Colchicine for Amyotrophic Lateral Sclerosis

Azienda Ospedaliero-Universitaria di Modena54 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Amyotrophic Lateral Sclerosis

Interventions

Colchicine 1 MG Oral TabletDRUG

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.

Colchicine 1 MG Oral TabletDRUG

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 Oral TabletDRUG

Corresponding tablets for 30 weeks

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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).

Locations (8)

Centro Sla, University of Bari

Bari, Italy

Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano

Milan, Italy

Irccs Carlo Besta

Milan, Italy

Irccs St. Raffaele Institute of Milano

Milan, Italy

Outcomes

Primary Outcomes

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.

Time frame: comparison between baseline and treatment end (week 30)

Secondary Outcomes

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

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

Time frame: week 30 and 54

Tracheostomy-free survival rate

Overall survival from randomization to date of death or tracheostomy

Time frame: Up to week 54

Changes in Forced Vital Capacity (FVC)

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

Time frame: Up to week 54

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

Time frame: at 8,18,30 and 54 week

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);

Time frame: at week 30 and 54, compared to baseline

changes in stress granules size, number and composition

Data from ClinicalTrials.gov

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