<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03293069</url>
  </required_header>
  <id_info>
    <org_study_id>2016_76</org_study_id>
    <secondary_id>2017-003763-35</secondary_id>
    <nct_id>NCT03293069</nct_id>
  </id_info>
  <brief_title>Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis</brief_title>
  <acronym>FAIR-ALS II</acronym>
  <official_title>Conservative Iron Chelation as a Disease-modifying Strategy in Amyotrophic Lateral Sclerosis: Multicentre, Parallel-group, Placebo-controlled, Randomized Clinical Trial of Deferiprone</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Lille</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, France</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Lille</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The alteration of iron metabolism is reported in animal models of amyotrophic lateral&#xD;
      sclerosis (ALS) as well as in sporadic and genetic forms (SOD1 and C9orf72) of ALS. The high&#xD;
      iron concentration of the brain, due to its high energy demand (high oxygen consumption),&#xD;
      makes motor neurons particularly vulnerable to energy deficit and oxidative stress.&#xD;
      Post-mortem examinations and MRI scans in patients with ALS have found signs of iron&#xD;
      accumulation in the central motor tract; and a high level of serum ferritin, which is a&#xD;
      marker of iron levels, is associated with a lower prognosis. In ALS mouse models, the use of&#xD;
      iron chelators has demonstrated neuroprotection and increased life expectancy, suggesting&#xD;
      that elimination of excess iron from the brain can prevent neuronal loss and, consequently, a&#xD;
      slow progression of the disease. Conservative chelation of iron refers to a modality whereby&#xD;
      much of the iron that binds to the chelator is redistributed in the body rather than&#xD;
      exhausted. Using a chelator, deferiprone, with this feature, in a safety pilot study, a very&#xD;
      good safety profile was observed. Deferiprone eliminated excess iron from brain regions,&#xD;
      reduced oxidative damage and cell death associated with regional iron deposits with no&#xD;
      apparent negative impact on the iron levels needed. Now, the efficacy of this new therapeutic&#xD;
      modality of neuroprotection is being evaluated in a randomized, double-blind,&#xD;
      placebo-controlled, multicenter study.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 1, 2019</start_date>
  <completion_date type="Anticipated">November 2023</completion_date>
  <primary_completion_date type="Anticipated">November 2023</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>CAFS score (Combined Assessment of Function and Survival)</measure>
    <time_frame>at 12 months</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in ALS Functional Rating Scale-Revised (ALSFRS-R) total score</measure>
    <time_frame>Baseline, at 12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause and respiratory insufficiency mortality</measure>
    <time_frame>at 12 months</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in muscle strength</measure>
    <time_frame>Baseline, at 12 months</time_frame>
    <description>Muscle strength measurements are determined by the overall mega-score for handheld dynamometry and manual muscular testing with a validated medical device provided</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the slow vital capacity</measure>
    <time_frame>Baseline, at 12 months</time_frame>
    <description>The slow vital capacity is measure by the maximum amount of air that can be exhaled following a deep breath. Reflecting the Respiratory insufficiency.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in body weight</measure>
    <time_frame>Baseline, at 12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Quality of life</measure>
    <time_frame>Baseline, at 12 months</time_frame>
    <description>Quality of life assessed using the five-item form of the ALS assessment questionnaire (ALSAQ-5) from baseline to 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DSMIV criteria</measure>
    <time_frame>at 12 months</time_frame>
    <description>Dementia (yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fronto-Temporal Dementia (FTD) criteria</measure>
    <time_frame>at 12 months</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Montreal Cognitive Assessment (MoCA)</measure>
    <time_frame>Baseline, at 12 months</time_frame>
    <description>MoCA evaluated of mild cognitive dysfunction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS)</measure>
    <time_frame>Baseline, at 12 months</time_frame>
    <description>ECAS determine cognitive and behavioral changes of patients suffering from Amyotrophic Lateral Sclerosis.&#xD;
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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">372</enrollment>
  <condition>Amyotrophic Lateral Sclerosis</condition>
