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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
45
Sub-cutaneous injections of Interleukin-2 (PROLEUKIN ®) Induction phase: 5 consecutive days. A week break. Maintenance phase: once a week during 16 weeks
Sub-cutaneous injections of placebo (NaCl) Induction phase: 5 consecutive days. A week break. Maintenance phase: once a week during 16 weeks.
GHU Saint Anne
Paris, France
RECRUITINGChange from baseline CDR score at 18 months
The primary endpoint will be evaluated in all patients evaluable for efficacy, i.e. patients who received at least one cure of IL-2 and were evaluated for cognitive and functional status at baseline and 18 months. The response variable will be dichotomized as follows: Responder patient = 1 (end of study CDR score \<= baseline CDR score) Non-responder patient = 0 (end of study CDR score \> baseline CDR score)
Time frame: 18 months
Rate of cognitive decline between placebo and treatment groups as assessed by changes in MMSE scores at baseline, 6, 12, and 18 months
MMSE total score out of 30
Time frame: 6, 12 and 18 months
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
ADAS-Cog total score out of 85
Time frame: 6, 12 and 18 months
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
ADSC-ADL MCI total score out of 53
Time frame: 6, 12 and 18 months
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
CDR sum of the boxes (CDR-SOB) total score out of 18
Time frame: 6, 12 and 18 months
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
Global and regional cortical \[18F\]-DPA-714 PET uptake ratio
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Time frame: 18 months
Change in peripheral frequency of Treg and other immune effectors at 18 months compared to baseline between placebo and treated groups
Tregs frequency, total lymphocytes as a biomarker of target engagement
Time frame: 6, 12 and 18 month
Change in hippocampal atrophy at 18 month compared to baseline between placebo and treated groups
Volume of hippocampus measured in T1 MRI
Time frame: 18 months
Number of patients with treatment related adverse events as assessed by clinical safety panel
Clinical safety will be assessed via the following assessments: Vital signs (including blood pressure, weight, BPM, temperature) - each visit ECG - at inclusion and at V22 (M18) Check-list questionnaire to assess clinical adverse events - each visit
Time frame: 18 months
Number of patients with treatment related adverse events as assessed by blood laboratory safety panel
Biological safety will be evaluated and controlled through blood laboratory safety tests which include the following: Thyroid function: T4 and TSH - at inclusion, at V21 Haematology (RBC, WBC, leukocyte formula, platelets) and C reactive protein (CRP) - at inclusion, 8 days before the randomization, each day of the induction phase (day 1 to day 5), before each injection of the maintenance phase until V7, then every fortnight until the last injection of the maintenance phase, and then at M6, M12 and M18. Biochemistry (electrolytes, proteins, albumin, urea, creatinine, glucose, AST, ALT, GGT, bilirubin) and Coagulation tests - at inclusion, 8 days before the randomization, every 2 months for 6 months (V9 and V17), and at M6, M12 and M18
Time frame: 18 months