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Safety and Immunogenicity of Repeated Doses of ABvac40 in Patients With a-MCI or Vm-AD

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ClinicalTrials.gov Identifier: NCT03461276
Recruitment Status : Recruiting
First Posted : March 12, 2018
Last Update Posted : March 14, 2018
Sponsor:
Information provided by (Responsible Party):
Araclon Biotech S.L.

Brief Summary:

Alzheimer's disease (AD) is the most common type of dementia, accounting for 50-75% of the estimated 47 million people with dementia worldwide. The amyloid cascade hypothesis of AD proposes that amyloid-β (Aβ) peptide accumulation in the brain, caused by an imbalance between Aβ production and clearance, is the initiating factor of a cascade ultimately leading to dementia.

Aβ peptides are generated from sequential cleavage of the amyloid precursor protein (APP), including Aβ40 and Aβ42. Aβ40 is the predominant variant (90%) among the secreted Aβ forms and although Aβ42 is more hydrophobic and prone to aggregate, and Aβ42 oligomers are regarded to be the most neurotoxic species, Aβ40 can also produce highly toxic diffusible aggregates, which can be prevented in vitro by specific anti-Aβ40 antibodies.

Several studies have proposed that a high concentration of Aβ40 in the brain distinguishes patients with AD from those who have senile plaques but are cognitively normal, pointing to the importance of Aβ40 in the onset of dementia. In keeping with this, previous studies have demonstrated that specific anti-Aβ40 antibodies label NFTs in the entorhinal cortex and the hippocampus of AD brains, and that these do not co-localize with tau NFTs, suggesting the presence of degenerating neuronal populations filled with C-terminal fragments of Aβx-40. In addition, Aβ40 is the main component of amyloid deposition around cerebral arteries causing cerebral amyloid angiopathy (CAA), which has a prevalence of about 80-90% in patients with AD (for more information see Lacosta et al. Alzheimer's Research & Therapy (2018) 10:12 DOI 10.1186/s13195-018-0340-8).

Considering those previous results suggesting that strategies targeting Aβ40 could represent novel disease-modifying therapies, we have developed ABvac40, the first active vaccine targeting the C-terminal end of the Aβ40 peptide.

The purpose of this Phase II study is to confirm in patients with a-MCI or vm-AD the level of safety and tolerability obtained in the ABvac40 Phase I clinical trial in patients with mm-AD. In addition, the study is aimed to better characterize the immune response elicited by ABvac40 and to explore its effects on AD biomarkers.


Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Alzheimer Disease Biological: ABvac40 Biological: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Multi-center, Randomized, Double-blind, Placebo-controlled, 24 Months Study in Patients With Amnestic Mild Cognitive Impairment or Very Mild Alzheimer's Disease to Investigate the Safety, Tolerability and Immune Response of Repeated Subcutaneous Injections of ABvac40
Actual Study Start Date : February 8, 2018
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ABvac40
Six administrations of ABvac40; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of ABvac40.
Biological: ABvac40
ABvac40 consists in a conjugate of Aβx-40 with a carrier protein (KLH) vehiculated in phosphate buffer containing 0.35% aluminium hydroxide as adjuvant.

Placebo Comparator: Placebo
Six administrations of Placebo; the first five administered once every 4 weeks and the sixth at week 42. Each administration consists of 1mL subcutaneous injection of the vaccine's vehicle buffer without the active component.
Biological: Placebo
Placebo consists in the vaccine's vehicle (phosphate buffer containing 0.35% aluminium hydroxide) without the conjugate.




