Rapamycin Treatment for ALS
- Conditions
- Amyotrophic Lateral Sclerosis
- Interventions
- Drug: Placebo Oral TabletDrug: Rapamycin
- Registration Number
- NCT03359538
- Lead Sponsor
- Azienda Ospedaliero-Universitaria di Modena
- Brief Summary
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
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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 63
Not provided
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description placebo Placebo Oral Tablet Patients assigned to this arm will take Riluzole as usual + placebo tablets Rapamycin 1 mg/m2 Placebo Oral Tablet Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 1 mg/m2/day Rapamycin 1 mg/m2 Rapamycin Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 1 mg/m2/day Rapamycin 2 mg/m2 Rapamycin Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 2 mg/m2/day
- Primary Outcome Measures
Name Time Method T-reg number comparison between baseline and treatment end (week 18) 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
- Secondary Outcome Measures
Name Time Method Tracheostomy-free survival rate Up to week 54 Overall survival from randomization to date of death or tracheostomy
Change in quality of life From baseline to week 8, 18, 30 and week 54 Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms
Number of serious adverse events (SAEs) and AEs in placebo and treatment arms At week 18 and 54 Rapamycin safety and tolerability in a cohort of ALS patients
Rapamycin efficacy in inhibiting Mtor pathway At week 8-18-30-54 Assessment of the phosphorylation of the S6 ribosomal protein (S6RP) comparing Rapamycin arms and placebo arm
Changes in CSF neurofilaments Baseline and week 18 Changes from baseline to week 18 of the levels of neurofilaments in CSF in treatment and placebo arms
Changes in blood biomarkers Baseline, week 8-18-30-54 Changes from baseline to week 8-18-30.54 of the levels of neurofilaments and vitamin D in treatment and placebo arms
Rapamycin-induced changes in inflammatory status Baseline and week 8-18-30-54 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
Changes in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised Up to week 54 ALSFRS-R score changes from baseline to week 4, 8, 12, 18, 30, 42 and week 54 in treatment and placebo arms.
Changes in Forced vital capacity (FVC) Up to week 54 Changes in FVC score from baseline to week 4, 8, 12, 18, 30, 42, 54 in treatment and placebo arms.
Changes in activation and homing capabilities of different T, B, natural killer (NK) cell subpopulations At baseline and at week 8-18-30-54 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.
Rapamycin capacity to pass through blood brain barrier At week 18 HPLC-MS (mass spectrometry) dosage of Rapamycin in CSF in placebo and treatment arm will be performed at treatment end
Trial Locations
- Locations (7)
Centro Clinico Nemo, Fondazione Serena Onlus, Milano
🇮🇹Milano, Italy
Centro Sla, Irccs A.O.U. S.Martino Ist, Genova
🇮🇹Genova, Italy
Centro Sla, Irccs Istituto Carlo Besta, Milano
🇮🇹Milano, Italy
Centro Sla, Universita' Di Padova
🇮🇹Padova, Italy
Centro Sla, Universita' Di Torino
🇮🇹Torino, Italy
Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena
🇮🇹Modena, Italy
Centro Sla, A.O.U. Maggiore Della Carita', Novara
🇮🇹Novara, Italy