| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | early Alzheimer’s disease | |
| E.1.1.1 | Medical condition in easily understood language | | early Alzheimer’s disease | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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 cognitive and functional domains over 6 months | |
| E.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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, indicating mild impairment in memory, attention, or language abilities
4. Has brain MRI showing medial temporal lobe atrophy as assessed by the Scheltens’ scale (score ≥2) 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 7.1.11.
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. Written informed consent of study-related procedures and of genetic investigations signed and dated by the patient and the caregiver.
8. 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 | |
| E.4 | Principal 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
3. History of chronic alcohol or drug abuse/ dependence within the past 5 years
4. Presence of autoimmune disease, autoinflammatory syndrome, or immunological deficiency syndrome (including human immunodeficiency virus (HIV) infection)
5. 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
6. 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.
7. Presence of end stage kidney failure (on dialysis) (which may affect renal clearance of aluminium)
8. Patient has hemochromatosis
9. 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
10. 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)
11. Current or anticipated use of allergy immunotherapies
12. Patient has received or plans to receive any aluminium-adjuvanted vaccines within 14 days prior to any dose of study drug
13. Pregnancy (for patients of childbearing potential, see additional considerations in Section 5.3)
14. 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
15. Contraindication for CSF collection, including certain conditions and / or medications such as high doses of blood thinning agents
16. 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
17. Participation in the active treatment phase of any non-AD clinical trial within 30 days prior to Visit 1
18. 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.5.1 | Primary end point(s) | | Composite score assessing cognition [adapted AD Assessment Scale cognitive (aADAS-cog)] and daily function [adapted AD Cooperative Study Activities of Daily Living (aADCS-ADL)] over 6 months | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | Safety Endpoints
- Incidence of treatment-emergent adverse events (TEAEs)
Key Efficacy Endpoint
- Change from baseline in Clinical Dementia Rating - sum of boxes (CDR-sb)
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.5.2.1 | Timepoint(s) of evaluation of this end point | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Austria | | France | | Poland | | Bulgaria | | Germany | | Slovakia | | United Kingdom | |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
