RAP-ALS: Rapamycin Treatment for ALS

Sponsor

Azienda Ospedaliero-Universitaria di Modena (Other)

Overall Status

Completed

CT.gov ID

NCT03359538

Collaborator

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

Enrollment

Locations

Arms

52.9

Actual Duration (Months)

7.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Rapamycin Drug: Placebo Oral Tablet	Phase 2

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

63 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Masking Description:

treatment double blinded to patients and physicians

Primary Purpose:

Treatment

Official Title:

Rapamycin (Sirolimus) Treatment for Amyotrophic Lateral Sclerosis

Actual Study Start Date :

Sep 19, 2017

Actual Primary Completion Date :

Dec 15, 2020

Actual Study Completion Date :

Feb 15, 2022

Arms and Interventions

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

Arm

Intervention/Treatment

Placebo Comparator: placebo

Patients assigned to this arm will take Riluzole as usual + placebo tablets

Drug: Placebo Oral Tablet

tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage

Active Comparator: Rapamycin 1 mg/m2

Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 1 mg/m2/day

Drug: Rapamycin

tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage

Other Names:

Rapamune

Drug: Placebo Oral Tablet

tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage

Active Comparator: Rapamycin 2 mg/m2

Patients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 2 mg/m2/day

Drug: Rapamycin

tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage

Other Names:

Rapamune

Outcome Measures

Primary Outcome Measures

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

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 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
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 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.
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.
Tracheostomy-free survival rate [Up to week 54]
Overall survival from randomization to date of death or tracheostomy
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.
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Patient diagnosed with a laboratory supported , clinically "probable" or "definite" amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks,

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centro Sla, Irccs A.O.U. S.Martino Ist, Genova	Genova	Italy
2	Centro Clinico Nemo, Fondazione Serena Onlus, Milano	Milano	Italy
3	Centro Sla, Irccs Fondazione Salvatore Maugeri, Milano	Milano	Italy
4	Centro Sla, Irccs Istituto Carlo Besta, Milano	Milano	Italy
5	Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena	Modena	Italy	41126
6	Centro Sla, A.O.U. Maggiore Della Carita', Novara	Novara	Italy
7	Centro Sla, Universita' Di Padova	Padova	Italy
8	Centro Sla, Universita' Di Torino	Torino	Italy

Sponsors and Collaborators

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