FAIR-ALS II: Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis

Sponsor

University Hospital, Lille (Other)

Overall Status

Recruiting

CT.gov ID

NCT03293069

Collaborator

Ministry of Health, France (Other)

240

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Deferiprone Drug: Placebo Oral Tablet	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

240 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 30, 2019

Anticipated Primary Completion Date :

Nov 1, 2023

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Deferiprone Half of participants will receive twice-daily oral deferiprone taken over 12 months.	Drug: Deferiprone One 600 mg delayed-release tablets of deferiprone twice a day, for at 30 mg/kg/day Other Names: DFP
Placebo Comparator: Placebo Half of participants will receive the placebo Twice-daily oral placebo taken over 12 months	Drug: Placebo Oral Tablet the placebo twice daily morning and evening.

Arm

Intervention/Treatment

Experimental: Deferiprone

Half of participants will receive twice-daily oral deferiprone taken over 12 months.

Drug: Deferiprone

One 600 mg delayed-release tablets of deferiprone twice a day, for at 30 mg/kg/day

Other Names:

DFP

Placebo Comparator: Placebo

Half of participants will receive the placebo Twice-daily oral placebo taken over 12 months

Drug: Placebo Oral Tablet

the placebo twice daily morning and evening.

Outcome Measures

Primary Outcome Measures

CAFS score (Combined Assessment of Function and Survival) [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

Secondary Outcome Measures

Changes in ALS Functional Rating Scale-Revised (ALSFRS-R) total score [Baseline, at 12 months]
All-cause and respiratory insufficiency mortality [at 12 months]
Time to death for all cause or respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥ 23 h per day for 14 consecutive days) from baseline until 12 month
Changes in muscle strength [Baseline, at 12 months]
Muscle strength measurements are determined by the overall mega-score for handheld dynamometry and manual muscular testing with a validated medical device provided
Change in the slow vital capacity [Baseline, at 12 months]
The slow vital capacity is measure by the maximum amount of air that can be exhaled following a deep breath. Reflecting the Respiratory insufficiency.
Changes in body weight [Baseline, at 12 months]
Change in Quality of life [Baseline, at 12 months]
Quality of life assessed using the five-item form of the ALS assessment questionnaire (ALSAQ-5) from baseline to 12 months
DSMIV criteria [at 12 months]
Dementia (yes/no)
Fronto-Temporal Dementia (FTD) criteria [at 12 months]
Using the revised guidelines for the diagnosis of behavioral variant frontotemporal dementia based on recent literature and collective experience by Rascovsky K et al 2011; Lamarre AK et al 2013
Change in Montreal Cognitive Assessment (MoCA) [Baseline, at 12 months]
MoCA evaluated of mild cognitive dysfunction.
Change in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) [Baseline, at 12 months]
ECAS determine cognitive and behavioral changes of patients suffering from Amyotrophic Lateral Sclerosis. With ECAS, ALS-specific (fluency, executive functions and social cognition, language) and ALS-nonspecific (memory, visuospatial functions) functions can be analyzed to enable the distinction from other diseases with cognitive and behavioral impairments.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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
If the patient is under riluzole, it has to be for at least 1 month (to rule out the principal risk of hepatitis; neutropenia is exceptional)
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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Chr Angers	Angers	France
2	Chru Brest	Brest	France
3	Hopital Pierre Wertheimer - Hcl - Bron	Bron	France
4	Chu Cote de Nacre - Caen	Caen	France
5	Chu de Clermont-Ferrand	Clermont-Ferrand	France
6	Hôpital Roger Salengro, CHU	Lille	France	59000
7	C H U Dupuytren Limoges	Limoges	France
8	Aphm Hopital La Timone	Marseille	France
9	Chu de Nancy	Nancy	France
10	Chu de Nice Hopital Pasteur	Nice	France
11	Hu Pitie Salpetriere Aphp	Paris	France	75013
12	Hopital de Hautepierre	Strasbourg	France	67091
13	Chu de Bordeaux - Talence	Talence	France
14	Chu Toulouse	Toulouse	France	31300
15	Chu de Tours	Tours	France