Rapamycin Treatment for ALS

Amyotrophic Lateral Sclerosis Clinical Trial

— RAP-ALS  

Official title:

Rapamycin (Sirolimus) Treatment for Amyotrophic Lateral Sclerosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03359538
• Other study ID #: RAP-ALS
• Status: Completed
• Phase: Phase 2
• Start date: September 19, 2017
• Est. completion date: February 15, 2022

Study information

• Verified date: August 2022
• Source: Azienda Ospedaliero-Universitaria di Modena
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: February 15, 2022
• Est. primary completion date: December 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• Rapamycin
tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage
• Placebo Oral Tablet
tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage

Locations

Country	Name	City	State
Italy	Centro Sla, Irccs A.O.U. S.Martino Ist, Genova	Genova
Italy	Centro Clinico Nemo, Fondazione Serena Onlus, Milano	Milano
Italy	Centro Sla, Irccs Fondazione Salvatore Maugeri, Milano	Milano
Italy	Centro Sla, Irccs Istituto Carlo Besta, Milano	Milano
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	Centro Sla, Universita' Di Padova	Padova
Italy	Centro Sla, Universita' Di Torino	Torino

Sponsors (9)

Lead Sponsor	Collaborator
Azienda Ospedaliero-Universitaria di Modena	Azienda Ospedaliera Niguarda Cà Granda, Azienda Ospedaliero Universitaria Maggiore della Carita, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Fondazione Salvatore Maugeri, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, University of Modena and Reggio Emilia, University of Padova, University of Turin, Italy

Country where clinical trial is conducted

Italy, 

References & Publications (20)

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Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008 Jan 22;5(1):e8. doi: 10.1371/journal.pmed.0050008. — View Citation

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Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004 Jun;36(6):585-95. Epub 2004 May 16. — View Citation

Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH. Activation of autophagy by inflammatory signals limits IL-1ß production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012 Jan 29;13(3):255-63. doi: 10.1038/ni.2215. — View Citation

Staats KA, Hernandez S, Schönefeldt S, Bento-Abreu A, Dooley J, Van Damme P, Liston A, Robberecht W, Van Den Bosch L. Rapamycin increases survival in ALS mice lacking mature lymphocytes. Mol Neurodegener. 2013 Sep 11;8:31. doi: 10.1186/1750-1326-8-31. — View Citation

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* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Tracheostomy-free survival rate	Overall survival from randomization to date of death or tracheostomy	Up to week 54
Secondary	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
Secondary	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