  <arm_group>
    <arm_group_label>Deferiprone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Half of participants will receive twice-daily oral deferiprone taken over 12 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Half of participants will receive the placebo Twice-daily oral placebo taken over 12 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Deferiprone</intervention_name>
    <description>One 600 mg delayed-release tablets of deferiprone twice a day, for at 30 mg/kg/day</description>
    <arm_group_label>Deferiprone</arm_group_label>
    <other_name>DFP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>the placebo twice daily morning and evening.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Categorized as; possible, laboratory supported probable, probable, or definite ALS&#xD;
             (revised El Escorial criteria)&#xD;
&#xD;
          -  Spinal and bulbar forms of ALS&#xD;
&#xD;
          -  Duration of the disease of less than 18 months since the first symptoms of motor&#xD;
             deficit or amyotrophy (isolated cramps or fasciculation will not be considered).&#xD;
&#xD;
          -  Duration of the disease of less than 6 months since the diagnosis&#xD;
&#xD;
          -  An upright slow vital capacity ≥ 75% of the predicted value for age, height, and sex&#xD;
             or at least one test on inspiratory pressure ≥ 60% of the predicted value for age,&#xD;
             height, and sex which could be either maximal inspiratory pressure or a SNIFF test.&#xD;
             (The best predictive test is sniff test but sometime patients are not able to do it.)&#xD;
             (In case of a limit abnormal value for one of them, it will be recommended that&#xD;
             patient re-assessment occurs three months later).&#xD;
&#xD;
          -  A mild functional handicap score for ALSFRS-R ≥36&#xD;
&#xD;
          -  An upright slow vital capacity &gt; 70% of the predicted value for age, height, and sex&#xD;
             and&#xD;
&#xD;
          -  Able to swallow (required for oral treatment)&#xD;
&#xD;
          -  Patients weight included between 40 kg and 130 kg&#xD;
&#xD;
          -  If the patient is under riluzole, it has to be for at least 1 month before inclusion&#xD;
             with stable dose (to rule out the principal risk of hepatitis)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with high frequency of comorbidity or vital risks that may reasonably impair&#xD;
             life expectancy&#xD;
&#xD;
          -  Progressing axis I psychiatric disorders (psychosis, hallucinations, substance&#xD;
             addiction, bipolar disorder, severe depression, suicidal ideation), in accordance with&#xD;
             the Diagnostic and Statistical Manual of Mental Disorders. Before entry into the&#xD;
             study, exclusion or stabilization of conditions must occur for patients suffering from&#xD;
             mild or moderate depressive episodes (not in remission) or severe and uncontrolled&#xD;
             anxiety.&#xD;
&#xD;
          -  Dementia according to the Diagnostic and Statistical Manual of Mental Disorders&#xD;
&#xD;
          -  Exposure to any other experimental drug up to 30 days before day 1&#xD;
&#xD;
          -  Due to the risk of agranulocytosis (estimated at 2%) caused by the Investigational&#xD;
             Medicinal Products (IMPs) and the unknown mechanism by which this agranulocytosis is&#xD;
             induced, combining Deferiprone with other medicinal products known to cause&#xD;
             agranulocytosis (as described in the IB) will not be allowed. Such medicinal products&#xD;
             include clozapine as well as some NSAIDs (e.g. Phenylbutazone or Metamizole),&#xD;
             antithyroid agents, sulfonamide antibiotics or methotrexate.&#xD;
&#xD;
          -  A history of relapsing neutropenia&#xD;
&#xD;
          -  Patients with agranulocytosis or with a history of agranulocytosis.&#xD;
&#xD;
          -  Hypersensitivity to Deferiprone&#xD;
&#xD;
          -  Patients with anaemia (regardless of latter aetiology) or a history of another&#xD;
             haematological disease. Haemochromatosis is not an exclusion criterion if controlled.&#xD;
&#xD;
          -  Pregnant or breastfeeding women or women of childbearing potential not taking highly&#xD;
             effective contraception.&#xD;
&#xD;
          -  Kidney or liver failure.&#xD;
&#xD;
          -  Inability to provide informed consent.&#xD;
&#xD;
          -  Participation in another clinical trial within 1 month prior to inclusion in the study&#xD;
&#xD;
          -  Patients under trusteeship&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Devos, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Lille</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Chr Angers</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chru Brest</name>
      <address>
        <city>Brest</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Pierre Wertheimer - Hcl - Bron</name>
