<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/NCT03039673</url>
  </required_header>
  <id_info>
    <org_study_id>H2020/PHRC-N/2014/GB-01</org_study_id>
    <secondary_id>No 633413</secondary_id>
    <secondary_id>PHRC-N, 14-0077, 2014</secondary_id>
    <secondary_id>Leigh/Jul15/971-797</secondary_id>
    <nct_id>NCT03039673</nct_id>
  </id_info>
  <brief_title>MIROCALS: Modifying Immune Response and OutComes in ALS</brief_title>
  <acronym>MIROCALS</acronym>
  <official_title>Efficacy and Safety of Low-dose IL-2 (Ld-IL-2) as a Treg Enhancer for Controlling Neuro-inflammation in Newly Diagnosed Amyotrophic Lateral Sclerosis (ALS) Patients: A Randomized, Double-blind, Placebo- Controlled, Phase-II Proof of Concept/ Proof of Mechanism Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Hospitalier Universitaire de Nīmes</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre Hospitalier Universitaire de Nīmes</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>
      MIROCALS is a phase II study of ld-IL-2 as a therapeutic agent for ALS. A randomized (1:1),&#xD;
      placebo-controlled, double-blind, parallel group trial will be carried out to assess ld-IL-2&#xD;
      safety and clinical efficacy on survival and functional decline in newly diagnosed ALS&#xD;
      patients treated for 18 months. Randomization will be stratified according to (i) country (n&#xD;
      = 2 levels: UK, France) and (ii) site of onset (n= 2 levels: bulbar vs limb onset).&#xD;
&#xD;
      The primary objective to evaluate the clinical efficacy and safety of the experimental drug&#xD;
      (ld IL-2) over an 18 months period in order to establish the proof of concept (PoC) that&#xD;
      modifying immune responses through the enhancement of regulatory T cells modifies the rate of&#xD;
      ALS disease progression.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The secondary objectives of MIROCALS are:&#xD;
&#xD;
      To validate a new phase-II study design to improve the efficiency of drug development in ALS&#xD;
      with early determination of drug response using established biomarkers (BMs).&#xD;
&#xD;
      The aims of this new trial design are:&#xD;
&#xD;
      (i) To shorten future trials duration in ALS using an early drug responding surrogate marker&#xD;
      of disease activity; (ii) To establish the proof of mechanism (PoM) of the tested drugs;&#xD;
      (iii) To identify drug responder status.&#xD;
&#xD;
      Additional exploratory objectives are:&#xD;
&#xD;
      (i) Deep immune &amp; inflammatory phenotyping (ii) Brain biomarkers (iii) Genomics and&#xD;
      Transcriptomics&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 19, 2017</start_date>
  <completion_date type="Actual">July 22, 2021</completion_date>
  <primary_completion_date type="Actual">July 22, 2021</primary_completion_date>
  <phase>Phase 2</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to death from date of randomization to date of death</measure>
    <time_frame>Month 21</time_frame>
    <description>Time to death from date of randomization to date of death as documented in death certificates, or date of last documented news for patients lost to follow-up, or 640 days for patients who survive more than 640 days (censoring at 640 days). Death certificates are collected by the centre's principal investigator from the City Hall of the patients' home or birth place.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">304</enrollment>
  <condition>Amyotrophic Lateral Sclerosis</condition>
  <arm_group>
    <arm_group_label>low dose interleukin-2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients randomized to this arm will receive subcutaneous injections of low-dose interleukin-2 in addition to oral Riluzole treatment.&#xD;
Intervention: Riluzole Intervention: IL-2</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients randomized to this arm will receive subcutaneious placebo injections (5% glucose water solution) in addition to oral Riluzole treatment.&#xD;
Intervention: Riluzole Intervention: 5% glucose water solution</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Riluzole</intervention_name>
    <description>All patients will be treated with Riluzole for a period of three months prior to final inclusion and randomization. Riluzole treatment will continue throughout the 18 months of follow-up planned for in this protocol.&#xD;
Riluzole treatment is part of routine care for patients with ALS.</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>low dose interleukin-2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>IL-2</intervention_name>
    <description>The dose of IL-2 to be used in this study will be 2.0 million IU/day.&#xD;
Each treatment course will last 5 days (i.e. 1 sub-cutaneous injection per day for 5 consecutive days). The 5-day course will be repeated every 4-weeks over an 18-month treatment period.&#xD;
In case of intolerance, a flexible dose-reduction schedule is available.</description>
    <arm_group_label>low dose interleukin-2</arm_group_label>
    <other_name>low dose interleukin-2</other_name>
    <other_name>ultra low dose interleukin-2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5% glucose water solution</intervention_name>
    <description>The placebo consists of 5% glucose water solution, which is the matrix with which low-dose IL-2 injections are prepared in the experimental arm. Placebo injections are prepared in exactly the same manner as IL-2 injections, just without the IL-2.&#xD;
Each treatment course will last 5 days (i.e. 1 sub-cutaneous injection per day for 5 consecutive days). The 5-day course will be repeated every 4-weeks over an 18-month treatment period.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Main Inclusion criteria&#xD;
&#xD;
          -  Patient is 18 years old and less than 76 years old&#xD;
&#xD;
          -  Possible, Probable, Probable laboratory-supported or Definite ALS as defined by El&#xD;
