Evaluation of Low-Dose Aldesleukin and Sodium Chloride in Immunomodulation for Early Alzheimer's Disease Patients

The primary objective of this study is to evaluate the **rate of decline** in patients with early **Alzheimer Disease** by assessing changes in the Clinical Dementia Rating (CDR) over an 18-month period. This is compared between the group receiving low-dose IL-2 treatment and the placebo group. The clinical relevance of this objective lies in determining the efficacy of IL-2 as a potential therapeutic intervention for slowing cognitive decline in Alzheimer's Disease.

Secondary objectives include:

• Investigating the impact of low-dose IL-2 treatment on cognitive and functional parameters at various time points, including the end of the treatment period and at 6, 12, and 18 months post-induction.
• Assessing regional and longitudinal variations in brain neuroinflammation using [18F]-DPA-714 PET imaging at baseline, post-treatment, and 18 months after treatment induction.
• Evaluating the peripheral frequency of Tregs and other immune effectors as biomarkers of target engagement.
• Monitoring the progression of hippocampal and regional cortical atrophy via MRI.
• Assessing the progression of synaptic density using MRI NODDI sequences.
• Evaluating the clinical and biological safety and tolerability of IL-2 treatment.

The clinical trial focuses on participants diagnosed with **Alzheimer Disease**, encompassing both male and female subjects. The study population includes adults aged over 18 years, with no specific upper age limit provided. Participants are required to have a clinical and biological diagnosis of Alzheimer's Disease, supported by progressive amnestic syndrome and relevant cerebrospinal fluid biomarkers. Additionally, a brain MRI must align with the diagnosis, as assessed by the investigator. The trial does not involve a vulnerable population. Participants must have stable doses of antidepressants or acetylcholinesterase inhibitors for at least one month prior to inclusion if applicable. They should also have adequate vision and hearing for neuropsychological testing. A permanent caregiver must be available to assist with compliance and attend follow-up visits. Written informed consent is mandatory, and participants must be fluent and literate in French, with a French social security number. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the therapeutic efficacy of a low-dose **IL-2**-based immunomodulatory approach in patients with early **Alzheimer Disease**. This study is a randomized, double-blind, controlled trial, with a primary endpoint focused on the rate of decline assessed through the Clinical Dementia Rating (CDR) change at 18 months between the placebo group and the treated patients. The trial is expected to last until June 10, 2027, with recruitment having commenced on October 11, 2022. Participants will be involved in the study for a maximum treatment period of 21 days, with the possibility of early termination if they do not meet the inclusion criteria or if adverse effects occur.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, clinical and biological diagnosis of Alzheimer's Disease, and stable treatment with antidepressants or acetylcholinesterase inhibitors. Following the inclusion visit, participants will attend regular treatment visits from V3 to V19, where compliance with the protocol will be monitored. Follow-up visits, including V20, V21, and V22, will assess the participants' condition and the primary endpoint. The end-of-study visit will conclude the trial, evaluating the overall outcomes and any long-term effects of the treatment.

Participants are required to have a permanent caregiver who can attend the inclusion and follow-up visits, supervise compliance, and report on the participant's condition. The trial involves the administration of **sodium chloride** and **aldesleukin**, with the latter being the active substance in the investigational product. The study is conducted under strict ethical guidelines, with informed consent obtained from all participants. The trial is authorized in France, and participants must have a French social security number and be fluent in French. The study's design ensures rigorous monitoring and evaluation to achieve reliable and valid results.

The clinical trial involves the administration of two primary treatments. The first treatment is **CHLORURE DE SODIUM 0,9 % B. BRAUN**, a **solution for injection** provided in ampoule form. The active substance in this treatment is **sodium chloride**, a chemical compound. The solution is administered via **cutaneous use**. The maximum daily dose is 1 ml, with a total maximum dose of 21 ml over a treatment period of 21 days. This product is manufactured by B.BRAUN MELSUNGEN AG and is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

The second treatment is **PROLEUKIN 18 millions U.I.**, a **powder for solution injectable**. The active substance is **aldesleukin**, a protein-based compound. Similar to the first treatment, it is administered through **cutaneous use**. The maximum daily dose is 1 million IU, with a total maximum dose of 21 million IU over a 21-day treatment period. This product is manufactured by IOVANCE BIOTHERAPEUTICS B.V and is also not a paediatric formulation. The trial will ensure adherence to the dosing schedule and monitor participant compliance.

Both treatments are part of a therapeutic evaluation of a low-dose IL-2-based immunomodulatory approach in patients with early Alzheimer's disease. The primary endpoint of the trial is to assess the rate of decline through CDR change at 18 months between the placebo group and the treated patients. The trial is conducted under authorized conditions, ensuring the safety and efficacy of the treatments administered.

Efficacy in this clinical trial will be assessed primarily through the rate of decline in patients with early **Alzheimer's Disease (AD)**, as measured by changes in the Clinical Dementia Rating (CDR) scale over an 18-month period. The primary endpoint is the comparison of CDR changes between the placebo group and the treated patients. The CDR scale is a validated tool used to quantify the severity of symptoms of dementia, and it will be employed to evaluate the progression of cognitive impairment in participants.

Data collection will occur at specified intervals, with clinical follow-up visits scheduled at various timepoints, including V1, V20, V21, and V22. The trial will also involve treatment visits from V3 to V19, during which compliance with the protocol will be monitored. The study is designed to ensure that participants have adequate vision and hearing for neuropsychological testing, as determined by the investigator. The trial is set to conclude with a primary endpoint date of December 10, 2026, and a secondary endpoint date of June 10, 2027.