      <address>
        <city>Bron</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu Cote de Nacre - Caen</name>
      <address>
        <city>Caen</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu de Clermont-Ferrand</name>
      <address>
        <city>Clermont-Ferrand</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Roger Salengro, CHU</name>
      <address>
        <city>Lille</city>
        <zip>59000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C H U Dupuytren Limoges</name>
      <address>
        <city>Limoges</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aphm Hopital La Timone</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu de Nancy</name>
      <address>
        <city>Nancy</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu de Nice Hopital Pasteur</name>
      <address>
        <city>Nice</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hu Pitie Salpetriere Aphp</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital de Hautepierre</name>
      <address>
        <city>Strasbourg</city>
        <zip>67091</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu de Bordeaux - Talence</name>
      <address>
        <city>Talence</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu Toulouse</name>
      <address>
        <city>Toulouse</city>
        <zip>31300</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu de Tours</name>
      <address>
        <city>Tours</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>September 21, 2017</study_first_submitted>
  <study_first_submitted_qc>September 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 26, 2017</study_first_posted>
  <last_update_submitted>November 4, 2022</last_update_submitted>
  <last_update_submitted_qc>November 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Conservative Iron Chelation</keyword>
  <keyword>Disease-modifying Strategy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Motor Neuron Disease</mesh_term>
    <mesh_term>Amyotrophic Lateral Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Deferiprone</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03293069
org study id: 2016_76
secondary id: 2017-003763-35
nct id: NCT03293069
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: CAFS score (Combined Assessment of Function and Survival)
time frame: at 12 months
description: 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
measure: Changes in ALS Functional Rating Scale-Revised (ALSFRS-R) total score
time frame: Baseline, at 12 months
measure: All-cause and respiratory insufficiency mortality
time frame: at 12 months
description: 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
measure: Changes in muscle strength
time frame: Baseline, at 12 months
description: Muscle strength measurements are determined by the overall mega-score for handheld dynamometry and manual muscular testing with a validated medical device provided
measure: Change in the slow vital capacity
time frame: Baseline, at 12 months
description: The slow vital capacity is measure by the maximum amount of air that can be exhaled following a deep breath. Reflecting the Respiratory insufficiency.
measure: Changes in body weight
time frame: Baseline, at 12 months
measure: Change in Quality of life
time frame: Baseline, at 12 months
description: Quality of life assessed using the five-item form of the ALS assessment questionnaire (ALSAQ-5) from baseline to 12 months
measure: DSMIV criteria
time frame: at 12 months
description: Dementia (yes/no)
measure: Fronto-Temporal Dementia (FTD) criteria
time frame: at 12 months
description: 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
measure: Change in Montreal Cognitive Assessment (MoCA)
time frame: Baseline, at 12 months
description: MoCA evaluated of mild cognitive dysfunction.
measure: Change in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS)
time frame: Baseline, at 12 months
description: 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.
arm group label: Deferiprone
arm group type: Experimental
description: Half of participants will receive twice-daily oral deferiprone taken over 12 months.
arm group label: Placebo
arm group type: Placebo Comparator
description: Half of participants will receive the placebo Twice-daily oral placebo taken over 12 months
intervention type: Drug
intervention name: Deferiprone
description: One 600 mg delayed-release tablets of deferiprone twice a day, for at 30 mg/kg/day
arm group label: Deferiprone
other name: DFP
intervention type: Drug
intervention name: Placebo Oral Tablet
description: the placebo twice daily morning and evening.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: David Devos, MD,PhD
role: Principal Investigator
affiliation: University Hospital, Lille
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Motor Neuron Disease
mesh term: Amyotrophic Lateral Sclerosis
mesh term: Sclerosis
mesh term: Deferiprone