<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/NCT02263638</url>
  </required_header>
  <id_info>
    <org_study_id>2014-000609-10</org_study_id>
    <secondary_id>35RC13_8811_THERA</secondary_id>
    <nct_id>NCT02263638</nct_id>
  </id_info>
  <brief_title>Treatment of Refractory Hemochromatosis Rheumatism by Anakinra: a Preliminary Phase II Study</brief_title>
  <acronym>THERA</acronym>
  <official_title>Treatment of Refractory Hemochromatosis Rheumatism by Anakinra: a Preliminary Phase II Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rennes University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rennes University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Treatment of refractory hemochromatosis rheumatism by Anakinra. Prospective, multicenter,&#xD;
      non-randomised, single-arm, open-label, phase II trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hereditary hemochromatosis (HH) is a genetic disease characterized by tissue iron overload.&#xD;
      The most common genotype is homozygosity for the p.Cys282Tyr mutation of the HFE gene (MIM&#xD;
      235200). It is a serious disease which can lead to life threatening complications such as&#xD;
      cirrhosis, liver carcinoma, heart failure or diabetes mellitus. Currently, these&#xD;
      complications can be prevented by phlebotomies. Two-thirds of patients complain of joint&#xD;
      symptoms which represent a major cause of impaired quality of life. Phlebotomies are&#xD;
      ineffective on HH rheumatism and patients' quality of life is very often altered while life&#xD;
      threatening complications are prevented. Furthermore, there is a significant higher risk for&#xD;
      joint replacement surgery in these patients compared to controls (X 9). There is currently no&#xD;
      approved treatment for hemochromatosis rheumatism. As it looks like severe osteoarthritis,&#xD;
      calcium pyrophosphate deposition disease (CPDD) or chondrocalcinosis, symptomatic treatments&#xD;
      are employed such as analgesics (type I or II), non-steroidal anti-inflammatory drugs or&#xD;
      colchicine in case of acute joint flare, corticosteroids intra-articular injections or&#xD;
      occasionally oral glucocorticoids. However in some cases these treatments remain ineffective&#xD;
      leading to a true disability.&#xD;
&#xD;
      Frequently, there are local inflammatory symptoms. Interleukin 1ß (IL1ß) plays a key role in&#xD;
      the pathogenesis of crystal arthropathies (CPDD or gout).&#xD;
&#xD;
      Anakinra (IL-1Ra), a drug approved in France for rheumatoid arthritis, has been tested in&#xD;
      short series or case controls in refractory gout, CPDD and only in two patients with HH&#xD;
      rheumatism. The aim of this phase II study is to test the efficacy of anakinra in patients&#xD;
      with hemochromatosis and refractory joint pain. It is also to evaluate the opportunity to&#xD;
      perform a phase III trial. In the absence of available data on the evolution of this&#xD;
      rheumatism treated by anakinra in this population of patients resistant to standard therapy,&#xD;
      the investigators consider that a phase III trial would not be justifiable if the rate of&#xD;
      success is insufficient.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Poor recruitment&#xD;
  </why_stopped>
  <start_date type="Actual">February 4, 2015</start_date>
  <completion_date type="Actual">September 4, 2018</completion_date>
  <primary_completion_date type="Actual">September 4, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of patients with improvement of joint pain</measure>
    <time_frame>Day 15</time_frame>
    <description>Improvement is defined as the minimal clinically important improvement of joint pain and is assessed on a 0-100 mm visual analogue scale (VAS)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of the disease activity</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
    <description>Assessment of the disease activity by Visual analog scale (VAS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the number of painful joints</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
    <description>Assessment of the number of painful joints by a clinical exam</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the number of swollen joints</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
    <description>Assessment of the number of swollen joints by a clinical exam</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of analgesics consumption</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of non-steroidal anti-inflammatory drugs (NSAID) consumption</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of colchicine consumption</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of steroids injections consumption</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the quality of life</measure>
    <time_frame>Day 0, day 15, day 30, day 90</time_frame>
    <description>Assessment of the quality of life by the SF36 questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the quality of life</measure>
    <time_frame>Day 0, day 15, day 30, day 90</time_frame>
    <description>Assessment of the quality of life by the HAQ questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional evaluation</measure>
    <time_frame>Day 0, day 15, day 30, day 90</time_frame>
    <description>Functional evaluation by WOMAC index for hip and knee</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional evaluation</measure>
    <time_frame>Day 0, day 15, day 30, day 90</time_frame>
    <description>Functional evaluation by Dreiser index for hands</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of joint damage</measure>
    <time_frame>Day 0, day 90</time_frame>
    <description>Assessment of joint damage by X-rays and Doppler ultrasound</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Synovial fluid analysis</measure>
    <time_frame>3 months</time_frame>
    <description>Puncture if acute joint effusion : cells count</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Synovial fluid analysis</measure>
    <time_frame>3 months</time_frame>
