient cannot be included in the study if the experimental drug was an immunotherapeutic drug, including IVIG or a vaccine against Alzheimer's disease unless documentation of receipt of placebo is available.
Patients with alcohol or drug abuse or dependence.
Absolute (having a pacemaker or implantable defibrillator) or relative (bare metal stent or stent implanted in the last six months) contraindications to MRI examination. Feeling of claustrophobic do not let perform MRI or PET scan.
Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits).
Women of childbearing potential, pregnant or nursing.
Significant alterations in the EKG that are associated with an added risk for the patient.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
ABvac40	ABvac40	Six administrations of ABvac40; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of ABvac40.
Placebo	Placebo	Six administrations of Placebo; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of the vaccine's vehicle buffer without the active component.
ABvac40	ABvac40	Six administrations of ABvac40; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of ABvac40.
Placebo	Placebo	Six administrations of Placebo; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of the vaccine's vehicle buffer without the active component.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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 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).
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, 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).
Mini Mental State Examination Score	Part A (baseline, and post-baseline at Week 24A, Week 50A, Week 77A, and Week 104A)	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.
Clinical Dementia Rating-Sum of Boxes Score	Part A (Week 24A, Week 50A, Week 77A, and Week 104A)	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.
Repeatable Battery for the Assessment of Neuropsychological Status Score	Part A (Week 24A, Week 50A, Week 77A, and Week 104A)	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.
Alzheimer's Disease Cooperative Study - Activities of Daily Living, Mild Cognitive Impairment Score	Part A (Week 24A, Week 50A, Week 77A, and Week 104A)	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.
Trail Making Test Scores	Part A (Week 24A, Week 50A, Week 77A, and Week 104A)	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.
Investigator Global Evaluation Score	Part A (Week 24A, Week 50A, and Week 104A)	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.
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 Overall Severity Index Score	Part A (Week 50A and Week 104A)	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.
EuroQol 5 Dimensions 5 Levels - Visual Analogue Scale Score	Part A (Week 50A and Week 104A)	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'.

Trial Locations

Locations (23): Fundació ACE
🇪🇸
Barcelona, Spain
Hospital Vall d'Hebron
🇪🇸
Barcelona, Spain
Hospital del Mar
🇪🇸
Barcelona, Spain
Hospital U. de Burgos
🇪🇸
Burgos, Spain
Hospital Santa Maria de Lleida
🇪🇸
Lleida, Spain
Complejo Hospitalario Ruber Juan Bravo
🇪🇸
Madrid, Spain
Hospital Universitario 12 Octubre
🇪🇸
Madrid, Spain
Hospital Clínico San Carlos
🇪🇸
Madrid, Spain
Hospital Clínico Universitario Lozano Blesa
🇪🇸
Zaragoza, Spain
Hospital Mútua de Terrasa
🇪🇸
Terrassa, Barcelona, Spain
CUN - Clínica Universidad de Navarra
🇪🇸
Pamplona, Navarra, Spain
Barcelona Beta Brain Research Center (BBRC)
🇪🇸
Barcelona, Spain
Hôpital François Mitterrand
🇫🇷
Dijon, Bourgogne, France
CHU de Montpellier
🇫🇷
Montpellier, France
Centre de Recherche Clinique du Gérontopôle
🇫🇷
Toulouse, France
San Giovanni di Dio - Fatebenefratelli
🇮🇹
Brescia, Italy
Hospital Universitario Donosti
🇪🇸
San Sebastian, Guipuzcoa, Spain
Hospital San Pedro
🇪🇸
Logroño, La Rioja, Spain
Hospital Ramón y Cajal
🇪🇸
Colmenar Viejo, Madrid, Spain
Cae Oroitu
🇪🇸
Algorta, Vizcaya, Spain
Hospital General Universitario de Alicante
🇪🇸
Alicante, Spain
Hospital de la Santa Creu i Sant Pau
🇪🇸
Barcelona, Spain
Karolinska Universitetssjukhuset
🇸🇪
Stockholm, Sweden