Primary Outcome Measures :
  1. Incidence of treatment-emergent adverse events [safety and tolerability] [ Time Frame: 24 months ]
    Rate of adverse events in the ABvac40 and Placebo arms

  2. Immune response [ Time Frame: 24 months ]
    Level of anti-Abeta40 antibodies in plasma



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Ages Eligible for Study:   55 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A subject must meet all the following inclusion criteria:

  1. Male or female between 55 and 80 years of age, both inclusive, at the time of signing informed consent.
  2. The patient (or legal representative, if applicable) and a close relative/caregiver must read the subject information sheet, agree to participate in the clinical trial and sign the informed consent form (the patient and a close relative/caregiver).
  3. Presence of a stable caregiver to attend the patient study visits.
  4. Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), according to age and education level.
  5. Clinical Dementia Rating (CDR) scale scoring 0.5.
  6. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score on the Delayed Memory Index (DMI) of 85 or lower.
  7. The results of the patient's MRI brain scan must be concordant with the diagnosis of clinical a-MCI or vm-AD according to the following criteria: Scheltens scale, and measurement of white matter and past haemorrhages.
  8. If the patient is receiving treatment for AD, must have been stable during the two months before the selection visit.
  9. Treatment for concomitant diseases must be stable during the previous month before the treatment of the study.
  10. Positive assessment of the candidate by the investigator for complying with the requirements and procedures of the study.

Exclusion Criteria:

A subject meeting any of the following exclusion criteria is NOT eligible for participation in the study.

  1. Known allergy to components of the vaccine or prior history of anaphylaxis, a severe allergic reaction or a history of hypersensitivity to any component of the formulation.

    Allergy to fish or shellfish.

  2. Active infectious disease (i.e. hepatitis B, C). Positive syphilis serology.
  3. History or presence of autoimmune disease, except mild eczema, rhinitis or psoriasis.
  4. Presence or history of immunodeficiency (i.e. HIV).
  5. Significant kidney and/or liver disease, as defined by plasma creatinine ≥2.5 mg/dL (221 micromol/l) and/or total bilirubin > 3 mg/dL (51.3 micromol/l) measured at the local site laboratory.
  6. History of asthma or reactive airway disease with bronchospasm in the last 6 months, or currently on regular treatment.
  7. Major uncontrolled systemic condition (e.g. diabetes, congestive heart failure, hypertension).
  8. History of cancer (≤5 years since the last specific treatment). Exceptions: basocellular carcinoma.
  9. Significant alterations in hematological, biochemical or urine analytical parameters, particularly those relating to levels of vitamin B12, folic acid or thyroid tests.
  10. History of any other central nervous system disorder, degenerative or nondegenerative neurological or psychiatric condition that, in the investigator's opinion could be the cause of the dementia, or could explain the cognitive impairment, or that might interfere with cognitive function directly or by its treatment.
  11. Geriatric Depression Scale (GDS; abbreviated version), score >5
  12. Has a "yes" answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.
  13. History or signs of cerebrovascular disease (ischemic or haemorrhagic stroke, transient ischemic attack), or diagnosis of possible, probable or clear vascular dementia according to NINDS-AIREN criteria.
  14. Presence on MRI of a relevant pattern of microvascular disease (Leukoaraiosis, Fazekas score ≥2 in the deep white matter scale or ≥4 in the global score) or more than one lacunar or territorial infarcts. Any other MRI finding that, in the opinion of the investigator, might be a relevant contributing cause of subject´s cognitive impairment.
  15. History of bleeding disorder or predisposing conditions, blood clotting or clinically significant abnormal results on coagulation profile at Screening, as determined by the Investigator. Presence of up to 3 microhemorrhages will be acceptable.
  16. Patients being treated with anticoagulants or antiaggregant therapy (aspirin at a prophylactic dose ≤ 325 mg daily or clopidogrel at a dose ≤75 mg daily are allowed) should not be recruited in the study.
  17. Modified Hachinski Ischemic Scale, score higher than 4.
  18. Surgery (with general anaesthetic) within the previous three months to be included in the trial, or programed during the study period.
  19. Treatment within 30 days prior to visit 0 with systemic corticosteroids or other immunosuppressant's.
  20. The vaccination against influenza, must be avoided within 3 months before inclusion.
  21. Patients, who have previously been randomized in this trial.
  22. Participation in another clinical trial within the previous 1 month to screening visit, or within the previous 12 months after the last dose to the screening visit in the case of subjects who participated in trials with a study drug whose intention was to modify the progression AD unless documentation of receipt of placebo is available. The patient cannot be included in the study if the experimental drug was an immunotherapeutic drug, including IVIG or a vaccine against Alzheimer's disease unless documentation of receipt of placebo is available.
  23. Patients with alcohol or drug abuse or dependence.
  24. Absolute (having a pacemaker or implantable defibrillator) or relative (bare metal stent or stent implanted in the last six months) contraindications to MRI examination.