             Escorial Revised ALS diagnostic criteria&#xD;
&#xD;
          -  Disease duration &lt;= 24 months&#xD;
&#xD;
          -  Slow Vital capacity &gt;= 70% of normal&#xD;
&#xD;
          -  No prior or present riluzole treatment&#xD;
&#xD;
          -  Lumbar punctures accepted by patient and done&#xD;
&#xD;
        Main Exclusion criteria&#xD;
&#xD;
          -  Other neurodegenerative disease that could explain signs or symptoms&#xD;
&#xD;
          -  Contra indication for lumbar puncture (history of allergy to xylocaine, presence of&#xD;
             contra-indicated treatment, or coagulation test abnormality, clinically significant&#xD;
             coagulopathy or thrombocytopenia)&#xD;
&#xD;
          -  Non authorized treatment&#xD;
&#xD;
          -  Other disease or disorders that could preclude functional assessment, or&#xD;
             life-threatening disorders&#xD;
&#xD;
          -  Any documented, active, past or present, auto-immune disorders except asymptomatic&#xD;
             Hashimoto thyroiditis&#xD;
&#xD;
          -  Using assisted ventilation&#xD;
&#xD;
          -  Feeding through gastrostomy or nasogastric tube&#xD;
&#xD;
          -  Women of child-bearing potential or sexually active man without contraception&#xD;
&#xD;
          -  Pregnant or breast feeding woman&#xD;
&#xD;
          -  Any clinically significant laboratory abnormality (excepting cholesterol,&#xD;
             triglyceride, glucose, CK, ferritin)&#xD;
&#xD;
          -  History of documented symptomatic and treated asthma within the past 5 years&#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>Nigel Leigh, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brighton and Sussex Medical School</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gilbert Bensimon, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Centre Hospitalier Universitaire de Nîmes</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHRU de Lille - Hôpital Roger Salengro</name>
      <address>
        <city>Lille</city>
        <zip>59037</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Limoges - Hôpital Dupuytren</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HCL - Hôpital Neurologique P. Wertheimer</name>
      <address>
        <city>Lyon</city>
        <zip>69677</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>APHM - Hôpital de la Timone</name>
      <address>
        <city>Marseille</city>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU de Montpellier - Hôpital Gui de Chauliac</name>
      <address>
        <city>Montpellier Cedex 5</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Nice - Hôpital Pasteur</name>
      <address>
        <city>Nice</city>
        <zip>06002</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>APHP - Groupe Hospitalier Pitié-Salpetrière</name>
      <address>
        <city>Paris Cedex 13</city>
        <zip>75651</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CENTRE HOSPITALIER DE SAINT BRIEUC - Hôpital Yves Le Foll</name>
      <address>
        <city>Saint Brieuc</city>
        <zip>22027</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Strasbourg - Hôpital de Hautepierre</name>
      <address>
        <city>Strasbourg</city>
        <zip>67098</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU de Tours - Hôpital Bretonneau</name>
      <address>
        <city>Tours</city>
        <zip>37044</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Trafford Centre for Biomedical Research</name>
      <address>
        <city>Brighton</city>
        <zip>BN1 9RY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Neurological Sciences, Queen Elizabeth University Hospital</name>
      <address>
        <city>Glasgow</city>
        <zip>G514TF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North-East London and Essex MND Regional Care Centre</name>
      <address>
        <city>London</city>
        <zip>E1 4NS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King's MND Care and Research Centre</name>
      <address>
        <city>London</city>
        <zip>SE5 8AF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre for Neuromuscular Diseases - National Hospital of Neurology</name>
      <address>
        <city>London</city>
        <zip>WC1N 3BG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Salford Royal NHS Foundation Trust, Neurology Dept</name>
      <address>
        <city>Manchester</city>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheffield Care and Research Centre</name>
      <address>
        <city>Sheffield</city>
        <zip>S10 2JF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>January 31, 2017</study_first_submitted>
  <study_first_submitted_qc>January 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 1, 2017</study_first_posted>
  <last_update_submitted>April 1, 2022</last_update_submitted>
  <last_update_submitted_qc>April 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 11, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>interleukin-2</keyword>
  <keyword>low-dose interleukin-2</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>Interleukin-2</mesh_term>
    <mesh_term>Riluzole</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03039673
org study id: H2020/PHRC-N/2014/GB-01
secondary id: No 633413
secondary id: PHRC-N, 14-0077, 2014
secondary id: Leigh/Jul15/971-797
nct id: NCT03039673
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
MIROCALS is a phase II study of ld-IL-2 as a therapeutic agent for ALS. A randomized (1:1),
      placebo-controlled, double-blind, parallel group trial will be carried out to assess ld-IL-2
      safety and clinical efficacy on survival and functional decline in newly diagnosed ALS
      patients treated for 18 months. Randomization will be stratified according to (i) country (n
      = 2 levels: UK, France) and (ii) site of onset (n= 2 levels: bulbar vs limb onset).

