Rapamycin Treatment for ALS

Study Overview
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Brief Summary
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In the last years research has pointed out potential mechanisms of pathogenesis in ALS including lack of degradation of abnormally accumulated proteins inside motor neurons, and an unbalanced function of the immune system leading to the prevalence of a neurotoxic function over neuroprotection. These two mechanisms contribute to ALS progression hence representing important therapeutic targets to modify disease expression. With a phase II clinical trial the investigators aim to study the biological response in ALS treated with Rapamycin, to obtain predictive information for a larger study. Eight Italian Centres will enroll 63 patients; treatment will be double blinded to patients and physicians, and will last 18 weeks.Follow up will be carried out for 36 months (total duration: 54 weeks).

Detailed Description
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This is a phase II randomized, double-blind, placebo-controlled, multicenter clinical trial for people with ALS. The aim is to study the biological and clinical effect of Rapamycin (in two different doses) in addition to Riluzole on ALS patients through comparison with patients treated with Riluzole and placebo. Rapamycin has been shown to enhance proteins degradation, and this has been associated with beneficial effects in models of neurodegeneration. Its immunomodulatory effects are also well established, notably the ability to suppress inflammatory neurotoxic responses mediated by T cells. As ALS is characterized by heterogeneous pathology and protein accumulation, some patients may respond to therapies that accelerate the clearance of abnormally accumulated proteic aggregates, while suppressing neurotoxic immune elements. Subjects will be enrolled in 3 groups of 21 subjects; treatment will be double blinded to patients and physicians, and will last 18 weeks. Active treatment will include oral Rapamycin at different doses: Rapamycin 1mg/m2/day or Rapamycin 2mg/m2/day. Rapamycin will be administered at fast, in the morning, once a day. Rapamycin levels will be measured (HPLC) to avoid toxicity (>15 ng/ml), but treating neurologists will have no access to blood laboratory data. Dosages will be adjusted accordingly and sham adjustments will be done in the placebo Group too. Post-treatment follow up will be 36 weeks. Globally the study will lasts 24 months. To monitor adverse events, examination and routine laboratory work (cell count, lipids and protein profile, kidney and liver function, C reactive protein) will be performed before taking Rapamycin/placebo. Non-routine laboratory studies include quantification and characterization of Tregs, lymphocytes phenotype, mTOR (mammilian target of rapamycin) downstream pathway activation in peripheral blood mononuclear cells (PBMC), inflammasome components in PBMC and proinflammatory cytokine production in monocytes, peripheral biomarkers. Cerebrospinal fluid (CSF) will be taken at baseline and at week 18 to measure neurofilaments and to dose Rapamycin to understand whether sufficient levels of Rapamycin can be found in the central nervous system (CNS).

Official Title
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Rapamycin (Sirolimus) Treatment for Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Rapamycin
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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 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, tuberculosis, 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 superoxide dismutase 1 (SOD1) mutation or with familial ALS and a family member carrying SOD1 mutation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>Patients assigned to this arm will take Riluzole as usual + placebo tablets | Drug: Placebo Oral Tablet<br>* tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage<br>|
| Active Comparator: Rapamycin 1 mg/m2<br>Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 1 mg/m2/day | Drug: Rapamycin<br>* tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage<br>* Other names: Rapamune;Drug: Placebo Oral Tablet<br>* tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage<br>|
| Active Comparator: Rapamycin 2 mg/m2<br>Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 2 mg/m2/day | Drug: Rapamycin<br>* tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T-reg number | Proportion of patients exhibiting a positive response (considered as increase in Treg of at least 30%), comparing baseline and treatment end between Rapamycin and placebo arm | comparison between baseline and treatment end (week 18) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of serious adverse events (SAEs) and AEs in placebo and treatment arms | Rapamycin safety and tolerability in a cohort of ALS patients | At week 18 and 54 | 
| Rapamycin capacity to pass through blood brain barrier | HPLC-MS (mass spectrometry) dosage of Rapamycin in CSF in placebo and treatment arm will be performed at treatment end | At week 18 | 
| Rapamycin efficacy in inhibiting Mtor pathway | Assessment of the phosphorylation of the S6 ribosomal protein (S6RP) comparing Rapamycin arms and placebo arm | At week 8-18-30-54 | 
| Changes in activation and homing capabilities of different T, B, natural killer (NK) cell subpopulations | Change from baseline to each time point (week 8, 18, 30, and 54) of the activation and homing capabilities of different T, B, NK cell subpopulations comparing Rapamycin arms and placebo arm. | At baseline and at week 8-18-30-54 | 
| Changes in CSF neurofilaments | Changes from baseline to week 18 of the levels of neurofilaments in CSF in treatment and placebo arms | Baseline and week 18 | 
| Changes in blood biomarkers | Changes from baseline to week 8-18-30.54 of the levels of neurofilaments and vitamin D in treatment and placebo arms | Baseline, week 8-18-30-54 | 
| Rapamycin-induced changes in inflammatory status | Changes from baseline to each time point (week 8, 18, 30, and 54) in inflammatory status (cytokines and cells) (molecular analysis of the inflammasome system) comparing Rapamycin arms and placebo arm | Baseline and week 8-18-30-54 | 
| Changes in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised | ALSFRS-R score changes from baseline to week 4, 8, 12, 18, 30, 42 and week 54 in treatment and placebo arms. | Up to week 54 | 
| Tracheostomy-free survival rate | Overall survival from randomization to date of death or tracheostomy | Up to week 54 | 
| Changes in Forced vital capacity (FVC) | Changes in FVC score from baseline to week 4, 8, 12, 18, 30, 42, 54 in treatment and placebo arms. | Up to week 54 | 
| Change in quality of life | Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms | From baseline to week 8, 18, 30 and week 54 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Rapamycin