Rapamycin (Sirolimus) treatment for amyotrophic lateral sclerosis

Phase 1

Conditions: definite or probable ALS
MedDRA version: 20.0Level: PTClassification code 10002026Term: Amyotrophic lateral sclerosisSystem Organ Class: 10029205 - Nervous system disorders
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Registration Number: EUCTR2016-002399-28-IT

Lead Sponsor: AZIENDA OSPEDALIERO-UNIVERSITARIA POLICLINICO DI MODENA

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 63

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 this age range: 1
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 45
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 18

Exclusion Criteria

-Prior use of Sirolimus
-Prior allergy/sensitivity to Sirolimus or macrolides
-Any medical disorder that would make immunosuppression contraindicated, including but not limited to, acute infections requiring antibiotics, patients with known diagnosis of HIV, TBC, hepatitis B or C infection or history of malignancy
-Severe comorbidities (heart, renal, liver failure), autoimmune diseases or any type of interstitial lung disease
-White blood cells<4,000/mm³, platelets count<100,000/mm³, hematocrit<30%
-Patient who underwent non invasive ventilation, tracheotomy and /or gastrostomy
-Women who are pregnant or breastfeeding
-Participation in pharmacological studies within the last 30 days before screening
-Patients with known SOD1 mutation

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess whether Rapamycin administration increases Tregs number in treated patients compared to control arm;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).;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);Timepoint(s) of evaluation of this end point: Week 18

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Measuring Rapamycin level in CSF<br>2. Quantifying the phosphorylation of the S6 ribosomal protein (S6RP) between Rapamycin arm and placebo arm<br>3. Measure changes in different biomarkers (creatinin e albumin, CK, vitamin D, neurofilament) between Rapamycin arm and placebo arm<br>4. Molecular analysis of the inflammasome system between Rapamycin arm and placebo arm<br>5. Amyotrophic Lateral Sclerosis functional rationg scale (ALSFRS)<br>6. Overall survival<br>7. Survival rate<br>8. Forced vital capacity (FVC) score;Timepoint(s) of evaluation of this end point: 1. Week 18<br>2. Baseline, week 8, 18 (treatment end), 30 and 54<br>3. Baseline, week 8, 18 (treatment end), 30 and 54<br>4. Baseline, week 8, 18 (treatment end), 30 and 54<br>5. Baseline, week 4, 8, 12, 18, 30, 42 e 54<br>6. From randomization to date of Death or tracheostomy<br>7. Week 18, 30, 42 and 54<br>8. Week 4, 8, 12, 18, 30, 42, 54