Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis: Multicentre, Parallel-group, Placebo-controlled, Randomized Clinical Trial of Deferiprone
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 372
- 试验地点
- 15
- 主要终点
- CAFS score (Combined Assessment of Function and Survival)
研究概览
简要总结
The alteration of iron metabolism is reported in animal models of amyotrophic lateral sclerosis (ALS) as well as in sporadic and genetic forms (SOD1 and C9orf72) of ALS. The high iron concentration of the brain, due to its high energy demand (high oxygen consumption), makes motor neurons particularly vulnerable to energy deficit and oxidative stress. Post-mortem examinations and MRI scans in patients with ALS have found signs of iron accumulation in the central motor tract; and a high level of serum ferritin, which is a marker of iron levels, is associated with a lower prognosis. In ALS mouse models, the use of iron chelators has demonstrated neuroprotection and increased life expectancy, suggesting that elimination of excess iron from the brain can prevent neuronal loss and, consequently, a slow progression of the disease. Conservative chelation of iron refers to a modality whereby much of the iron that binds to the chelator is redistributed in the body rather than exhausted. Using a chelator, deferiprone, with this feature, in a safety pilot study, a very good safety profile was observed. Deferiprone eliminated excess iron from brain regions, reduced oxidative damage and cell death associated with regional iron deposits with no apparent negative impact on the iron levels needed. Now, the efficacy of this new therapeutic modality of neuroprotection is being evaluated in a randomized, double-blind, placebo-controlled, multicenter study.
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)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Categorized as; possible, laboratory supported probable, probable, or definite ALS (revised El Escorial criteria)
- •Spinal and bulbar forms of ALS
- •Duration of the disease of less than 18 months since the first symptoms of motor deficit or amyotrophy (isolated cramps or fasciculation will not be considered).
- •Duration of the disease of less than 6 months since the diagnosis
- •An upright slow vital capacity ≥ 75% of the predicted value for age, height, and sex or at least one test on inspiratory pressure ≥ 60% of the predicted value for age, height, and sex which could be either maximal inspiratory pressure or a SNIFF test. (The best predictive test is sniff test but sometime patients are not able to do it.) (In case of a limit abnormal value for one of them, it will be recommended that patient re-assessment occurs three months later).
- •A mild functional handicap score for ALSFRS-R ≥36
- •An upright slow vital capacity > 70% of the predicted value for age, height, and sex and
- •Able to swallow (required for oral treatment)
- •Patients weight included between 40 kg and 130 kg
- •If the patient is under riluzole, it has to be for at least 1 month before inclusion with stable dose (to rule out the principal risk of hepatitis)
排除标准
- •Patients with high frequency of comorbidity or vital risks that may reasonably impair life expectancy
- •Progressing axis I psychiatric disorders (psychosis, hallucinations, substance addiction, bipolar disorder, severe depression, suicidal ideation), in accordance with the Diagnostic and Statistical Manual of Mental Disorders. Before entry into the study, exclusion or stabilization of conditions must occur for patients suffering from mild or moderate depressive episodes (not in remission) or severe and uncontrolled anxiety.
- •Dementia according to the Diagnostic and Statistical Manual of Mental Disorders
- •Exposure to any other experimental drug up to 30 days before day 1
- •Due to the risk of agranulocytosis (estimated at 2%) caused by the Investigational Medicinal Products (IMPs) and the unknown mechanism by which this agranulocytosis is induced, combining Deferiprone with other medicinal products known to cause agranulocytosis (as described in the IB) will not be allowed. Such medicinal products include clozapine as well as some NSAIDs (e.g. Phenylbutazone or Metamizole), antithyroid agents, sulfonamide antibiotics or methotrexate.
- •A history of relapsing neutropenia
- •Patients with agranulocytosis or with a history of agranulocytosis.
- •Hypersensitivity to Deferiprone
- •Patients with anaemia (regardless of latter aetiology) or a history of another haematological disease. Haemochromatosis is not an exclusion criterion if controlled.
- •Pregnant or breastfeeding women or women of childbearing potential not taking highly effective contraception.
- •Kidney or liver failure.
- •Inability to provide informed consent.
- •Participation in another clinical trial within 1 month prior to inclusion in the study
- •Patients under trusteeship
研究组 & 干预措施
Deferiprone
Half of participants will receive twice-daily oral deferiprone taken over 12 months.
干预措施: Deferiprone (Drug)
Placebo
Half of participants will receive the placebo Twice-daily oral placebo taken over 12 months
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
CAFS score (Combined Assessment of Function and Survival)
时间窗: at 12 months
CAFS score based on changes in amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) total scores and time to death from baseline (randomization visit) to 12 months
次要结局
- Changes in ALS Functional Rating Scale-Revised (ALSFRS-R) total score(Baseline, at 12 months)
- All-cause and respiratory insufficiency mortality(at 12 months)
- Changes in muscle strength(Baseline, at 12 months)
- Change in the slow vital capacity(Baseline, at 12 months)
- Changes in body weight(Baseline, at 12 months)
- Change in Quality of life(Baseline, at 12 months)
- DSMIV criteria(at 12 months)
- Fronto-Temporal Dementia (FTD) criteria(at 12 months)
- Change in Montreal Cognitive Assessment (MoCA)(Baseline, at 12 months)
- Change in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS)(Baseline, at 12 months)