18-months Safety Follow-up Study of AADvac1, an Active Tau Vaccine for Alzheimer's Disease

Study Overview
=================
Brief Summary
-----------------
This follow-up study continues to observe patients who have completed the phase 1 trial of AADvac1, for another 18 months. Long-term safety and behavior of the immune response to AADvac1 over time are the main points of interest. AADvac1 is a vaccine directed against pathologically modified Alzheimer tau protein that is the main constituent of neurofibrillary tangles (NFTs), and is intended to be a disease-modifying treatment for Alzheimer's disease, i.e. to halt its progress. As this study is a Phase I study focused on tolerability and safety, efficacy will be assessed in an exploratory manner.

Detailed Description
-----------------
AADvac1 is a candidate therapeutic vaccine for Alzheimer's disease that targets misfolded tau protein, a common denominator of neurofibrillary pathology. Based on preclinical results, the intervention is expected to reduce the number of neurofibrillary tangles, remove hyperphosphorylated tau protein and reduce the amount of oligomerized and insoluble pathological tau in the brain, to halt the spread of neurofibrillary pathology through the brain, and thus prevent associated cognitive decline. The vaccine's antigenic determinant is a synthetic peptide derived from a tau protein sequence, which is coupled to keyhole limpet hemocyanin (KLH) and uses aluminum hydroxide (Alhydrogel) as an adjuvant. At present AADvac1 is intended as an active immunotherapy for patients with diagnosed Alzheimer's disease (AD). According to need, patients will receive additional immunization doses beyond those administered in the preceding pase 1 trial; the raised titers of therapeutic antibodies and possible benefits of the treatment can extend beyond the duration of the study. Because of the central role of pathological misfolded tau protein in the etiology of AD, the vaccine is expected to be more effective than active or passive immunotherapies aiming to eliminate the amyloid β plaques that have been clinically investigated so far.

Official Title
-----------------
An 18-months Open Label Phase I Follow-up Study on Patients With Alzheimer's Disease Who Have Completed the AADvac1 Phase I Study AXON CO 18700

Conditions
-----------------
Alzheimer's Disease

Intervention / Treatment
-----------------
* Drug: AADvac1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Completion of visit V8 of the AADvac1 phase I study AXON CO 18700 (EUDRACT 2012-003916-29). Informed consent capability (as determined by an independent neurologist/psychiatrist). Written informed consent signed and dated by the patient and the caregiver. Availability of a partner/caregiver knowing the patient and being able to accompany the patient to the visits Adequate visual and auditory abilities and language skills to allow neuropsychological testing. Female patients are only eligible for the study if they are either surgically sterile or at least 2 years postmenopausal. Sexually active males must be using reliable contraception methods (i.e. condoms) or be surgically sterile. Exclusion Criteria: Pregnant women. Participation in another clinical trial during the course of this study. Contraindication for MRI imaging such as MRI-incompatible metallic endoprosthesis or MRI-incompatible stent implantation History and/or presence of autoimmune disease, if considered relevant by the investigator. Significant systemic illness (e.g., chronic renal failure, chronic liver disease, poorly controlled diabetes, poorly controlled congestive heart failure, congenital long QT syndrome, other deficiencies), if considered relevant by the investigator. Current treatment with immunosuppressive drugs.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 86 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AADvac1<br>Patients who have received 6 doses in the previous trial will be administered 1-2 booster doses of AADvac1 (2 if their antibody titers decline below those achieved in the previous trial). Patients who have received 3 doses in the previous trial will be administered another 3 doses, then vaccinated with booster doses as above. | Drug: AADvac1<br>* Active immunization against pathological Alzheimer's disease tau protein<br>* Other names: Axon peptide 108 conjugated to KLH;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability and safety profile of AADvac1 in patients with mild-to-moderate Alzheimer's disease | Safety is assessed via recording of all Adverse Events and Adverse Events Patients are observed via: MRI Clinical & neuro-psychiatric observation Cognitive testing ECG Blood biochemistry, hematology, coagulation measurement Urine analysis | Tolerability & safety are assessed over a period of 18+ months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of AADvac1 | Measurement of: Titres of antibodies reactive with AADvac1 Titres of antibodies reactive with Alzheimer tau protein Antibody isotype profiles | Immune response to the vaccine will be assessed over 18 month | 
| Patient cognition | Tests used: ADAS-Cog (Alzheimer's Disease Assessment Scale-cognitive subscale) COWAT (Controlled oral word association test) Category fluency | 18+ months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Alzheimer's disease, tau, dementia, elderly, cognitive, disease modifying, treatment, immunization, vaccine