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Colchicine for Amyotrophic Lateral Sclerosis (Co-ALS)

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ClinicalTrials.gov Identifier: NCT03693781
Recruitment Status : Not yet recruiting
First Posted : October 3, 2018
Last Update Posted : January 14, 2019
Sponsor:
Collaborators:
University of Modena and Reggio Emilia
University of Turin, Italy
Istituto Auxologico Italiano
IRCCS National Neurological Institute "C. Mondino" Foundation
University of Bari
IRCCS San Raffaele
University of Padova
University of Milan
Istituto Di Ricerche Farmacologiche Mario Negri
University of Campania "Luigi Vanvitelli"
Catholic University of the Sacred Heart
Information provided by (Responsible Party):
Jessica Mandrioli, Azienda Ospedaliero-Universitaria di Modena

Brief Summary:
The study evaluates the effects of two different Colchicine doses (0.01mg/kg/day or 0.005 mg/kg/day) compared to placebo in Amyotrophic Lateral Sclerosis (ALS) patients. Disease progression as defined by changes in ALSFRS-r is the primary outcome measure. Other measures of clinical progression and survival, together with safety and tolerability of Colchicine in ALS patients will be assessed.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: Colchicine 1 MG Oral Tablet Drug: Placebo Oral Tablet Phase 2

Detailed Description:

Recent evidence supports the disruption of the ubiquitin-proteasome-system and autophagy as central events in ALS. ALS is characterized by the presence of misfolded proteins prone to oligomerize into aggregates, which exert a toxic effect by affecting several intracellular functions. Heat shock protein B8 (HSPB8) recognizes and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs). Moreover, HSPB8-BAG3-HSP70 maintains the so called "granulostasis", a surveillance mechanism that avoids the conversion of dynamic stress granules (SGs) into aggregation-prone assemblies, which are a hallmark of ALS.

Colchicine enhances the expression of HSPB8 and of several autophagy players while blocking TDP-43 accumulation in neurons. Moreover, given the cross-talk between infalmmation and autophagy, the well-known antinflammatory action of Cochicine may contribute to cell homeostasis.

Based on these premises, this is a phase II randomized, double-blind, placebo-controlled, multicenter (9 MND Centres in Italy: 2 centres in Milan, Pavia, Turin, Modena, Padua, Rome, Naples, Bari), clinical trial to test efficacy of Colchicine in ALS.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Three arms of 18 patients each; in two arms two colchicine dosages will be tested compared to placebo in the control arm. The three arms will undergo treatment vs placebo in parallel
Masking: Double (Participant, Investigator)
Masking Description: placebo will be unrecognizable from active treatment (both in tablets)
Primary Purpose: Treatment
Official Title: Colchicine for Amyotrophic Lateral Sclerosis: a Phase II, Randomized, Double Blind, Placebo Controlled, Multicenter Clinical Trial
Estimated Study Start Date : January 30, 2019
Estimated Primary Completion Date : November 1, 2020
Estimated Study Completion Date : November 1, 2020


Arm Intervention/treatment
Active Comparator: Colchicine 0.01mg/kg/day + Riluzole 100 mg
Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day
Drug: Colchicine 1 MG Oral Tablet
Colchicine tablets depending on arm (0.01 mg/kg/day, 0.005 mg/kg/day, placebo) and on weight (>70 kg or <71 kg) for 30 weeks of duration.

Active Comparator: Colchicine 0.005 mg/kg/day + Riluzole 100 mg
Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day
Drug: Colchicine 1 MG Oral Tablet
Colchicine tablets depending on arm (0.01 mg/kg/day, 0.005 mg/kg/day, placebo) and on weight (>70 kg or <71 kg) for 30 weeks of duration.

Placebo Comparator: Placebo + Riluzole 100 mg
Placebo pills will be administered at fast, while taking Riluzole 100 mg/day
Drug: Placebo Oral Tablet
Corresponding tablets for 30 weeks




Primary Outcome Measures :
  1. Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R) [ Time Frame: comparison between baseline and treatment end (week 30) ]
    ALSFRS-R is a scale that measures disability in ALS; the scores range from 0 (maximum disability, the worst score) to 48 (no disability, the best score). We will measure total score changes from baseline to week 30 in treatment and placebo arms.


Secondary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events (safety and tolerability) [ Time Frame: week 30 and 54 ]
    Number of serious adverse events (SAEs) and AEs in placebo and treatment arms

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

  3. Changes in Forced Vital Capacity (FVC) [ Time Frame: Up to week 54 ]
    Changes in FVC score from baseline to week 8, 18, 30, 54 in treatment and placebo arms.

  4. Changes in quality of life [ Time Frame: at 8,18,30 and 54 week ]
    Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms

  5. enhancement of autophagy [ Time Frame: at week 30 and 54, compared to baseline ]
    assessment of mRNA and protein levels of p62, LC3, TFEB, ATGs, HSPB8, BAG3, BAG1, HSP70, and HSF1, in patients' PBMCs, lymphoblasts and fibroblasts (transcriptome profile);

  6. changes in stress granules size, number and composition [ Time Frame: at week 30 compared to baseline ]
    identification of changes in stress granules response and composition in patients' fibroblasts and lymphoblasts will be carried out by measuring granules size, number and composition by confocal microscopy using automated systems. The aberrant recruitment or sequestration of specific mRNA inside stress granules will be assessed by FISH using specific probes, followed by densitometric analysis as previously described by Gareau et al. (2011).

