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Colchicine for Amyotrophic Lateral Sclerosis (Co-ALS)

Primary Purpose

Amyotrophic Lateral Sclerosis

Status

Completed

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Colchicine 1 MG Oral Tablet

Placebo Oral Tablet

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring amyotrophic lateral sclerosis, stress granules, HSPB8, protein quality control, colchicine, ALSFRS-r, survival, safety

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Colchicine 0.01mg/kg/day + Riluzole 100 mg

Colchicine 0.005 mg/kg/day + Riluzole 100 mg

Placebo + Riluzole 100 mg

Arm Description

Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day

Placebo pills will be administered at fast, while taking Riluzole 100 mg/day

Outcomes

Primary Outcome Measures

Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)

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

Incidence of Treatment-Emergent Adverse Events (safety and tolerability)

Number of serious adverse events (SAEs) and AEs in placebo and treatment arms

Tracheostomy-free survival rate

Overall survival from randomization to date of death or tracheostomy

Changes in Forced Vital Capacity (FVC)

Changes in FVC score from baseline to week 8, 18, 30, 54 in treatment and placebo arms.

Changes in quality of life

Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms

enhancement of autophagy

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);

changes in stress granules size, number and composition

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).

quantification of insoluble species

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

modifications on extracellular vesicles secretion in blood and CSF

assessment of TDP-43, hyperphosphorylated TDP-43, SQSTM1/p62, UBQLN and OPTN in extracellular vesicles by plasma and CSF.

effects on biomarkers of neurodegeneration

creatinine, albumin, CK, and vitamin D in plasma as markers of disease severity; phosphorylated neurofilaments heavy chain

effects on biomarkers of inflammation

assessment of plasma/CSF IL18, its endogenous inhibitor IL-18BP, MCP1 and IL17

Full Information

NCT ID

NCT03693781

First Posted

September 30, 2018

Last Updated

February 28, 2023

Sponsor

Azienda Ospedaliero-Universitaria di Modena

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

1. Study Identification

Unique Protocol Identification Number

NCT03693781

Brief Title

Colchicine for Amyotrophic Lateral Sclerosis

Acronym

Co-ALS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Completed

Study Start Date

April 10, 2019 (Actual)

Primary Completion Date

April 14, 2022 (Actual)

Study Completion Date

January 3, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Azienda Ospedaliero-Universitaria di Modena

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Amyotrophic Lateral Sclerosis

Keywords

amyotrophic lateral sclerosis, stress granules, HSPB8, protein quality control, colchicine, ALSFRS-r, survival, safety

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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

ParticipantInvestigator

Masking Description

placebo will be unrecognizable from active treatment (both in tablets)

Allocation

Randomized

Enrollment

54 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Colchicine 0.01mg/kg/day + Riluzole 100 mg

Arm Type

Active Comparator

Arm Description

Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day

Arm Title

Colchicine 0.005 mg/kg/day + Riluzole 100 mg

Arm Type

Active Comparator

Arm Description

Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day

Arm Title

Placebo + Riluzole 100 mg

Arm Type

Placebo Comparator

Arm Description

Placebo pills will be administered at fast, while taking Riluzole 100 mg/day

Intervention Type

Drug

Intervention Name(s)

Colchicine 1 MG Oral Tablet

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Colchicine 1 MG Oral Tablet

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo Oral Tablet

Intervention Description

Corresponding tablets for 30 weeks

Primary Outcome Measure Information:

Title

Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)

Description

Time Frame

comparison between baseline and treatment end (week 30)

Secondary Outcome Measure Information:

Title

Incidence of Treatment-Emergent Adverse Events (safety and tolerability)

Description

Number of serious adverse events (SAEs) and AEs in placebo and treatment arms

Time Frame

week 30 and 54

Title

Tracheostomy-free survival rate

Description

Overall survival from randomization to date of death or tracheostomy

Time Frame

Up to week 54

Title

Changes in Forced Vital Capacity (FVC)

Description

Changes in FVC score from baseline to week 8, 18, 30, 54 in treatment and placebo arms.

Time Frame

Up to week 54

Title

Changes in quality of life

Description

Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms

Time Frame

at 8,18,30 and 54 week

Title

enhancement of autophagy

Description

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);

Time Frame

at week 30 and 54, compared to baseline

Title

changes in stress granules size, number and composition

Description

Time Frame