Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis

Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis: Multicentre, Parallel-group, Placebo-controlled, Randomized Clinical Trial of Deferiprone

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.

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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