  7. quantification of insoluble species [ Time Frame: at week 30 compared to baseline ]
    assessment of overall levels and the relative ratio between soluble and insoluble species of TDP-43, TDP-43 fragments, SQSTM1/p62, UBQLN, OPTN in fibroblasts and lymphoblasts derived from the same patients

  8. modifications on extracellular vesicles secretion in blood and CSF [ Time Frame: at week 30 compared to baseline ]
    assessment of TDP-43, hyperphosphorylated TDP-43, SQSTM1/p62, UBQLN and OPTN in extracellular vesicles by plasma and CSF.

  9. effects on biomarkers of neurodegeneration [ Time Frame: at week 30 compared to baseline ]
    creatinine, albumin, CK, and vitamin D in plasma as markers of disease severity; phosphorylated neurofilaments heavy chain

  10. effects on biomarkers of inflammation [ Time Frame: at week 30 compared to baseline ]
    assessment of plasma/CSF IL18, its endogenous inhibitor IL-18BP, MCP1 and IL17



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients diagnosed with a laboratory supported, clinically "probable" or "definite" amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks, 2000)
  • Sporadic ALS
  • ALS phenotypes: classic or bulbar
  • Female or male patients aged between 18 and 80 years old
  • Disease duration from symptoms onset no longer than 18 months at the screening visit
  • Patients 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
  • Patients with a FVC (Forced Vital Capacity) equal or more than 65 % predicted normal value for gender, height, and age at the screening visit Patients able and willing to comply with study procedures as per protocol
  • Patients able to understand, and capable of providing informed consent at screening visit prior to any protocol-specific procedures
  • Use of highly effective contraception

Exclusion Criteria:

  • Prior use of Colchicine
  • Prior allergy/sensitivity to Colchicine
  • Receiving Colchicine or other anti-inflammatory drugs (such as corticosteroids, methotrexate, anti-neoplastic, Interleukin 1-1b antagonist, Tumor necrosis factor-alpha inhibitor)
  • Receiving food or co-medications such as strong-moderate cytochrome P450 3A4 inhibitors that will result in elevated plasma level of Colchicine
  • Inflammatory disorders (SLE, Rheumatoid arthritis, connective tissue disorder) or chronic infections (HIV, hepatitis B or C infection) or significant history of malignancy
  • Severe renal (eGFR< 30ml/min/1.73m2), or liver failure or liver aminotransferase (ALT/AST > 2x Upper limit of normal),
  • Existing blood dyscrasia (e.g., myelodysplasia)
  • White blood cells<4,000/mm³, platelets count<100,000/mm³, hematocrit<30%
  • Severe comorbidities (heart, renal, liver failure), autoimmune diseases or any type of interstitial lung disease
  • Patients 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 the following ALS phenotypes: flail arm, flail leg, UMN-p, respiratory, PLS, progressive muscular atrophy.
  • Patients with familial ALS defined as presence of at least one first degree family member (parents/son/daughter/brother/sister) affected by ALS.
  • Patients with known pathogenic mutations (SOD1, TARDBP, FUS, C9ORF72).

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): NCT03693781


Contacts
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Contact: Jessica Mandrioli, MD 059-3961640 j.mandrioli@ausl.mo.it
Contact: Nicola Fini, MD 0593961640 n.fini@ausl.mo.it

Locations
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Italy
Centro Sla, University of Bari Not yet recruiting
Bari, Italy
Contact: Isabella L Simone, Prof.         
Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano Not yet recruiting
Milano, Italy
Contact: Vincenzo Silani, Prof.         
Irccs St. Raffaele Institute of Milano Not yet recruiting
Milano, Italy
Contact: Nilo Riva, MD         
Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena Not yet recruiting
Modena, Italy, 41126
Contact: Jessica Mandrioli, MD    +390593961722      
Università della Campania Gianluigi Vanvitelli Not yet recruiting
Napoli, Italy
Contact: Maria R Monsurrò, MD         
Centro Sla, Universita' Di Padova Not yet recruiting
Padova, Italy
Contact: Gianni Sorarù, MD         
Als Centre, "C. Mondino" National Neurological Institute, University of Pavia Not yet recruiting
Pavia, Italy
Contact: Mauro Ceroni, Prof.         
, Neuromuscular Omnicentre Centre, Rome, Catholic University, Rome Not yet recruiting
Roma, Italy
Contact: Mario Sabatelli, 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
University of Turin, Italy
Istituto Auxologico Italiano
IRCCS National Neurological Institute "C. Mondino" Foundation
University of Bari
IRCCS San Raffaele
University of Padova
University of Milan
Istituto Di Ricerche Farmacologiche Mario Negri
University of Campania "Luigi Vanvitelli"
Catholic University of the Sacred Heart
Investigators
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Principal Investigator: Jessica Mandrioli Azienda Ospedaliero-Universitaria di Modena

Publications:

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Responsible Party: Jessica Mandrioli, Principal Investigator, Azienda Ospedaliero-Universitaria di Modena
ClinicalTrials.gov Identifier: NCT03693781     History of Changes
Other Study ID Numbers: Co-ALS
First Posted: October 3, 2018    Key Record Dates
Last Update Posted: January 14, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: de-identified individual participant data will be made available after study completion upon specific request
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: The data will become available at study completion (after final data analysis)
Access Criteria: specific personal request by the subject

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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
stress granules
HSPB8
protein quality control
colchicine
ALSFRS-r
survival
safety

Additional relevant MeSH terms:
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Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Colchicine
Riluzole
Gout Suppressants
Antirheumatic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anticonvulsants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents