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    Summary
    EudraCT Number:2022-003532-73
    Sponsor's Protocol Code Number:ADVANCE-AD04-001
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2023-02-02
    Trial 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 ConcernedAustria - BASG
    A.2EudraCT number2022-003532-73
    A.3Full title of the trial
    A Phase 2b, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Assess the Safety and Efficacy of AD04 in Patients with Early Alzheimer’s Disease - ADVANCE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2b, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Assess the Safety and Efficacy of AD04 in Patients with Early Alzheimer’s Disease - ADVANCE
    A.4.1Sponsor's protocol code numberADVANCE-AD04-001
    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 SponsorADvantage Therapeutics GmbH
    B.1.3.4CountryAustria
    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 supportADvantage Therapeutics GmbH
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationADvantage Therapeutics GmbH
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street AddressKarl-Farkas-Gasse 22
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1030
    B.5.3.4CountryAustria
    B.5.4Telephone number004369911098989
    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 nameAD04
    D.3.2Product code AD04
    D.3.4Pharmaceutical form Solution 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 INNAluminium hydroxide
    D.3.9.3Other descriptive nameAluminium hydroxide
    D.3.9.4EV Substance CodeSUB33625
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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) No
    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) No
    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 placeboSolution 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
    early Alzheimer’s disease
    E.1.1.1Medical condition in easily understood language
    early Alzheimer’s disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10001897
    E.1.2Term Alzheimer's disease (incl subtypes)
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of AD04 in slowing progression of the disease in patients with early Alzheimer’s disease (AD) based on the evaluation of the time savings in cognitive, functional and global domains over 6 months
    E.2.2Secondary objectives of the trial
    - To investigate safety and tolerability of AD04 in early AD patients over 12 months
    - To assess the effect of AD04 in global clinical activity and quality of life over 12 months
    - To obtain surrogate biomarkers of AD (wet and structural), immunity, and lipid metabolism over 12 months
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged 50-85 years old
    2. Has a diagnosis of probable AD based on the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria, integrating both clinical and neuropathological criteria
    3. Has a Mini-Mental State Examination (MMSE) score between 22 and 30
    Note: Regarding inclusion criterion #2, it is obvious that patients with an MMSE score ≥27 may not fulfill all NINCDS/ADRDA criteria, especially those referring to or requiring a state of dementia. In such cases, inclusion criteria #4 and #5 ensure the specificity of the diagnosis (prodromal stage of AD/AD-type mild cognitive impairment [MCI]).
    4. Has brain MRI showing medial temporal lobe atrophy as assessed by the Scheltens’ scale (score ≥2, at least at one site) or has AD-type CSF signature at a 7:3 ratio of Scheltens to CSF signature. This criterion was chosen with the goal of having a patient cohort which reflects as closely as possible that of the AFF006 study; specific cut-offs for CSF AD biomarkers will be defined based on the methodology of the selected central laboratory.
    5. Has a Free and Cued Selective Reminding Test (FCSRT) total recall ≤40 or free recall ≤17, indicating hippocampal damage, episodic memory impairment, and amnestic syndrome
    6. Must have results of a physical examination, including visual and auditory acuity within the acceptable range for the age group to allow neuropsychological testing
    7. Has Hachinski Ischemia Scale score ≤4 to distinguish AD from vascular dementia
    8. Written informed consent of study-related procedures and of genetic investigations signed and dated by the patient and the caregiver.
    9. Availability of a partner/caregiver knowing the patient and being able to accompany the patient at the visits. He/ she will be in frequent contact with the participant (defined as at least 10 hours per week), will accompany the participant to the planned study visits and/or be available by telephone at designated times
    10. Women of childbearing potential and men with female partners of childbearing potential must use an effective methods of birth control during the course of the trial and for at least 90 days after the last dose in a manner such that risk of failure is minimized. Male participants should refrain from donating sperm during the intervention period and for at least 90 days after the last dose of study intervention*
    11. Women of childbearing potential and men with female partners of childbearing potential must use 2 effective method of birth control during the course of the trial and for at least 90 days after the last dose in a manner such that risk of failure is minimized. Male participants should refrain from donating sperm during the intervention period and for at least 90 days after the last dose of study intervention (see additional considerations in Section 5.3)**
    * = This inclusion criterion is only valid for patients enrolled in Germany.
    ** = This inclusion criterion is only valid for patients enrolled in Austria, Bulgaria, France, Slovakia and Poland.
    E.4Principal exclusion criteria
    1. Known or suspected allergy, or history of anaphylaxis, to vaccines or their excipients, if considered relevant by the Investigator
    2. Any medical or neurological condition (other than AD) that might cause the participant’s cognitive impairment including e.g.
