Colchicine for Amyotrophic Lateral Sclerosis (Co-ALS)

February 28, 2023 updated by: JESSICA MANDRIOLI, Azienda Ospedaliero-Universitaria di Modena

Colchicine for Amyotrophic Lateral Sclerosis: a Phase II, Randomized, Double Blind, Placebo Controlled, Multicenter Clinical Trial

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Bari, Italy
        • Centro Sla, University of Bari
      • Milano, Italy
        • Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano
      • Milano, Italy
        • Irccs Carlo Besta
      • Milano, Italy
        • Irccs St. Raffaele Institute of Milano
      • Modena, Italy, 41126
        • Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena
      • Napoli, Italy
        • Università della Campania Gianluigi Vanvitelli
      • Pavia, Italy
        • Als Centre, "C. Mondino" National Neurological Institute, University of Pavia
      • Roma, Italy
        • , Neuromuscular Omnicentre Centre, Rome, Catholic University, Rome

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / 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
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
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
Corresponding tablets for 30 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
comparison between baseline and treatment end (week 30)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
week 30 and 54
Tracheostomy-free survival rate
Time Frame: Up to week 54
Overall survival from randomization to date of death or tracheostomy
Up to week 54
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.
Up to week 54
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
at 8,18,30 and 54 week
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);
at week 30 and 54, compared to baseline
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).
at week 30 compared to baseline
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
at week 30 compared to baseline
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.
at week 30 compared to baseline
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
at week 30 compared to baseline
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
at week 30 compared to baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 10, 2019

Primary Completion (Actual)

April 14, 2022

Study Completion (Actual)

January 3, 2023

Study Registration Dates

First Submitted

September 30, 2018

First Submitted That Met QC Criteria

October 1, 2018

First Posted (Actual)

October 3, 2018

Study Record Updates

Last Update Posted (Actual)

March 1, 2023

Last Update Submitted That Met QC Criteria

February 28, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

de-identified individual participant data will be made available after study completion upon specific request

IPD Sharing Time Frame

The data will become available at study completion (after final data analysis)

IPD Sharing Access Criteria

specific personal request by the subject

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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