    Feeling of claustrophobic do not let perform MRI or PET scan.

  25. Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits).
  26. Women of childbearing age, pregnant or nursing.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03461276


Contacts
Contact: Irene SanJose +34976796562 info@araclon.com

Locations
France
CHU de Montpellier Not yet recruiting
Montpellier, France, 34295
Contact: Christine Lesage       c-lesage@chu-montpellier.fr   
Centre de Recherche Clinique du Gérontopôle Not yet recruiting
Toulouse, France, 31059
Contact: Isabelle Carrié       carrie.i@chu-toulouse.fr   
Italy
San Giovanni di Dio - Fatebenefratelli Not yet recruiting
Brescia, Italy, 25125
Spain
Hospital Mutua de Terrasa Recruiting
Terrassa, Barcelona, Spain, 08221
Contact: Judit López       neurologia@mutuaterrassa.es   
Hospital Universitario Donosti Recruiting
San Sebastian, Guipuzcoa, Spain, 20014
Contact: Miren Zulaica-Ijurco       miren.zulaicaijurco@osakidetza.eus   
Hospital Ramón y Cajal Recruiting
Colmenar Viejo, Madrid, Spain, 28034
Contact: Monica Aguliar         
CUN - Clinica Universitaria de Navarra Recruiting
Pamplona, Navarra, Spain, 31008
Contact: Joana Reis       jreis@unav.es   
Cae Oroitu Recruiting
Algorta, Vizcaya, Spain, 48993
Contact: Joana Barreras-Martinez       joana@oroitu.com   
Hospital General Universitario de Alicante Recruiting
Alicante, Spain, 03010
Hospital de la Santa Creu i Sant Pau Recruiting
Barcelona, Spain, 08025
Contact: Roser Ribosa       rribosa@santpau.cat   
Fundació ACE Recruiting
Barcelona, Spain, 08028
Contact: Mar Buendía       mbuendia@fundacioace.com   
Hospital Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Contact: Diana Liébana       dianaliebanag@hotmail.com   
Hospital del Mar Recruiting
Barcelona, Spain
Contact: Nuria Massuet       nmassuet@imim.es   
Hospital U. de Burgos Recruiting
Burgos, Spain, 09006
Contact: Carolina Santolaya       csantolaya@hubu.es   
Hospital Santa Maria de Lleida Recruiting
Lleida, Spain, 25198
Contact: Nuria Badia       nbadia@gss.scs.es   
Complejo Hospitalario Ruber Juan Bravo Recruiting
Madrid, Spain, 28006
Contact: Nuria Villares       nurvillares@yahoo.es   
Hospital Universitario 12 Octubre Recruiting
Madrid, Spain, 28010
Contact: Sara Llamas       laisset@hotmail.com   
Hospital Clínico San Carlos Recruiting
Madrid, Spain, 28040
Contact: Marta Palacios       marta13_12@hotmail.com   
Hospital Clínico Universitario Lozano Blesa Recruiting
Zaragoza, Spain, 50009
Sweden
Karolinska Universitetssjukhuset Not yet recruiting
Stockholm, Sweden, 141 86
Contact: Marie Larksater       marie.larksater@sll.se   
Sponsors and Collaborators
Araclon Biotech S.L.
Investigators
Study Director: Manuel Sarasa Araclon Biotech Ltd

Publications of Results:
Responsible Party: Araclon Biotech S.L.
ClinicalTrials.gov Identifier: NCT03461276     History of Changes
Other Study ID Numbers: AB1601
First Posted: March 12, 2018    Key Record Dates
Last Update Posted: March 14, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Aluminum Hydroxide
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Antacids
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents