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

Alzheimer's Disease Clinical Trial

— ADAMANT  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02579252
• Other study ID #: AC-AD-003
• Secondary ID: 2015-000630-30
• Status: Completed
• Phase: Phase 2
• Start date: March 2016
• Est. completion date: June 2019

Study information

• Verified date: November 2019
• Source: Axon Neuroscience SE
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 208
• Est. completion date: June 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

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).

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Biological:
• AADvac1

Drug:
• Placebo

Locations

Country	Name	City	State
Austria	Universitätsklinik für Neurologie	Graz	Steiermark
Austria	Abteilung Psychiatrie und Psychotherapie, LKH Hall	Hall in Tirol	Tirol
Austria	Ordination Dr. Bancher	Horn	Niederosterreich
Austria	Universitätsklinikum Innsbruck	Innsbruck	Tirol
Czechia	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 Kralove
Czechia	Narodni ustav dusevniho zdravi (NÚDZ), Department of cognitive disorders - AD Center	Klecany
Czechia	Fakultni nemocnice v Motole	Praha
Czechia	Vseobecna fakultni nemocnice v Praze	Praha
Germany	Neuro Centrum Odenwald	Erbach	Rheinland-Pfalz
Germany	Arzneimittelforschung Leipzig (AFL)	Leipzig	Sachsen
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	Nürnberg
Germany	Universitätsklinikum Ulm, Klinik und Poliklinik für Neurologie	Ulm
Poland	Podlaskie Centrum Psychogeriatrii	Bialystok
Poland	Pallmed prowadzacy NZOZ Dom Sue Ryder w Bydgoszczy Centrum Psychoneurologii Wieku Podeszlego	Bydgoszcz
Poland	Care Clinic	Katowice
Poland	Wielospecjalistyczna Poradnia Lekarska Synapsis	Katowice
Poland	Centrum Neurologii Klinicznej, Krakowska Akademia Neurologii	Kraków
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	Warszawa
Poland	Wroclawskie Centrum Alzheimerowskie	Wroclaw
Romania	"Dr. Constantin Gorgos" Psychiatry Hospital Titan	Bucharest
Slovakia	Neurologicka ambulancia	Banska 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	Kosice
Slovakia	NEURES, s.r.o. Neurologicka ambulancia	Krompachy
Slovakia	Centrum zdravia R.B.K., s.r.o., Psychiatricka ambulancia	Svidnik
Slovakia	Pro Mente Sana S.R.O., Psychiatricka Ambulancia	Trencin
Slovakia	Fakultna nemocnica s poliklinikou Zilina, Psychiatricke oddelenie	Zilina
Slovenia	Univerzitetni klinicni Center Ljubljana, Neurology Clinic	Ljubljana
Slovenia	University Clinical Centre Maribor	Maribor
Sweden	Skånes Universitetssjukhus Malmö, Minneskliniken	Malmö
Sweden	Sahlgrenska Universitetssjukhuset, Minnesmottagningen	Mölndal
Sweden	Karolinska Universitetssjukhuset Huddinge	Stockholm
Sweden	Akademiska Sjukhuset I Uppsala, Minnes-och geriatrikmottagningen	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
Axon Neuroscience SE

Countries where clinical trial is conducted

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

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)		24 months
Other	Exploratory: MRI volumetry		24 months
Other	Exploratory: Cerebrospinal fluid (CSF) biomarkers		24 months
Primary	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	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
Secondary	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
Secondary	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
Secondary	Immunogenicity		24 months