A Randomized, Placebo-controlled, Multicenter, Clinical Trial of Colchicine in Amyotrophic Lateral Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 87
- 试验地点
- 5
- 主要终点
- Changes in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
placebo will be unrecognizable from active treatment (both in tablets)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Colchicine 0.005 mg/kg/day + Riluzole 100 mg
Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day
干预措施: Colchicine 0.5 MG Oral Tablet (Drug)
Placebo + Riluzole 100 mg
Placebo pills will be administered at fast, while taking Riluzole 100 mg/day
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Changes in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)
时间窗: Baseline to Week 30 (double-blind treatment period)
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.
次要结局
- Longitudinal change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score(Baseline to Weeks 4, 8, 12, 18, 24, 30, 42, 54, and 66)
- Change in ROADS score(Baseline to Weeks 8, 18, 30, 42, 54, and 66)
- Tracheostomy-free survival rate(From randomization to Week 66)
- Change in Forced Vital Capacity (FVC)(Baseline to Weeks 8, 18, 30, 42, 54, and 66)
- Change in Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) score(Baseline to 30, and 66)
- Change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) domain-specific subscores(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)(Onset to baseline and Baseline to weeks 30)
- Exploratory target-engagement objectives: Change in TDP-43 species in PBMCs(Baseline to weeks 30, and 66)
- Exploratory target-engagement objectives: Change in platelet TDP-43 levels(Baseline to weeks 30, and 66)
- Exploratory target-engagement objectives: Change in TDP-43-regulated splicing events(Baseline to weeks 30, and 66)
- Exploratory target-engagement objectives: Change in peripheral biomarker levels(Baseline to weeks 30, and 66)
- Exploratory target-engagement objectives: Change in cerebrospinal fluid biomarker levels(Baseline to weeks 30)
- Exploratory target-engagement objectives: Change in TDP-43 aggregates in skin biopsies and microvesicles(Baseline to weeks 30)
研究者
Giulia Gianferrari
sponsor-investigator
Azienda Ospedaliero-Universitaria di Modena