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

NCT ID: NCT02579252

Last Updated: 2019-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 208 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-31
• Study Completion Date: 2019-06-30

Brief Summary

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

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.

Conditions

Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

AADvac1

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.

Group Type: EXPERIMENTAL

AADvac1

Intervention Type: BIOLOGICAL

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

AADvac1

Intervention Type: BIOLOGICAL

Placebo

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

• 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).

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Axon Neuroscience SE

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Reinhold Schmidt, Prof. MD.

Role: PRINCIPAL_INVESTIGATOR

Medical University, Graz, Austria

Locations

Ordination Dr. Bancher

Horn, Lower Austria, Austria

Universitätsklinik für Neurologie

Graz, Styria, Austria

Abteilung Psychiatrie und Psychotherapie, LKH Hall

Hall in Tirol, Tyrol, Austria

Universitätsklinikum Innsbruck

Innsbruck, Tyrol, Austria

Fakultni nemocnice u sv. Anny v Brne, Mezinarodni centrum klinickeho vyzkumu (ICRC), Centrum pro kognitivni poruchy, Neuro 2

Brno, , Czechia

Fakultni nemocnice Hradec Kralove, Neurologicka Klinika

Hradec Králové, , Czechia

Narodni ustav dusevniho zdravi (NÚDZ), Department of cognitive disorders - AD Center

Klecany, , Czechia

Vseobecna fakultni nemocnice v Praze

Prague, , Czechia

Fakultni nemocnice v Motole

Prague, , Czechia

Neuro Centrum Odenwald

Erbach, Rhineland-Palatinate, Germany

Arzneimittelforschung Leipzig (AFL)

Leipzig, Saxony, Germany

Universität Heidelberg, Zentralinstitut für Seelische Gesundheit

Mannheim, , Germany

Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik fur Psychiatrie und Psychotherapie

München, , Germany

Praxis Dr. Klaus Christian Steinwachs

Nuremberg, , Germany

Universitätsklinikum Ulm, Klinik und Poliklinik für Neurologie

Ulm, , Germany

Podlaskie Centrum Psychogeriatrii

Bialystok, , Poland

Pallmed prowadzacy NZOZ Dom Sue Ryder w Bydgoszczy Centrum Psychoneurologii Wieku Podeszlego

Bydgoszcz, , Poland

Wielospecjalistyczna Poradnia Lekarska Synapsis

Katowice, , Poland

Care Clinic

Katowice, , Poland

Centrum Neurologii Klinicznej, Krakowska Akademia Neurologii

Krakow, , Poland

KO-MED Centra Kliniczne Sp. z o.o.

Lublin, , Poland

Oddzial Neurologiczny

Olsztyn, , Poland

NZOZ Neuro-Kard

Poznan, , Poland

EUROMEDIS Sp. z o.o.

Szczecin, , Poland

Centrum Medyczne NeuroProtect

Warsaw, , Poland

Wrocławskie Centrum Alzheimerowskie

Wroclaw, , Poland

"Dr. Constantin Gorgos" Psychiatry Hospital Titan

Bucharest, , Romania

Neurologicka ambulancia

Banská Bystrica, , Slovakia

Nestatna psychiatricka ambulancia

Bratislava, , Slovakia

Univerzitna nemocnica Bratislava, Nemocnica Stare Mesto, I. Neurologicka klinika LF UK a UNB

Bratislava, , Slovakia

Univerzitna nemocnica Bratislava, Psychiatricka klinika LFUK a UNB

Bratislava, , Slovakia

Univerzitna nemocnica L Pasteura Kosice, Psychiatricka klinika

Košice, , Slovakia

NEURES, s.r.o. Neurologicka ambulancia

Krompachy, , Slovakia

Centrum zdravia R.B.K., s.r.o., Psychiatricka ambulancia

Svidník, , Slovakia

Pro Mente Sana S.R.O., Psychiatricka Ambulancia

Trenčín, , Slovakia

Fakultna nemocnica s poliklinikou Zilina, Psychiatricke oddelenie

Žilina, , Slovakia

Univerzitetni klinični Center Ljubljana, Neurology Clinic

Ljubljana, , Slovenia

University Clinical Centre Maribor

Maribor, , Slovenia

Skånes Universitetssjukhus Malmö, Minneskliniken

Malmo, , Sweden

Sahlgrenska Universitetssjukhuset, Minnesmottagningen

Mölndal, , Sweden

Karolinska Universitetssjukhuset Huddinge

Stockholm, , Sweden

Akademiska Sjukhuset I Uppsala, Minnes-och geriatrikmottagningen

Uppsala, , Sweden

Countries

Austria; Czechia; Germany; Poland; Romania; Slovakia; Slovenia; Sweden

References

Kontsekova E, Zilka N, Kovacech B, Skrabana R, Novak M. Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer's disease. Alzheimers Res Ther. 2014 Aug 1;6(4):45. doi: 10.1186/alzrt277. eCollection 2014.

Reference Type: BACKGROUND

PMID: 25478018 (View on PubMed)

Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model. Alzheimers Res Ther. 2014 Aug 1;6(4):44. doi: 10.1186/alzrt278. eCollection 2014.

Reference Type: BACKGROUND

PMID: 25478017 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27955995 (View on PubMed)

Kovacech B, Cullen NC, Novak P, Hanes J, Kontsekova E, Katina S, Parrak V, Fresser M, Vanbrabant J, Feldman HH, Winblad B, Stoops E, Vanmechelen E, Zilka N. Post hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer's disease, positive for plasma p-tau217. Alzheimers Res Ther. 2024 Nov 23;16(1):254. doi: 10.1186/s13195-024-01620-7.

Reference Type: DERIVED

PMID: 39580468 (View on PubMed)

Other Identifiers

2015-000630-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AC-AD-003

Identifier Type: -

Identifier Source: org_study_id