Colchicine for Amyotrophic Lateral Sclerosis: a Phase II, Randomized, Double Blind, Placebo Controlled, Multicenter Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 8
- 主要终点
- Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)
研究概览
简要总结
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.
详细描述
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.
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
- Double (Participant, 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
- •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
排除标准
- •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).
研究组 & 干预措施
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)
Colchicine 0.01mg/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 1 MG Oral Tablet (Drug)
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 1 MG Oral Tablet (Drug)
结局指标
主要结局
Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)
时间窗: comparison between baseline and treatment end (week 30)
ALSFRS-R is a scale that measures disability in ALS; the scores range from 0 (maximum disability, the worst score) to 48 (no disability, the best score). We will measure total score changes from baseline to week 30 in treatment and placebo arms.
次要结局
- Incidence of Treatment-Emergent Adverse Events (safety and tolerability)(week 30 and 54)
- enhancement of autophagy(at week 30 and 54, compared to baseline)
- Tracheostomy-free survival rate(Up to week 54)
- Changes in Forced Vital Capacity (FVC)(Up to week 54)
- quantification of insoluble species(at week 30 compared to baseline)
- effects on biomarkers of inflammation(at week 30 compared to baseline)
- effects on biomarkers of neurodegeneration(at week 30 compared to baseline)
- changes in stress granules size, number and composition(at week 30 compared to baseline)
- modifications on extracellular vesicles secretion in blood and CSF(at week 30 compared to baseline)
- Changes in quality of life(at 8,18,30 and 54 week)
研究者
JESSICA MANDRIOLI
Principal Investigator
Azienda Ospedaliero-Universitaria di Modena