Rapamycin (Sirolimus) treatment for amyotrophic lateral sclerosis

INTERVENTION: Trade Name: RAPAMUNE ‐ 1 MG 100 COMPRESSE RIVESTITE IN BLISTER USO ORALE Product Name: Rapamune Pharmaceutical Form: Coated tablet CONDITION: definite or probable ALS ; MedDRA version: 20.0 Level: PT Classification code 10002026 Term: Amyotrophic lateral sclerosis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To assess whether Rapamycin administration increases Tregs number in treated patients compared to control arm Primary end point(s): Proportion of patients exhibiting a positive response (considered as increase in Treg of at least 30%), comparing baseline and treatment end (WEEK 18) between Rapamycin and placebo arm, using mAbs anti‐CD3,‐4,‐25,‐127,‐FoxP3 plus activation (HLA‐DR,CD38) and homing (CXCR3) markers and flow cytometry (FCM) Secondary Objective: To assess safety and tolerability of Rapamycin in ALS patients; to assess the minimum dosage to have RAPAMYCIN in CSF; to assess changes in immunological (activation and homing of T,B,NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); to assess clinical activity (ALSFRS‐R, survival, FVC) and effect on quality of life (ALSAQ40). To assess if and at what dosage Rapamycin passes through blood brain barrier (BBB). Timepoint(s) of evaluation of this end point: Week 18 SECONDARY OUTCOME: Secondary end point(s): 1. Measuring Rapamycin level in CSF ; 2. Quantifying the phosphorylation of the S6 ribosomal protein (S6RP) between Rapamycin arm and placebo arm ; 3. Measure changes in different biomarkers (creatinin e albumin, CK, vitamin D, neurofilament) between Rapamycin arm and placebo arm ; 4. Molecular analysis of the inflammasome system between Rapamycin arm and placebo arm ; 5. Amyotrophic Lateral Sclerosis functional rationg scale (ALSFRS) ; 6. Overall survival ; 7. Survival rate ; 8. Forced vital capacity (FVC) score Timepoint(s) of evaluation of this end point: 1. Week 18 ; 2. Baseline, week 8, 18 (treatment end), 30 and 54 ; 3. Baseline, week 8, 18 (treatment end), 30 and 54 ; 4. Baseline, week 8, 18 (treatment end), 30 and 54 ; 5. Baseline, week 4, 8, 12, 18, 30, 42 e 54 ; 6. From randomization to date of Death or tracheostomy ; 7. Week 18, 30, 42 and 54 ; 8. Week 4, 8, 12, 18, 30, 42, 54 INCLUSION CRITERIA: ‐ Patient diagnosed with a laboratory supported , clinically “probable” or “definite” amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks, 2000) ‐ Familial or sporadic ALS ‐ Female or male patients aged between 18 and 75 years old ‐ Disease duration from symptoms onset no longer than 18 months at the screening visit ‐ Patient treated with a stable dose of Riluzole (100 mg/day) for at least 30 days prior to screening ‐ Patients with a weight > 50 kg and a BMI =18 ‐ Patient with a FVC = 70 % predicted normal value for gender, height, and age at the screening visit ‐ Patient able and willing to comply with study procedures as per protocol ‐ Patient able to understand, and capable of providing informed consent at screening visit prior to any protocol‐specific procedures ‐ Use of effective contraception both for males and females Are the trial subjects under 18? no Number of subjects for