Colchicine for Amyotrophic Lateral Sclerosis

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.

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).