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    Summary
    EudraCT Number:2015-000630-30
    Sponsor's Protocol Code Number:AC-AD-003
    National Competent Authority:Slovenia - JAZMP
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-06-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSlovenia - JAZMP
    A.2EudraCT number2015-000630-30
    A.3Full title of the trial
    “ADAMANT”
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to find out whether AADvac1 is safe and efficient for patient with mild Alzheimer's disease
    A.3.2Name or abbreviated title of the trial where available
    ADAMANT
    A.4.1Sponsor's protocol code numberAC-AD-003
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAXON NEUROSCIENCE SE
    B.1.3.4CountryCyprus
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAXON NEUROSCIENCE SE
    B.4.2CountryCyprus
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAXON Neuroscience CRM Services SE
    B.5.2Functional name of contact pointMedical department
    B.5.3 Address:
    B.5.3.1Street AddressDvorakovo nabrezie 10
    B.5.3.2Town/ cityBratislava
    B.5.3.3Post code81102
    B.5.3.4CountrySlovakia
    B.5.4Telephone number00421220921620
    B.5.5Fax number00421220921624
    B.5.6E-mailadamant@axon-neuroscience.eu
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAADvac1
    D.3.2Product code AADvac1
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAADvac1
    D.3.9.2Current sponsor codeAxon Peptide 108 (coupled to KLH)
    D.3.9.3Other descriptive nameAADVAC1
    D.3.9.4EV Substance CodeSUB121521
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number133.33
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSuspension for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alzheimer’s disease
    E.1.1.1Medical condition in easily understood language
    Alzheimer’s disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate safety and tolerability of long-term AADvac1 treatment of patients with mild Alzheimer’s disease.
    E.2.2Secondary objectives of the trial
    • To evaluate efficacy of AADvac1 treatment in slowing or cessation of cognitive and functional decline in patients with mild Alzheimer’s disease, as measured by Clinical Dementia Rating Scale Sum of Boxes (CDR-SB).
    • To evaluate efficacy of AADvac1 treatment in slowing or cessation of cognitive decline in patients with mild Alzheimer’s disease, as measured by a composite score of a battery of cognitive tests assessing multiple domains of cognition.
    • To evaluate the effect of AADvac1 treatment on patient functioning as measured by the ADCS-MCI-ADL questionnaire
    • To evaluate immunogenicity of AADvac1 by measuring antibody titres and antibody isotype profiles.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient has a diagnosis of probable Alzheimer’s disease according to the revised NIA-AA criteria (McKhann 2011).
    2. Patient has a MMSE total score ≥ 20 and ≤ 26 at Screening.
    3. Patient has a brain MRI finding consistent with the diagnosis of Alzheimer’s disease at Screening.
    4. Patient has evidence of the AD pathophysiological process at Screening, defined as one or both of the following:
    a. medial temporal lobe atrophy as assessed on brain MRI and according to a Scheltens score of ≥ 2 (rated on a scale of 0-4 on the more atrophied side)
    b. positive AD biomarker signature in the CSF (total tau protein > 400 pg/mL AND pT181 tau protein > 60 pg/mL AND Aβ42 < 600 pg/mL AND Aβ42:Aβ40 ratio < 0,089)
    5. Patient had completed 6 years of formal elementary education.
    6. Patients aged 50-85 years inclusive at Screening.
    7. Patient is fluent in the local language and possesses sufficient auditory and visual capacities to allow neuropsychological testing.
    8. Patient is able to read and understand the informed consent.
    9. Patient is on a stable therapy with an acetylcholinesterase inhibitor for at least 3 months prior to screening visit.
    10. If the patient is on memantine treatment, the dose regimen must be stable for at least 3 months prior to Screening (V01).
    11. Patient has a Hachinski Ischemia Scale score ≤ 4 at Screening.
    12. Availability of a caregiver who sufficiently knows the patient and will be able to accompany the patient on the study visits and to participate in study assessments of the patient where required.
    13. Female patients are only eligible for the study if they are either surgically sterile or at least 2 years postmenopausal.
    14. 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 consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continuing throughout the study period.
    15. Patient provides written informed consent.

    E.4Principal exclusion criteria
    1. Female patient who is pregnant or breastfeeding.
    2. Patient has been participating in another clinical study within 3 months prior to Screening.
    3. Patient is not expected to complete the clinical study.
    4. Patient has known allergy to components of the vaccine currently or in the past, if considered relevant by the investigator.
    5. Patient has known contraindication for MRI imaging such as MRI-incompatible metallic endoprosthesis or MRI-incompatible stent implantation or other as judged by the Investigator.
    6. Any of the following detected by brain MRI:
    a) Infarction in the territory of large vessels
    b) More than one lacunar infarct defined as a focal lesion of CSF signal intensity with a diameter of less than 1.5 cm in any dimension.
    c) Any lacunar infarct in a strategically important location such as the thalamus, hippocampus of either hemisphere, head of the left caudate nucleus.
    d) Confluent hemispheric deep white matter lesions (Fazekas grade 3).
    e) Other focal lesions which may be responsible for the cognitive status of the patient such as infectious disease, space-occupying lesions, normal pressure hydrocephalus or any other abnormalities associated with significant central nervous disease other than Alzheimer’s disease.
