Rapamycin Treatment for ALS
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 2

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).
    

Intervention name(s): Rapamycin; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage; tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage
Other intervention name(s): Rapamune
Intervention MeSH terms: Sirolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Rapamycin