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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Advantage Therapeutics GmbH

Participant type

Patients, Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

8 Nov 2023 → ongoing

Decision date (initial)

2024-12-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-518523-30-00

EudraCT number

2022-003532-73

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Pharmacodynamic, Dose response, Therapy

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.

Secondary objectives 3

1. To investigate safety and tolerability of AD04 in early AD patients over 12 months
2. To assess the effect of AD04 in global clinical activity and quality of life over 12 months
3. To obtain surrogate biomarkers of AD (wet and structural) over 12 months

Conditions and MedDRA coding

early Alzheimer’s disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Aged 50-85 years old
2. 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).
3. 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
4. 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]).
5. 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. For more details refer to Section 7.1.13
6. 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
7. Must have results of a physical examination, including visual and auditory acuity within the acceptable range for the age group to allow neuropsychological testing
8. Has Hachinski Ischemia Scale score ≤4 to distinguish AD from vascular dementia
9. Written informed consent of study-related procedures and of genetic investigations signed and dated by the patient and the caregiver
10. 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

Exclusion criteria 28

1. Known or suspected allergy, or history of anaphylaxis, to vaccines or their excipients, if considered relevant by the Investigator
2. e) Has had a history within the last 5 years of a serious infectious disease affecting the brain
3. f) Clinically significant unstable psychiatric illness in the past 6 Months.
4. g) Has a Geriatric Depression Scale score > 6 (on the staff-administered short form)
5. k) Patient with past or present suicidal ideation and intent as assessed by the Columbia Suicidality Severity Rating Scale (CSSRS), or who, in the clinical judgment of the investigator, presents a serious risk of suicide
6. l) Presence of autoimmune disease, autoinflammatory syndrome, or immunological deficiency syndrome (including human immunodeficiency virus (HIV) infection)
7. m) 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
8. n) 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.
9. o) Presence of end stage kidney failure (on dialysis) (which may affect renal clearance of aluminium)
10. p) Patient has hemochromatosis
11. 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
12. h) Hypothyroidism or vitamin B12 deficiency (patients with corrected hypothyroidism or vitamin B12 deficiency are eligible for the study provided that treatment has been stable for 3 months before study entry)
13. 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)
14. Current or anticipated use of allergy immunotherapies
15. Patient has received or plans to receive any aluminium-adjuvanted vaccines within 14 days prior to any dose of study drug
16. i) Patients with long covid-19 showing long-term neurological sequelae within the past 12 months at the time of screening
17. j) History of chronic alcohol or drug abuse/ dependence within the past 5 years
18. Any medical or neurological condition (other than AD) that might cause the participant’s cognitive impairment, including (a-p)::
19. a) History or evidence of cerebrovascular disease (stroke, transient ischemic attack, intracerebral hemorrhage), or diagnosis of possible, probable or definite vascular dementia in accordance with National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria
20. b) 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
21. c) Evidence of a clinically relevant Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, mental retardation, hypoxic cerebral damage, or head trauma with loss of consciousness that led to persistent cognitive deficits
22. d) Refractory epilepsy (has had seizures within the past 2 years)
23. Pregnancy (for patients of childbearing potential, see additional considerations in Section 5.3)
24. 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
25. Contraindication for CSF collection, including certain conditions and / or medications such as high doses of blood thinning agents
26. 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
27. Participation in the active treatment phase of any non-AD clinical trial within 30 days prior to Visit 1.
28. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 5

1. Safety Endpoints - Incidence of treatment-emergent adverse events (TEAEs)
2. Key Secondary Efficacy Endpoint - Change from baseline in Clinical Dementia Rating - sum of boxes (CDRsb).
3. Other Secondary Efficacy Endpoints (I-III) - I. Global statistical test (GST) combining cognition [ADAS-cog] and daily function [ADCS-ADL] II. Change from baseline in hippocampal volume (total, right, and left), measured by volumetric Magnetic Resonance Imaging (MRI) III. Change from baseline in cognition score (ADAS-cog and aADAS-cog).
4. Other Secondary Efficacy Endpoints (IV-VII) - IV. Change from baseline in function score (ADCS-ADL and aADCS-ADL) V. Neuropsychiatric inventory (NPI) VI. Clinician’s Global Impressions of Change (CGIC) VII. Assessment of Quality of Life in patients with AD and their caregivers (QOL-AD)
5. Exploratory endpoints – 1. 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) 2. Levels of circulating biomarkers 3. PK/PD relationships

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Advantage Therapeutics GmbH

Sponsor organisation

Advantage Therapeutics GmbH

Address

Karl-Farkas-Gasse 22, Landstrasse Landstrasse

City

Vienna

Postcode

1030

Country

Austria

Scientific contact point

Organisation

Advantage Therapeutics GmbH

Contact name

Achim Schneeberger

Public contact point

Organisation

Advantage Therapeutics GmbH

Contact name

Achim Schneeberger

Third parties 11

Locations

2 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications