Clinical trial NCT05468073: Therapeutic Evaluation of Low-dose IL-2-based Immunomodulatory Approach in Patients With Early AD
Official title: Therapeutic Evaluation of Low-dose IL-2-based Immunomodulatory Approach in Patients With Early AD
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Alzheimer Disease
Keywords: Interleukin
Neuroinflammation
Regulatory T cells
Microglia
Synaptic density
Lead sponsor: Centre Hospitalier St Anne
Sponsor class: OTHER
Collaborators: name: For Drug Consulting
First posted: 2022-07-21
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study aims at evaluating the therapeutic efficacy and safety of low-dose IL-2 immunomodulatory treatment in patients with early AD, in a phase II, randomized, double blind, placebo-controlled phase II clinical trial. Patients with AD at early stage will be recruited and randomized (2:1) in each treatment group.

The primary endpoint is the rate of decline assessed through CDR change at 18 months between the placebo group and the treated patients.

Detailed description: This study aims to investigate the immunomodulatory therapeutic potential and safety of low-dose (ld) IL-2 in a randomized, double blind, and placebo-controlled phase II clinical trial.

Conservative diagnosis criteria based on clinical and CSF biomarkers have been established to avoid risks of misdiagnosis.

The treatment consist of 21 cures of subcutaneous injections of either placebo or low-dose (1MIU/day) IL-2 (PROLEUKIN ®). Patients will receive 5 consecutive injections during the induction phase which will be followed by a week break. During the maintenance phase a total of 16 injections will be administered weekly. Total duration of treatment for each patient is anticipated to be 18 weeks. Patients will be followed-up for 18 months after the first injection.

At inclusion, in addition to the clinical evaluation, a hybrid PET/MRI (using \[18F\]-DPA-714) scan will be performed. After randomized patients successfully complete the treatment phases, they will be followed-up through 3 clinical and 1 neuroimaging visits to assess cogitive and functional decline. Clinical visits are scheduled at 6, 12, and 18 months after treatment induction. Another hybrid PET/MRI (using \[18F\]-DPA-714) scan will be performed at 19 months following induction.

Eligibility criteria: Inclusion Criteria:

* Patients aged \> 18
* Age of disease onset \< 70 years
* Clinical and biological diagnosis of AD based on

  * Progressive amnestic syndrome associated or not with other cognitive impairments
  * Biological criteria: CSF biomarkers suggestive of AD.
* Brain MRI congruent with the diagnosis, left to the appreciation of the investigator
* CDR (Clinical Dementia Rating Scale) = 0.5 or 1
* If patients have an antidepressant or acetylcholinesterase inhibitors treatment, patients must be treated with stable doses of treatment for at least 1 month before inclusion.
* Have a caregiver who provides a separate written informed consent to participate. If a caregiver/study informant cannot continue, one replacement is allowed.
* Have adequate vision and hearing for neuropsychological testing in the opinion of the investigator.
* Have given written informed consent approved by the ethical review board (ERB) governing the site.
* The patient has to have a French social security number and be fluent and literate in French.

Exclusion Criteria:

* Subject with a psychiatric evolutionary and/or badly checked.
* Subject with a grave, severe or unstable pathology (left to the judgement of the investigator) the nature of which can interfere with the variables of evaluation.
* Epileptic subjects
* Subject under guardianship or curatorship
* Subject presenting contraindications to the MRI
* Known or supposed history (\< or = 5 years) of severe alcoholism or misuse of drugs
* Vascular, inflammatory or expansive, visible lesion in the MRI, which can interfere on the criteria of diagnosis.
* No health insurance
* Women of childbearing potential: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
* History of auto-immune disease
* History within the past 10 years of a primary or recurrent malignant disease
* Diagnosis or history of other possible etiology of dementia, including but not limited to other neurodegenerative disorders (FTD, LBD, VaD, HD, PD, PSP-CBD).
* Renal dysfunction at inclusion, clearance \<30 mL/min
* Chronic hepatic diseases as indicated by liver function tests abnormalities
* Abnormal thyroid function
* Therapeutic trial within 1 year preceding the first study period, or participation in a trial with active or passive immunization against amyloid if patient was assigned to the active treatment arm.
* Clinically significant evidence of Active viral infection (CMV, EBV, HCV, HBV, TPHA-VDRL, HIV)
* Current or medical history of severe cardiopathy,
* - Severe dysfunction in a vital organ
* Patients with White Blood Count (WBC) \< 4.000/mm3; platelets \< 100.000/mm3; hematocrit (HCT) \< 30%.
* Patients with serum bilirubin and creatinine outside normal range.
* Patients with organ allografts.
* Patients who are likely to require corticosteroids

Primary outcomes:
measure: Change from baseline CDR score at 18 months
timeFrame: 18 months
Secondary outcomes:
measure: Rate of cognitive decline between placebo and treatment groups as assessed by changes in MMSE scores at baseline, 6, 12, and 18 months
timeFrame: 6, 12 and 18 months
measure: Rate of cognitive decline between placebo and treatment groups as assessed by changes in ADAS-Cog 13 items scores at baseline, 6, 12, and 18 months
timeFrame: 6, 12 and 18 months
measure: Rate of functional decline between placebo and treatment groups as assessed by changes in ADCS-ADL MCI scores at baseline, 6, 12, and 18 months
timeFrame: 6, 12 and 18 months
measure: Rate of functional decline between placebo and treatment groups as assessed by changes in CDR (sum of boxes) scores at baseline, 6, 12, and 18 months
timeFrame: 6, 12 and 18 months
measure: Change in neuroimmune reaction as assessed by [18F]-DPA-714 PET global cortical index and regional cortical binding at baseline and 18 months between placebo and treated groups
timeFrame: 18 months
measure: Change in peripheral frequency of Treg and other immune effectors at 18 months compared to baseline between placebo and treated groups
timeFrame: 6, 12 and 18 month
measure: Change in hippocampal atrophy at 18 month compared to baseline between placebo and treated groups
timeFrame: 18 months
measure: Number of patients with treatment related adverse events as assessed by clinical safety panel
timeFrame: 18 months
measure: Number of patients with treatment related adverse events as assessed by blood laboratory safety panel
timeFrame: 18 months
Other outcomes:
Locations:
city: Paris
country: France
facility: GHU Saint Anne
Study officials:
affiliation: GHU Saint Anne
name: Marie SARAZIN, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: INSERM UMRS 938
name: Guillaume DOROTHEE, PhD
role: STUDY_CHAIR
affiliation: Service Hospitalier Frédéric Joliot / CEA
name: Michel BOTTLAENDER, Dr
role: STUDY_CHAIR
References: