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Rapamycin Treatment for ALS (RAP-ALS)

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ClinicalTrials.gov Identifier: NCT03359538
Recruitment Status : Active, not recruiting
First Posted : December 2, 2017
Last Update Posted : July 21, 2021
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

Tracking Information
First Submitted Date  ICMJE November 8, 2017
First Posted Date  ICMJE December 2, 2017
Last Update Posted Date July 21, 2021
Actual Study Start Date  ICMJE September 19, 2017
Actual Primary Completion Date December 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 27, 2017)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 1, 2017)
  • 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
  • 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
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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.
  • Tracheostomy-free survival rate [ Time Frame: Up to week 54 ]
    Overall survival from randomization to date of death or tracheostomy
  • 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.
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: November 27, 2017)
  • Number of 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
  • Rapamycin capacity to pass through blood brain barrier [ Time Frame: At week 18 ]
    HPLC-MS dosage of Rapamycin in CSF in placebo and treatment arm will be perfomred at treatment end
  • 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
  • Changes in activation and homing capabilities of different T, B, 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.
  • 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
  • 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
  • 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
  • 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.
  • Tracheostomy-free survival rate [ Time Frame: Up to week 54 ]
    Overall survival from randomization to date of death or tracheostomy
  • 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.
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rapamycin Treatment for ALS
Official Title  ICMJE Rapamycin (Sirolimus) Treatment for Amyotrophic Lateral Sclerosis
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:
treatment double blinded to patients and physicians
Primary Purpose: Treatment
Condition  ICMJE Amyotrophic Lateral Sclerosis
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Placebo Comparator: placebo
    Patients assigned to this arm will take Riluzole as usual + placebo tablets
    Intervention: Drug: Placebo Oral Tablet
  • 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
    Interventions:
    • Drug: Rapamycin
    • Drug: Placebo Oral Tablet
  • 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
    Intervention: Drug: Rapamycin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 27, 2017)
63
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 15, 2021
Actual Primary Completion Date December 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03359538
Other Study ID Numbers  ICMJE RAP-ALS
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jessica Mandrioli, Azienda Ospedaliero-Universitaria di Modena
Study Sponsor  ICMJE Azienda Ospedaliero-Universitaria di Modena
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: Jessica Mandrioli, MD Azienda Ospedaliero-Universitaria di Modena
PRS Account Azienda Ospedaliero-Universitaria di Modena
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP