Clinical trial NCT03293069: Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis
Official title: Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis: Multicentre, Parallel-group, Placebo-controlled, Randomized Clinical Trial of Deferiprone
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Keywords: Conservative Iron Chelation
Disease-modifying Strategy
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2017-09-26
Enrollment: 372
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: CAFS score (Combined Assessment of Function and Survival)
timeFrame: at 12 months
Secondary outcomes:
measure: Changes in ALS Functional Rating Scale-Revised (ALSFRS-R) total score
timeFrame: Baseline, at 12 months
measure: All-cause and respiratory insufficiency mortality
timeFrame: at 12 months
measure: Changes in muscle strength
timeFrame: Baseline, at 12 months
measure: Change in the slow vital capacity
timeFrame: Baseline, at 12 months
measure: Changes in body weight
timeFrame: Baseline, at 12 months
measure: Change in Quality of life
timeFrame: Baseline, at 12 months
measure: DSMIV criteria
timeFrame: at 12 months
measure: Fronto-Temporal Dementia (FTD) criteria
timeFrame: at 12 months
measure: Change in Montreal Cognitive Assessment (MoCA)
timeFrame: Baseline, at 12 months
measure: Change in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS)
timeFrame: Baseline, at 12 months
Other outcomes:
Locations:
city: Angers
country: France
facility: Chr Angers
city: Brest
country: France
facility: Chru Brest
city: Bron
country: France
facility: Hopital Pierre Wertheimer - Hcl - Bron
city: Caen
country: France
facility: Chu Cote de Nacre - Caen
city: Clermont-Ferrand
country: France
facility: Chu de Clermont-Ferrand
city: Lille
country: France
facility: Hôpital Roger Salengro, CHU
city: Limoges
country: France
facility: C H U Dupuytren Limoges
city: Marseille
country: France
facility: Aphm Hopital La Timone
city: Nancy
country: France
facility: Chu de Nancy
city: Nice
country: France
facility: Chu de Nice Hopital Pasteur
city: Paris
country: France
facility: Hu Pitie Salpetriere Aphp
city: Strasbourg
country: France
facility: Hopital de Hautepierre
city: Talence
country: France
facility: Chu de Bordeaux - Talence
city: Toulouse
country: France
facility: Chu Toulouse
city: Tours
country: France
facility: Chu de Tours
Study officials:
affiliation: University Hospital, Lille
name: David Devos, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: