24 Months Safety and Efficacy Study of AADvac1 in Patients With Mild Alzheimer's Disease

Study Overview
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Brief Summary
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This study evaluates the safety and efficacy of AADvac1 in the treatment of patients with mild Alzheimer's disease. 60% of participants will receive AADvac1 and 40% of participants will receive placebo.

Detailed Description
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Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder of the brain. Over the course of the disease, pathological proteins accumulate in the brain, damaging neurons, thus causing them to lose their connections and die. Currently available treatments are designed to compensate for the neurotransmitter loss caused by the disease without affecting the disease process itself. AADvac1 is designed to raise antibodies against pathological tau protein (the primary constituent of neurofibrillary pathology in AD). These antibodies are expected to prevent tau protein from aggregating, to facilitate the removal of tau protein aggregates and prevent the spreading of pathology, slowing or halting the progress of the disease.

Official Title
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A 24 Months Randomised, Placebo-controlled, Parallel Group, Double Blinded, Multi Centre, Phase 2 Study to Assess Safety and Efficacy of AADvac1 Applied to Patients With Mild Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Biological: AADvac1
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria (abbreviated): Diagnosis of probable Alzheimer's disease according to the revised National Institute on Aging-Alzheimer's Association (NIA-AA) criteria (McKhann 2011). Mini Mental State Examination (MMSE) score ≥ 20 and ≤ 26. Brain MRI finding consistent with the diagnosis of Alzheimer's disease Medial temporal lobe atrophy: Scheltens score of ≥ 2 (on a scale of 0-4 on the more atrophied side) AND/OR positive AD biomarker profile in the CSF (amyloid+, tau+) At least 6 years of formal elementary education. Age 50-85 years. Fluency in the local language and sufficient auditory and visual capacities to allow neuropsychological testing. Ability to read and understand the informed consent. Stable therapy with an acetylcholinesterase inhibitor for at least 3 months prior to screening. If the patient is on memantine treatment, the dose regimen must be stable for at least 3 months prior to screening. Hachinski Ischemia Scale score ≤ 4. Availability of a caregiver. Female patients must be either surgically sterile or at least 2 years postmenopausal. Male patients must either be surgically sterile, or he and his female spouse/partner who is of childbearing potential must be using highly effective contraception starting at screening and continuing throughout the study period. Patient provides written informed consent. Exclusion criteria (abbreviated): Participation in another clinical study within 3 months prior to screening. Pregnant or breastfeeding female. Not expected to complete the clinical study. Known allergy to components of the vaccine. Contraindication for MRI imaging. Any of the following detected by brain MRI: Infarction in the territory of large vessels More than one lacunar infarct. Any lacunar infarct in a strategically important location. Confluent hemispheric deep white matter lesions (Fazekas grade 3). Other focal lesions which may be responsible for the cognitive status of the patient or any other abnormalities associated with significant central nervous disease other than Alzheimer's disease. Surgery (under general anaesthesia) within 3 months prior to screening and/or scheduled surgery (under general anaesthesia) during the whole study period. Patient has a history and/or currently suffers from a clinically significant autoimmune disease, or is expected to receive immunosuppressive or immunomodulatory treatment at the present or in the future. Recent history of cancer (last specific treatment ≤ 5 years prior to Screening). Myocardial infarction within 2 years prior to screening. Hepatitis B, C, HIV or Syphilis. Active infectious disease. Presence and/or history of immunodeficiency. Patient currently suffering from a clinically important systemic illness: poorly controlled congestive heart failure (NYHA ≥ 3) BMI > 40 poorly controlled diabetes (HbA1c > 7.5%) severe renal insufficiency (eGFR < 30 mL/min) chronic liver disease - ALT (alanine aminotransferase) > 66 U/L in females or > 80 U/L in males, AST (aspartate aminotransferase) > 82 U/L QTc interval prolongation in ECG (> 450 ms) other clinically significant systemic illness, if considered relevant by the investigator Hypothyroidism, defined as TSH (thyroid-stimulating hormone) elevation > 5.000 mcIU/mL, and/or FT4 levels < 0.7 ng/dL. Patients with corrected hypothyroidism are eligible for the study provided that treatment has been stable for 3 months before study entry. Valid diagnosis of a significant psychiatric illness such as schizophrenia, any type of psychotic disorder or bipolar affective disorder. Current depressive episode (Geriatric Depression Scale GDS ≥ 6) or major depressive episode within the last 1 years. Metabolic or toxic encephalopathy or dementia due to a general medical condition. History of alcohol or drug abuse or dependence within the past 2 years. Wernicke's encephalopathy. History or evidence of any CNS disorder other than AD that could be the cause of dementia. Cerebrovascular disease (ischemic or haemorrhagic stroke), or diagnosis of possible, probable or definite vascular dementia. Epilepsy. Treatment with experimental immunotherapeutics including intravenous immunoglobulin within 3 months prior to screening. Treatment with experimental therapies for AD aiming at disease-modification within 3 months prior to screening. Patient is currently being treated or was treated in the past with any active vaccines for AD. Treatment with immunosuppressive drugs. Change in dose of previous and current medications within the last 30 days prior to Screening (V01), if considered clinically relevant by the investigator. Vitamin B12 deficiency (serum vitamin B12 < 191 pg/mL).

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AADvac1<br>AADvac1 is a suspension for subcutaneous injection. AADvac1 is provided in single-use vials. Dosage: 40 µg Axon peptide 108 (coupled to keyhole limpet haemocyanin (KLH)) using aluminium hydroxide (containing 0.5 mg Al3+) as adjuvant, in a phosphate buffer. Patients receive 6 doses in 4-week intervals, and then 5 individual booster doses in 3-month intervals, for a total of 11 doses. | Biological: AADvac1<br> <br> |
| Placebo Comparator: Placebo<br>Placebo is a suspension for subcutaneous injection. Placebo is provided in single-use vials. Dosage: aluminium hydroxide (containing 0.5 mg Al3+), in a phosphate buffer. Patients receive 6 doses in 4-week intervals, and then 5 individual booster doses in 3-month intervals, for a total of 11 doses. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (all-case treatment-emergent adverse events except local reactions) | The safety and tolerability of AADvac1 in the treatment of patients with mild Alzheimer disease, as assessed by AEs, vital signs, ECG, laboratory measures, MRI of the brain, physical and neurological examination, Columbia Suicide Severity Rating Scale (C-SSRS) and review of the Patient Diary | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Dementia Rating (CDR) Sum of Boxes | The domain scores of the standard 6-domain CDR assessment will be summed up to obtain a Sum-of-Boxes score of 0-18 | 24 months | 
| Custom cognitive battery (composite standard score) | A composite standard score will be calculated from the following tests: Cogstate International Shopping List Task (memory) immediate free recall delayed free recall delayed recognition Cogstate One Card Learning Task (memory) Cogstate One Card Back Task (memory) Category Fluency Test (executive function, language) Letter Fluency Test (executive function, language) Digit Symbol Coding (executive functioning, working memory and processing speed) | 24 months | 
| Alzheimer's Disease Cooperative Study - Activities of Daily Living questionnaire (version for Mild Cognitive Impairment) (ADCS MCI ADL) | Activities of daily living will be assessed using the informant-based ADCS questionnaire (both the score for the 18-point and the 24-point version will be calculated) | 24 months | 
| Immunogenicity |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaccine, tau protein, active, immunization, KLH, immunotherapy, tau