    <description>Puncture if acute joint effusion : search for crystals presence</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Synovial fluid analysis</measure>
    <time_frame>3 months</time_frame>
    <description>Puncture if acute joint effusion : iron parameters markers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biological effects on inflammation and iron metabolism</measure>
    <time_frame>Day 0, day 15, day 30, day 60, day 90</time_frame>
    <description>Biological/Vaccine : iron and inflammatory markers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time at which Cmax of anakinra was observed (Tmax)</measure>
    <time_frame>Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose</time_frame>
    <description>Pharmacokinetics study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum observed concentration (Cmax) of anakinra</measure>
    <time_frame>Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose</time_frame>
    <description>Pharmacokinetics study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-life (T1/2) of anakinra</measure>
    <time_frame>Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose</time_frame>
    <description>Pharmacokinetics study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve of time 0 to the last detectable concentration (AUC0-last) of anakinra</measure>
    <time_frame>Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose</time_frame>
    <description>Pharmacokinetics study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve of time 0 to infinity (AUC0-∞) of anakinra</measure>
    <time_frame>Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose</time_frame>
    <description>Pharmacokinetics study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma clearance after administration (CL/F) of anakinra</measure>
    <time_frame>Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose</time_frame>
    <description>Pharmacokinetics study</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Refractory Hemochromatosis Rheumatism</condition>
  <arm_group>
    <arm_group_label>Anakinra</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One daily subcutaneous injection of a fixed dose of 100 mg will be administered at a fixed time by a nurse during a five day period</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra</intervention_name>
    <description>One daily subcutaneous injection of a fixed dose of 100 mg will be administered at a fixed time during a five day period</description>
    <arm_group_label>Anakinra</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with age equal to or over 18 years old,&#xD;
&#xD;
          -  Patients with proved hereditary hemochromatosis with homozygosity for the C282Y&#xD;
             mutation of the HFE gene,&#xD;
&#xD;
          -  Patients with rheumatism related to hemochromatosis, considered by the rheumatologist&#xD;
             refractory to usual treatment defined by a persistent painful symptomatology despite a&#xD;
             treatment of at least one month with level 2 analgesics (weak opioids) at maximal&#xD;
             dose, NSAID, colchicine, steroid injection or a combination of these treatments,&#xD;
&#xD;
          -  Patients with pain &gt; 40/100mm measured by VAS (pain of the last 48 hours),&#xD;
&#xD;
          -  Effective contraception to be used during treatment and until 48h after the last&#xD;
             administration for women of reproductive age,&#xD;
&#xD;
          -  Patients who have given written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Other cause of inflammatory rheumatisms such as Rheumatoid Arthritis,&#xD;
             Spondyloarthropathies, psoriatic arthritis, or systemic diseases,&#xD;
&#xD;
          -  Ongoing treatment with Methotrexate, Hydroxychloroquine, biologic or immunosuppressive&#xD;
             drugs&#xD;
&#xD;
          -  Malignant pathology, monoclonal gammopathy,&#xD;
&#xD;
          -  Intolerance to anakinra,&#xD;
&#xD;
          -  Contraindications to the use of anakinra: pregnancy or breastfeeding, hypersensitivity&#xD;
             to any of the excipients or to proteins from E. coli, severe renal impairment&#xD;
             (creatinine clearance &lt;30 ml / minute), neutropenia (neutrophil count &lt;1.5 x 109 / l),&#xD;
             ongoing infection&#xD;
&#xD;
          -  Patients that cannot follow the protocol,&#xD;
&#xD;
          -  Persons subject to major legal protection (safeguarding justice, guardianship,&#xD;
             trusteeship), persons deprived of liberty.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pascal Richette</last_name>
    <role>Principal Investigator</role>
    <affiliation>Groupe Hospitalier Lariboisière - Paris</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pascal Guggenbuhl</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rennes University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHRU de Lille</name>
      <address>
        <city>Lille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Groupe Hospitalier Lariboisière</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rennes University Hospital</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>October 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <last_update_submitted>March 8, 2019</last_update_submitted>
  <last_update_submitted_qc>March 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 12, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>hereditary haemochromatosis</keyword>
  <keyword>rheumatism</keyword>
  <keyword>anakinra</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rheumatic Diseases</mesh_term>
    <mesh_term>Hemochromatosis</mesh_term>
    <mesh_term>Collagen Diseases</mesh_term>
    <mesh_term>Hemosiderosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interleukin 1 Receptor Antagonist Protein</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/NCT02263638
org study id: 2014-000609-10
secondary id: 35RC13_8811_THERA
nct id: NCT02263638
lead sponsor: 
has dmc: No
Treatment of refractory hemochromatosis rheumatism by Anakinra. Prospective, multicenter,
      non-randomised, single-arm, open-label, phase II trial.
