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Rapamycin Treatment for ALS (RAP-ALS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03359538
Recruitment Status : Recruiting
First Posted : December 2, 2017
Last Update Posted : December 4, 2017
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Jessica Mandrioli, 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).


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).


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Study Type : Interventional  (Clinical Trial)
Estimated 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 : September 19, 2017
Estimated Primary Completion Date : April 19, 2019
Estimated Study Completion Date : September 19, 2019


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 Name: 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 Name: Rapamune




Primary Outcome Measures :
  1. T-reg number [ Time Frame: 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 :
  1. Number of serious adverse events (SAEs) and AEs in placebo and treatment arms [ Time Frame: At week 18 and 54 ]
    Rapamycin safety and tolerability in a cohort of ALS patients

  2. Rapamycin capacity to pass through blood brain barrier [ Time Frame: At week 18 ]
    HPLC-MS (mass spectrometry) dosage of Rapamycin in CSF in placebo and treatment arm will be performed at treatment end

  3. Rapamycin efficacy in inhibiting Mtor pathway [ Time Frame: At week 8-18-30-54 ]
    Assessment of the phosphorylation of the S6 ribosomal protein (S6RP) comparing Rapamycin arms and placebo arm

  4. Changes in activation and homing capabilities of different T, B, natural killer (NK) cell subpopulations [ Time Frame: 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.

  5. Changes in CSF neurofilaments [ Time Frame: Baseline and week 18 ]
    Changes from baseline to week 18 of the levels of neurofilaments in CSF in treatment and placebo arms

  6. Changes in blood biomarkers [ Time Frame: 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

  7. Rapamycin-induced changes in inflammatory status [ Time Frame: 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

  8. Changes in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised [ Time Frame: 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.

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

  10. Changes in Forced vital capacity (FVC) [ Time Frame: Up to week 54 ]
    Changes in FVC score from baseline to week 4, 8, 12, 18, 30, 42, 54 in treatment and placebo arms.

  11. Change in quality of life [ Time Frame: 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03359538


Contacts
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Contact: Jessica Mandrioli, MD +300593961700 j.mandrioli@ausl.mo.it

Locations
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Italy
Centro Sla, Irccs A.O.U. S.Martino Ist, Genova Not yet recruiting
Genova, Italy
Contact: Claudia Caponnetto, MD         
Centro Clinico Nemo, Fondazione Serena Onlus, Milano Not yet recruiting
Milano, Italy
Contact: Christian Lunetta, MD         
Centro Sla, Irccs Fondazione Salvatore Maugeri, Milano Not yet recruiting
Milano, Italy
Contact: Kalliopi Marinou, MD         
Centro Sla, Irccs Istituto Carlo Besta, Milano Not yet recruiting
Milano, Italy
Contact: Eleonora Dalla Bella, MD         
Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena Recruiting
Modena, Italy, 41126
Contact: Jessica Mandrioli, MD    +390593961722      
Centro Sla, A.O.U. Maggiore Della Carita', Novara Not yet recruiting
Novara, Italy
Contact: Letizia Mazzini, MD         
Centro Sla, Universita' Di Padova Not yet recruiting
Padova, Italy
Contact: Gianni Sorarù, MD         
Centro Sla, Universita' Di Torino Not yet recruiting
Torino, Italy
Contact: Adriano Chiò, Prof.         
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
Investigators
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Principal Investigator: Jessica Mandrioli, MD Azienda Ospedaliero-Universitaria di Modena

Publications:
Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Staropoli JF, Xin WW, Chesi A, Raphael AR, McKenna-Yasek D, Cady J, Vianney de Jong JM, Kenna KP, Smith BN, Topp S, Miller J, Gkazi A; FALS Sequencing Consortium, Al-Chalabi A, van den Berg LH, Veldink J, Silani V, Ticozzi N, Shaw CE, Baloh RH, Appel S, Simpson E, Lagier-Tourenne C, Pulst SM, Gibson S, Trojanowski JQ, Elman L, McCluskey L, Grossman M, Shneider NA, Chung WK, Ravits JM, Glass JD, Sims KB, Van Deerlin VM, Maniatis T, Hayes SD, Ordureau A, Swarup S, Landers J, Baas F, Allen AS, Bedlack RS, Harper JW, Gitler AD, Rouleau GA, Brown R, Harms MB, Cooper GM, Harris T, Myers RM, Goldstein DB. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015 Mar 27;347(6229):1436-41. doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.

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Responsible Party: Jessica Mandrioli, MD, PI, Azienda Ospedaliero-Universitaria di Modena
ClinicalTrials.gov Identifier: NCT03359538     History of Changes
Other Study ID Numbers: RAP-ALS
First Posted: December 2, 2017    Key Record Dates
Last Update Posted: December 4, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Jessica Mandrioli, Azienda Ospedaliero-Universitaria di Modena:
Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Rapamycin
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs