The goal of this clinical trial is to evaluate whether low-dose colchicine can slow disease progression in patients with amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder affecting motor neurons. The study is designed to answer whether patients receiving colchicine show a slower decline in functional status, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), over a 30-week double-blind treatment period compared to patients receiving placebo. Additional questions include whether colchicine has an effect on respiratory function, disability progression, quality of life, and overall survival. Researchers will compare participants receiving colchicine at a dose of 0.005 mg/kg/day with those receiving placebo, both in addition to standard-of-care therapy with riluzole, to assess potential differences in disease progression. Participants will be randomly assigned in a 2:1 ratio to colchicine or placebo. They will take the assigned study medication for 30 weeks during a double-blind phase and then continue into a 36-week open-label extension phase, during which all participants will receive colchicine while remaining blinded to their initial treatment assignment. Throughout the study, participants will undergo regular clinical evaluations, including assessments of motor and respiratory function, functional disability, and quality of life, for a total follow-up period of up to 66 weeks. Blood samples will also be collected to investigate biological markers of neurodegeneration and inflammation.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
87
Low-dose colchicine administered orally at 0.005 mg/kg/day as an add-on to standard-of-care therapy with riluzole. Participants receive colchicine once daily or every other day depending on body weight (≥70 kg: 0.5 mg daily; \<70 kg: 0.5 mg every other day) using matching oral tablets. The intervention is administered during a 30-week double-blind phase followed by a 36-week open-label extension phase.
Matching placebo oral tablets identical in appearance, taste, and administration schedule to colchicine. Participants receive placebo in addition to standard-of-care therapy with riluzole. The placebo is administered orally once daily or every other day depending on body weight, following the same dosing schedule as the active treatment arm, during the 30-week double-blind phase. Participants subsequently enter a 36-week open-label extension phase during which all participants receive active colchicine.
Centro Clinico Nemo
Milan, Milano, Italy
CENTRO SLA, Ospedale Civile di Baggiovara, AOU Modena
Modena, Modena, Italy
CENTRO SLA, AOU Università Degli Studi Della Campania Luigi Vanvitelli
Naples, Napoli, Italy
CENTRO SLA, AOU Maggiore Della Carità
Novara, Novara, Italy
CENTRO SLA, Fondazione Istituto Neurologico Nazionale Casimiro Mondino IRCCS
Pavia, Pavia, Italy
Changes in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)
To assess whether low-dose colchicine slows disease progression in ALS by comparing the monthly rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score between the colchicine and placebo groups during the double-blind treatment phase.
Time frame: Baseline to Week 30 (double-blind treatment period)
Longitudinal change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score
Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score from baseline over time in both treatment groups. The ALSFRS-R total score ranges from 0 to 48, with higher scores indicating better functional status.
Time frame: Baseline to Weeks 4, 8, 12, 18, 24, 30, 42, 54, and 66
Change in ROADS score
Change in Changes in functional disability, assessed using the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) score from baseline over time in both treatment groups. The ROADS score ranges from 0 to 100, with higher scores indicating better functional status.
Time frame: Baseline to Weeks 8, 18, 30, 42, 54, and 66
Tracheostomy-free survival rate
Overall survival from randomization to date of death or tracheostomy
Time frame: From randomization to Week 66
Change in Forced Vital Capacity (FVC)
Changes in FVC score from baseline over time in both treatment groups.
Time frame: Baseline to Weeks 8, 18, 30, 42, 54, and 66
Change in Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) score
Change in quality of life assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) score from baseline over time in both treatment groups. The ALSAQ-40 score ranges from 0 to 100, with higher scores indicating greater impairment and worse health-related quality of life.
Time frame: Baseline to 30, and 66
Change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) domain-specific subscores
Change in domain-specific subscores of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) from baseline over time in both treatment groups, to explore differential treatment effects across functional domains. Each ALSFRS-R item is scored from 0 to 4, with higher scores indicating better functional status; domain-specific subscores (e.g., bulbar and motor domains) are calculated as the sum of the corresponding items.
Time frame: Baseline to weeks 4, 8, 12, 18, 24, 30, 42, 54, and 66
Difference in monthly change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score (delta FS)
Difference in the monthly change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score from treatment initiation to Week 30 (end of treatment), compared with the monthly change in ALSFRS-R total score from disease onset to treatment initiation. The ALSFRS-R total score ranges from 0 to 48, with higher scores indicating better functional status. For the calculation of the pre-treatment monthly change, an ALSFRS-R score of 48 is assumed at disease onset for each patient.
Time frame: Onset to baseline and Baseline to weeks 30
Exploratory target-engagement objectives: Change in TDP-43 species in PBMCs
Change in autophagic clearance of TDP-43 species in peripheral blood mononuclear cells (PBMCs), assessed by measuring PBS- and RIPA-soluble and insoluble fractions, including phosphorylated forms and C-terminal fragments, from baseline to Week 30 and Week 66. Between-group mean differences will be estimated at Week 30 and Week 66.
Time frame: Baseline to weeks 30, and 66
Exploratory target-engagement objectives: Change in platelet TDP-43 levels
Change in platelet TDP-43 levels, including cleaved and phosphorylated forms, from baseline to Week 30 and Week 66.
Time frame: Baseline to weeks 30, and 66
Exploratory target-engagement objectives: Change in TDP-43-regulated splicing events
Change in TDP-43-regulated splicing events in POLDIP3, ATG4B, and MARK3 mRNA in whole blood from baseline to Week 30 and Week 66.
Time frame: Baseline to weeks 30, and 66
Exploratory target-engagement objectives: Change in peripheral biomarker levels
Assess the effect of colchicine on peripheral biomarkers, including creatinine (mg/dL), albumin (g/dL), CRP (mg/dL), urate (mg/dL), and neurofilament light chain (NfL, pg/ml), as well as inflammatory markers (MCP1, serpinA1, TREM2, GFAP, and CHI3L1, pg/ml), measured in blood between baseline, week 30 and week 66.
Time frame: Baseline to weeks 30, and 66
Exploratory target-engagement objectives: Change in cerebrospinal fluid biomarker levels
Evaluate colchicine' effects on neurodegenerative (NfL, pg/mL) and neuroinflammatory markers (MCP1, SerpinA1, TREM2, GFAP, CHI3L1 and UCHL1, pg/mL) measured in CSF between baseline and week 30 (optional for patients)
Time frame: Baseline to weeks 30
Exploratory target-engagement objectives: Change in TDP-43 aggregates in skin biopsies and microvesicles
Change in TDP-43 aggregates measured in skin biopsies and microvesicles from baseline to Week 30 (optional for patients)
Time frame: Baseline to weeks 30
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