Colchicine for Amyotrophic Lateral Sclerosis

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.

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).