      The primary objective to evaluate the clinical efficacy and safety of the experimental drug
      (ld IL-2) over an 18 months period in order to establish the proof of concept (PoC) that
      modifying immune responses through the enhancement of regulatory T cells modifies the rate of
      ALS disease progression.
The secondary objectives of MIROCALS are:

      To validate a new phase-II study design to improve the efficiency of drug development in ALS
      with early determination of drug response using established biomarkers (BMs).

      The aims of this new trial design are:

      (i) To shorten future trials duration in ALS using an early drug responding surrogate marker
      of disease activity; (ii) To establish the proof of mechanism (PoM) of the tested drugs;
      (iii) To identify drug responder status.

      Additional exploratory objectives are:

      (i) Deep immune & inflammatory phenotyping (ii) Brain biomarkers (iii) Genomics and
      Transcriptomics
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Time to death from date of randomization to date of death
time frame: Month 21
description: Time to death from date of randomization to date of death as documented in death certificates, or date of last documented news for patients lost to follow-up, or 640 days for patients who survive more than 640 days (censoring at 640 days). Death certificates are collected by the centre's principal investigator from the City Hall of the patients' home or birth place.
arm group label: low dose interleukin-2
arm group type: Experimental
description: Patients randomized to this arm will receive subcutaneous injections of low-dose interleukin-2 in addition to oral Riluzole treatment.
Intervention: Riluzole Intervention: IL-2
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients randomized to this arm will receive subcutaneious placebo injections (5% glucose water solution) in addition to oral Riluzole treatment.
Intervention: Riluzole Intervention: 5% glucose water solution
intervention type: Drug
intervention name: Riluzole
description: All patients will be treated with Riluzole for a period of three months prior to final inclusion and randomization. Riluzole treatment will continue throughout the 18 months of follow-up planned for in this protocol.
Riluzole treatment is part of routine care for patients with ALS.
arm group label: Placebo
arm group label: low dose interleukin-2
intervention type: Drug
intervention name: IL-2
description: The dose of IL-2 to be used in this study will be 2.0 million IU/day.
Each treatment course will last 5 days (i.e. 1 sub-cutaneous injection per day for 5 consecutive days). The 5-day course will be repeated every 4-weeks over an 18-month treatment period.
In case of intolerance, a flexible dose-reduction schedule is available.
arm group label: low dose interleukin-2
other name: low dose interleukin-2
other name: ultra low dose interleukin-2
intervention type: Drug
intervention name: 5% glucose water solution
description: The placebo consists of 5% glucose water solution, which is the matrix with which low-dose IL-2 injections are prepared in the experimental arm. Placebo injections are prepared in exactly the same manner as IL-2 injections, just without the IL-2.
Each treatment course will last 5 days (i.e. 1 sub-cutaneous injection per day for 5 consecutive days). The 5-day course will be repeated every 4-weeks over an 18-month treatment period.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Nigel Leigh, MD, PhD
role: Principal Investigator
affiliation: Brighton and Sussex Medical School
last name: Gilbert Bensimon, MD, PhD
role: Study Director
affiliation: Centre Hospitalier Universitaire de Nîmes
facility: 
facility: 
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country: France
country: United Kingdom
responsible party type: Sponsor
mesh term: Motor Neuron Disease
mesh term: Amyotrophic Lateral Sclerosis
mesh term: Sclerosis
mesh term: Interleukin-2
mesh term: Riluzole
sharing ipd: Yes