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

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"

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: AADvac1

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 5020
    • Univeristätsklinik für Neurologie, PMU, Christian-Doppler Klinik
  • Wien, Austria, 1090
    • Medizinische Universität Wien
  • Wien, Austria, A-1220
    • Sozialmedizinisches Zentrum Ost (SMZ Ost) /Donauspital, Memory Clinic and Karl Landsteiner Institut for Amnestic disorders
  • Steiermark
    • Graz, Steiermark, Austria, 8036
      • Medizinische Universität Graz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Completion of visit V8 of the AADvac1 phase I study AXON CO 18700 (EUDRACT 2012-003916-29).
2. Informed consent capability (as determined by an independent neurologist/psychiatrist).
3. Written informed consent signed and dated by the patient and the caregiver.
4. Availability of a partner/caregiver knowing the patient and being able to accompany the patient to the visits
5. Adequate visual and auditory abilities and language skills to allow neuropsychological testing.
6. Female patients are only eligible for the study if they are either surgically sterile or at least 2 years postmenopausal.
7. Sexually active males must be using reliable contraception methods (i.e. condoms) or be surgically sterile.

Exclusion Criteria:

1. Pregnant women.
2. Participation in another clinical trial during the course of this study.
3. Contraindication for MRI imaging such as MRI-incompatible metallic endoprosthesis or MRI-incompatible stent implantation
4. History and/or presence of autoimmune disease, if considered relevant by the investigator.
5. 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.
6. Current treatment with immunosuppressive drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AADvac1; 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; Active immunization against pathological Alzheimer's disease tau protein; Other Names: Axon peptide 108 (coupled to KLH), 40ug/0.3mL; 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

Collaborators and Investigators

• Sponsor: Axon Neuroscience SE
• Investigators: Principal Investigator: Reinhold Schmidt, Professor, Medizinische Universität Graz

Publications and helpful links

General Publications

• Novak P, Schmidt R, Kontsekova E, Kovacech B, Smolek T, Katina S, Fialova L, Prcina M, Parrak V, Dal-Bianco P, Brunner M, Staffen W, Rainer M, Ondrus M, Ropele S, Smisek M, Sivak R, Zilka N, Winblad B, Novak M. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease. Alzheimers Res Ther. 2018 Oct 24;10(1):108. doi: 10.1186/s13195-018-0436-1.
• Novak P, Schmidt R, Kontsekova E, Zilka N, Kovacech B, Skrabana R, Vince-Kazmerova Z, Katina S, Fialova L, Prcina M, Parrak V, Dal-Bianco P, Brunner M, Staffen W, Rainer M, Ondrus M, Ropele S, Smisek M, Sivak R, Winblad B, Novak M. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017 Feb;16(2):123-134. doi: 10.1016/S1474-4422(16)30331-3. Epub 2016 Dec 10.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: January 7, 2014
• First Submitted That Met QC Criteria: January 7, 2014
• First Posted (Estimate): January 9, 2014

Study Record Updates

• Last Update Posted (Actual): March 17, 2017
• Last Update Submitted That Met QC Criteria: March 15, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: treatment; dementia; Alzheimer's disease; tau; vaccine; elderly; immunization; cognitive; disease modifying
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: AC-AD-002; 2013-004499-36 (EudraCT Number)