Colchicine Effect on Amyotrophic Lateral Sclerosis Patients

Co-ALS II is a Phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial conducted in specialized ALS referral centers in Italy. The study investigates whether low-dose colchicine (0.005 mg/kg/day) can slow disease progression in patients with Amyotrophic Lateral Sclerosis (ALS), a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons.

The study is based on emerging evidence supporting a role for impaired proteostasis and neuroinflammation in ALS pathogenesis. In particular, intracellular accumulation of TDP-43 protein aggregates and dysfunction of autophagy-related pathways represent key pathogenic mechanisms. Preclinical data suggest that colchicine may enhance proteostasis mechanisms, including autophagy-related signaling pathways (e.g., TFEB, p62, LC3, and HSPB8), potentially facilitating clearance of toxic protein aggregates.

This hypothesis is further supported by findings from a previous exploratory Phase II study (Co-ALS), which suggested a potential slowing of ALSFRS-R decline with low-dose colchicine, although that study was limited by sample size and external constraints.

In Co-ALS II, 87 patients with definite or probable ALS will be randomized in a 2:1 ratio to receive colchicine or placebo in addition to standard therapy with riluzole. The study includes a screening period of up to 30 days, followed by a 30-week double-blind treatment phase and a 36-week open-label extension phase, resulting in a total follow-up of 66 weeks per participant.

The primary endpoint is the rate of decline in ALSFRS-R score over the 30-week double-blind period. Secondary endpoints include longitudinal changes in ALSFRS-R, Rasch-Built Overall ALS Disability Scale (ROADS), forced vital capacity (FVC), ALS Assessment Questionnaire-40 (ALSAQ-40), functional subdomain scores, and overall survival defined as time to death or tracheostomy.

Biological samples will be collected at baseline, week 30, and week 66 to investigate pharmacodynamic and mechanistic biomarkers. These include neurofilament light chain (NfL), TDP-43 aggregation markers in peripheral blood mononuclear cells, and circulating inflammatory mediators such as MCP-1, GFAP, and TREM2. Optional cerebrospinal fluid and skin biopsy sub-studies will further explore disease biology.

Safety will be closely monitored by an independent Data and Safety Monitoring Board (DSMB), which will periodically review unblinded safety data. Predefined stopping rules are in place for severe hematological or systemic toxicity.

Statistical analyses will compare treatment groups using longitudinal mixed-effects models and non-parametric methods as appropriate. Sample size calculations are based on observed effect sizes from the prior Co-ALS I study, with adjustment for anticipated dropout.

Inclusion criteria

• Patient age strictly between 18 and 80 years at the time of screening.
• Definitively established diagnosis of ALS (sporadic or familial) matching standardized clinical consensus parameters.
• Stable background regimen of European gold-standard Riluzole therapy maintained at a fixed dose of 100 mg/day for a minimum of 1 month prior to baseline randomization.
• BMI>17.5 Kg/m2
• Sufficient respiratory capability, verified by an upright Forced Vital Capacity (FVC) >= 70% of predicted normal values at screening (highest value of three sequential tests).
• Patient must display full cognitive and communicative capacity to provide written, personally signed Independent Ethics Committee-approved Informed Consent prior to initiation of any protocolized procedures.
• Use of highly effective contraception both for males and females

Exclusion criteria

• Concurrent participation or treatment within any other interventional or drug-based clinical trial.
• Clinically significant hepatic impairment (defined as baseline serum transaminases AST or ALT exceeding 3x Upper Limit of Normal [ULN], or total bilirubin exceeding 2x ULN).
• Severe renal insufficiency, documented bone marrow suppression, or significant hematological abnormalities.
• Known hypersensitivity or systemic intolerance to colchicine or any of the manufacturing excipients (lactose, sucrose, magnesium stearate, arabic gum).
• Pregnancy, active lactation, or unwillingness of fertile male/female subjects to strictly comply with highly effective double-barrier contraception regimens throughout the study and for 100 days post-final dose.