Clinical trial NCT02579252: 24 Months Safety and Efficacy Study of AADvac1 in Patients With Mild Alzheimer's Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: vaccine
tau protein
active
immunization
KLH
immunotherapy
tau
Lead sponsor: Axon Neuroscience SE
Sponsor class: INDUSTRY
First posted: 2015-10-19
Enrollment: 208
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Safety (all-case treatment-emergent adverse events except local reactions)
timeFrame: 24 months
Secondary outcomes:
measure: Clinical Dementia Rating (CDR) Sum of Boxes
timeFrame: 24 months
measure: Custom cognitive battery (composite standard score)
timeFrame: 24 months
measure: Alzheimer's Disease Cooperative Study - Activities of Daily Living questionnaire (version for Mild Cognitive Impairment) (ADCS MCI ADL)
timeFrame: 24 months
measure: Immunogenicity
timeFrame: 24 months
Other outcomes:
measure: Exploratory: Fludeoxyglucose Positron Emission Tomography (FDG PET) assessment of brain metabolism (change in cerebral glucose metabolic rate expressed as Standardised Uptake Value Ratio [SUVR] change, multiple regions of interest)
timeFrame: 24 months
measure: Exploratory: MRI volumetry
timeFrame: 24 months
measure: Exploratory: Cerebrospinal fluid (CSF) biomarkers
timeFrame: 24 months
Locations:
city: Horn
country: Austria
facility: Ordination Dr. Bancher
state: Niederosterreich
city: Graz
country: Austria
facility: Universitätsklinik für Neurologie
state: Steiermark
city: Hall in Tirol
country: Austria
facility: Abteilung Psychiatrie und Psychotherapie, LKH Hall
state: Tirol
city: Innsbruck
country: Austria
facility: Universitätsklinikum Innsbruck
state: Tirol
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny v Brne, Mezinarodni centrum klinickeho vyzkumu (ICRC), Centrum pro kognitivni poruchy, Neuro 2
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove, Neurologicka Klinika
city: Klecany
country: Czechia
facility: Narodni ustav dusevniho zdravi (NÚDZ), Department of cognitive disorders - AD Center
city: Praha
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha
country: Czechia
facility: Fakultni nemocnice v Motole
city: Erbach
country: Germany
facility: Neuro Centrum Odenwald
state: Rheinland-Pfalz
city: Leipzig
country: Germany
facility: Arzneimittelforschung Leipzig (AFL)
state: Sachsen
city: Mannheim
country: Germany
facility: Universität Heidelberg, Zentralinstitut für Seelische Gesundheit
city: München
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik fur Psychiatrie und Psychotherapie
city: Nürnberg
country: Germany
facility: Praxis Dr. Klaus Christian Steinwachs
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik und Poliklinik für Neurologie
city: Bialystok
country: Poland
facility: Podlaskie Centrum Psychogeriatrii
city: Bydgoszcz
country: Poland
facility: Pallmed prowadzacy NZOZ Dom Sue Ryder w Bydgoszczy Centrum Psychoneurologii Wieku Podeszlego
city: Katowice
country: Poland
facility: Wielospecjalistyczna Poradnia Lekarska Synapsis
city: Katowice
country: Poland
facility: Care Clinic
city: Kraków
country: Poland
facility: Centrum Neurologii Klinicznej, Krakowska Akademia Neurologii
city: Lublin
country: Poland
facility: KO-MED Centra Kliniczne Sp. z o.o.
city: Olsztyn
country: Poland
facility: Oddzial Neurologiczny
city: Poznan
country: Poland
facility: NZOZ Neuro-Kard
city: Szczecin
country: Poland
facility: EUROMEDIS Sp. z o.o.
city: Warszawa
country: Poland
facility: Centrum Medyczne NeuroProtect
city: Wroclaw
country: Poland
facility: Wrocławskie Centrum Alzheimerowskie
city: Bucharest
country: Romania
facility: "Dr. Constantin Gorgos" Psychiatry Hospital Titan
city: Banska Bystrica
country: Slovakia
facility: Neurologicka ambulancia
city: Bratislava
country: Slovakia
facility: Nestatna psychiatricka ambulancia
city: Bratislava
country: Slovakia
facility: Univerzitna nemocnica Bratislava, Nemocnica Stare Mesto, I. Neurologicka klinika LF UK a UNB
city: Bratislava
country: Slovakia
facility: Univerzitna nemocnica Bratislava, Psychiatricka klinika LFUK a UNB
city: Kosice
country: Slovakia
facility: Univerzitna nemocnica L Pasteura Kosice, Psychiatricka klinika
city: Krompachy
country: Slovakia
facility: NEURES, s.r.o. Neurologicka ambulancia
city: Svidnik
country: Slovakia
facility: Centrum zdravia R.B.K., s.r.o., Psychiatricka ambulancia
city: Trencin
country: Slovakia
facility: Pro Mente Sana S.R.O., Psychiatricka Ambulancia
city: Zilina
country: Slovakia
facility: Fakultna nemocnica s poliklinikou Zilina, Psychiatricke oddelenie
city: Ljubljana
country: Slovenia
facility: Univerzitetni klinični Center Ljubljana, Neurology Clinic
city: Maribor
country: Slovenia
facility: University Clinical Centre Maribor
city: Malmö
country: Sweden
facility: Skånes Universitetssjukhus Malmö, Minneskliniken
city: Mölndal
country: Sweden
facility: Sahlgrenska Universitetssjukhuset, Minnesmottagningen
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Huddinge
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset I Uppsala, Minnes-och geriatrikmottagningen
Study officials:
affiliation: Medical University, Graz, Austria
name: Reinhold Schmidt, Prof. MD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.