    - A significant number of >4 microhemorrhages, a single prior hemorrhage > 1 cm3, >2 lacunar infarcts, a single prior infarct > 1 cm3, radiological finding supporting the NINDS-AIREN criteria as operationalized in Stroke. 2003 Aug;34(8):1907-12, meningioma with a perpendicular diameter of >1cm or significant mass effect on the brain parenchyma, evidence of a cerebral contusion, encephalomalacia, aneurysms, brain neoplasms such as gliomas or subdural hematoma/effusion with a diameter of >1cm, diffuse white matter disease (Fazekas score – deep white matter score >3) or significant mass effect on the brain parenchyma assessed by MRI at screening
    - History of chronic alcohol or drug abuse/ dependence within the past 5 years
    -Patient with past or present suicidal ideation and intent as assessed by the Columbia Suicidality Severity Rating Scale (C-SSRS), or who, in the clinical judgment of the investigator, presents a serious risk of suicide
    - Presence of autoimmune disease, autoinflammatory syndrome, or immunological deficiency syndrome (including human immunodeficiency virus (HIV) infection)
    - Relevant cardiovascular, hepatic, gastroenterological, respiratory, endocrinological, hematologic disease, or any other condition that, in the Investigator's opinion, could interfere with the analyses of safety and efficacy in this study, unless patient has been on stable doses of medication for any of these concurrent illnesses for at least 3 months prior to study entry
    - History within the last 2 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen posttreatment; or has a life expectancy of <2 years.
    3. Presence of end stage kidney failure (on dialysis) (which may affect renal clearance of aluminium)
    4. Patient has hemochromatosis
    5. If on conventional AD therapies such as donepezil or memantine, anticholinergics in general (including neuroleptics with anticholinergic properties, certain bladder relaxants, anticholinergic drugs for use in lung diseases), or lipid-modifying therapies, doses must be stable for at least 3 months prior to the screening visit and during the entire trial period
    6. Current or anticipated use of immunosuppressive drugs such as, but not limited to, azathioprine, cyclosporine, methotrexate, tacrolimus, or mycophenylate within 2 months or any myelosuppressive or cytotoxic chemotherapies within the 12 months prior to the screening visit. Use of systemic corticosteroids equivalent to ≥20mg/week prednisone within the past 4 weeks before screening and during the course of the study (intranasal or inhaled steroids for allergies/asthma is allowed)
    7. Current or anticipated use of allergy immunotherapies
    8. Patient has received or plans to receive any aluminium-adjuvanted vaccines within 14 days prior to any dose of study drug
    9. Pregnancy (for patients of childbearing potential, see additional considerations in Section 5.3)
    10. Contraindication for MRI imaging, including but not limited to pacemakers; cochlear implants, cerebral aneurysm clips; implanted infusion pumps; implanted nerve stimulators; metallic splinters in the eye; other magnetic, electronic, or mechanical implants; claustrophobia; inability to lie motionless for 30 minutes; or any other clinical history or examination finding that, in the judgement of the Investigator, would pose a potential hazard in combination with MRI
    11. Contraindication for CSF collection, including certain conditions and / or medications such as high doses of blood thinning agents
    12. Patient has received any vaccine targeting Aβ or tau for the treatment of AD. For all other experimental AD drugs, including passive immunotherapies, participation in the active treatment phase of any AD clinical trial within 3 months (or 5 half-lives, whichever is longer), prior to Visit 1
    13. Participation in the active treatment phase of any non-AD clinical trial within 30 days prior to Visit 1
    14. Employee at the study site, spouse/partner or relative of any study staff (e.g., investigator, sub-investigators, or study nurse) or relationship to the Sponsor
    E.5 End points
    E.5.1Primary end point(s)
    Composite score assessing cognition [adapted AD Assessment Scale cognitive (aADAS-cog)], daily function [adapted AD Cooperative Study Activities of Daily Living (aADCS-ADL)] and CDR-sb over 6 months measured in overall time saved with treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    E.5.2Secondary end point(s)
    Safety Endpoints
    - Incidence of treatment-emergent adverse events (TEAEs)
    Key Secondary Efficacy Endpoint
    - Change from baseline in Clinical Dementia Rating - sum of boxes (CDR-sb)
    Other Secondary Efficacy Endpoints
    - Global statistical test (GST) combining cognition [ADAS-cog] and daily function [ADCS-ADL]
    - Change from baseline in hippocampal volume (total, right, and left), measured by volumetric Magnetic Resonance Imaging (MRI)
    -Change from baseline in cognition score (ADAS-cog and aADAS-cog)
    - Change from baseline in function score (ADCS-ADL and aADCS-ADL)
    - Neuropsychiatric inventory (NPI)
    -Clinician’s Global Impressions of Change (CGIC)
    Assessment of Quality of Life in patients with AD and their caregivers
    (QOL-AD)

    Exploratory endpoints
    The following biomarkers will be measured to support treatment effect and dosing regimen:
    -Concentrations of aluminium in the blood, cerebrospinal fluid (CSF), and urine for pharmacokinetic profiling of AD04 (AUC and cumulative maximum concentration adjusted for pre-dose baseline values)
    -Levels of circulating biomarkers of immune response, lipid metabolism, neuroinflammation, and brain atrophy (temporal dynamics and time dependencies)
    - PK/PD relationships (e.g., based on aluminium and IgG antibody measurements)
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    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 No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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 years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 61
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 61
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 Yes
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 122
    F.4.2.2In the whole clinical trial 122
    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)
    None
    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 Decision2023-10-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-06-27
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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