    7. Patient underwent surgery (under general anaesthesia) within 3 months prior to screening and/or has scheduled surgery (under general anaesthesia) during the whole study period.
    8. 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.
    9. Patient has a recent history of cancer (last specific treatment ≤ 5 years prior to Screening) (Exceptions: basal cell carcinoma, intraepithelial cervical neoplasia).
    10. Patient had myocardial infarction within the last 2 years prior to Screening.
    11. Patient has Hepatitis B, C, HIV or Syphilis confirmed by serology.
    12. Patient suffers from an active infectious disease.
    13. Presence and/or history of immunodeficiency.
    14. Patient currently suffering from a clinically important systemic illness that is likely to result in deterioration of the patient’s condition or affect the patient’s safety during the study:
    *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
    *other clinically significant systemic illness, if considered relevant by the investigator
    15. Patient suffers from hypothyroidism, defined as TSH (thyroid-stimulating hormone) elevation > 5.0 mIU/L, 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.
    16. Patient has valid diagnosis of a significant psychiatric illness such as schizophrenia, any type of psychotic disorder or bipolar affective disorder.
    17. Patient has a current depressive episode (Geriatric Depression Scale GDS ≥ 6 at Visit 01) or had a major depressive episode within the last 1 year.
    18. Patient has a metabolic or toxic encephalopathy or dementia due to a general medical condition.
    19. Patient has a history of alcohol or drug abuse or dependence within the past 2 years.
    20. Patient has Wernicke’s encephalopathy.
    21. Patient has a history or evidence of any CNS disorder other than AD that could be the cause of dementia (e.g., infectious or inflammatory/demyelinating CNS conditions, Creutzfeldt-Jakob disease, Parkinson’s disease, Huntington’s disease, brain tumour, subdural haematoma)
    22. Patient has a history with evidence of cerebrovascular disease (ischemic or haemorrhagic stroke), or diagnosis of possible, probable or definite vascular dementia.
    23. Patient has a history or presence of diagnosis of epilepsy.
    24. Patient is currently treated and/or was treated with experimental immunotherapeutics including IVIG within 3 months prior to screening.
    25. Patient is currently being treated and/or was treated with experimental therapies for AD aiming at disease-modification within 3 months prior to screening.
    26. Patient is currently being treated or was treated in the past with any active vaccines for AD.
    27. Patient is currently being treated with immunosuppressive drugs.
    28. Change in dose of previous and current medications which the patient is taking because of concomitant illnesses according to the medical history within the last 30 days prior to Screening (V01), if considered clinically relevant by the investigator.
    29. Patient has vitamin B12 deficiency (serum vitamin B12 < 191 pg/mL).
    E.5 End points
    E.5.1Primary end point(s)
    The safety assessment is based on the number, type and severity of adverse events.
    - The incidence of adverse events for each group will be summarized by system organ class, severity and duration.
    - Descriptive statistics for laboratory values, imaging and clinical observations, and their change from baseline will be prepared for each group.
    - Safety will be statistically analysed. Statistical analysis will only be used to draw attention to areas of concern.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - for active patients at every visit V01-V17
    E.5.2Secondary end point(s)
    • Mean change in CDR-SB score from Baseline to Visit V16 (week 104)
    • Mean change in standard (composite z-score) score of Custom Cognitive Battery from Baseline to Visit V16 (week 104). The composite Z score is calculated from the results of the following tests:
    o Cogstate International Shopping List Task (immediate and delayed recall, recognition): verbal episodic memory
    o Cogstate One Card Learning and One Card Back tasks: visual episodic memory
    o Letter Fluency Test & Category Fluency Test: executive function
    o Digit-Symbol Coding test: processing speed, working memory, executive function
    • Mean change in ADCS-MCI-ADL score from Baseline to Visit V16 (week 104).
    • Percentage of AADvac1-treated patients who develop an IgG antibody response against the “Axon peptide 108” component of AADvac1.
    • Geometric mean titre of AADvac1-induced antibodies (IgM and IgG against Axon peptide 108, anti-KLH)
    E.5.2.1Timepoint(s) of evaluation of this end point
    * Cognition (CDR-SB, Custom Cognitive Battery, and ADCS-MCI-ADL): V02, V05, V08, V09, V11, V12, V14, V15 and V16
    * Percentage of AADvac1-treated patients who develop an IgG antibody response against the “Axon peptide 108” component of AADvac1 (at any point in the study)
    * Geometric mean titre of AADvac1-induced antibodies (IgM and IgG against Axon peptide 108, anti-KLH): V02-V16

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA44
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 41
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 167
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    patients with incurable diseases (Alzheimer's disease)
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 208
    F.4.2.2In the whole clinical trial 208
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard medical treatment for Alzheimer's Disease is allowed to be taken on a stable dose throughout the study period and may be further taken after study conclusion.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-08-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-06-25
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