Hereditary hemochromatosis (HH) is a genetic disease characterized by tissue iron overload.
      The most common genotype is homozygosity for the p.Cys282Tyr mutation of the HFE gene (MIM
      235200). It is a serious disease which can lead to life threatening complications such as
      cirrhosis, liver carcinoma, heart failure or diabetes mellitus. Currently, these
      complications can be prevented by phlebotomies. Two-thirds of patients complain of joint
      symptoms which represent a major cause of impaired quality of life. Phlebotomies are
      ineffective on HH rheumatism and patients' quality of life is very often altered while life
      threatening complications are prevented. Furthermore, there is a significant higher risk for
      joint replacement surgery in these patients compared to controls (X 9). There is currently no
      approved treatment for hemochromatosis rheumatism. As it looks like severe osteoarthritis,
      calcium pyrophosphate deposition disease (CPDD) or chondrocalcinosis, symptomatic treatments
      are employed such as analgesics (type I or II), non-steroidal anti-inflammatory drugs or
      colchicine in case of acute joint flare, corticosteroids intra-articular injections or
      occasionally oral glucocorticoids. However in some cases these treatments remain ineffective
      leading to a true disability.

      Frequently, there are local inflammatory symptoms. Interleukin 1ß (IL1ß) plays a key role in
      the pathogenesis of crystal arthropathies (CPDD or gout).

      Anakinra (IL-1Ra), a drug approved in France for rheumatoid arthritis, has been tested in
      short series or case controls in refractory gout, CPDD and only in two patients with HH
      rheumatism. The aim of this phase II study is to test the efficacy of anakinra in patients
      with hemochromatosis and refractory joint pain. It is also to evaluate the opportunity to
      perform a phase III trial. In the absence of available data on the evolution of this
      rheumatism treated by anakinra in this population of patients resistant to standard therapy,
      the investigators consider that a phase III trial would not be justifiable if the rate of
      success is insufficient.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of patients with improvement of joint pain
time frame: Day 15
description: Improvement is defined as the minimal clinically important improvement of joint pain and is assessed on a 0-100 mm visual analogue scale (VAS)
measure: Assessment of the disease activity
time frame: Day 0, day 15, day 30, day 60, day 90
description: Assessment of the disease activity by Visual analog scale (VAS)
measure: Assessment of the number of painful joints
time frame: Day 0, day 15, day 30, day 60, day 90
description: Assessment of the number of painful joints by a clinical exam
measure: Assessment of the number of swollen joints
time frame: Day 0, day 15, day 30, day 60, day 90
description: Assessment of the number of swollen joints by a clinical exam
measure: Assessment of analgesics consumption
time frame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of non-steroidal anti-inflammatory drugs (NSAID) consumption
time frame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of colchicine consumption
time frame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of steroids injections consumption
time frame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of the quality of life
time frame: Day 0, day 15, day 30, day 90
description: Assessment of the quality of life by the SF36 questionnaire
measure: Assessment of the quality of life
time frame: Day 0, day 15, day 30, day 90
description: Assessment of the quality of life by the HAQ questionnaire
measure: Functional evaluation
time frame: Day 0, day 15, day 30, day 90
description: Functional evaluation by WOMAC index for hip and knee
measure: Functional evaluation
time frame: Day 0, day 15, day 30, day 90
description: Functional evaluation by Dreiser index for hands
measure: Assessment of joint damage
time frame: Day 0, day 90
description: Assessment of joint damage by X-rays and Doppler ultrasound
measure: Synovial fluid analysis
time frame: 3 months
description: Puncture if acute joint effusion : cells count
measure: Synovial fluid analysis
time frame: 3 months
description: Puncture if acute joint effusion : search for crystals presence
measure: Synovial fluid analysis
time frame: 3 months
description: Puncture if acute joint effusion : iron parameters markers
measure: Biological effects on inflammation and iron metabolism
time frame: Day 0, day 15, day 30, day 60, day 90
description: Biological/Vaccine : iron and inflammatory markers
measure: Time at which Cmax of anakinra was observed (Tmax)
time frame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
description: Pharmacokinetics study
measure: Maximum observed concentration (Cmax) of anakinra
time frame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
description: Pharmacokinetics study
measure: Half-life (T1/2) of anakinra
time frame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
description: Pharmacokinetics study
measure: Area under the concentration-time curve of time 0 to the last detectable concentration (AUC0-last) of anakinra
time frame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
description: Pharmacokinetics study
measure: Area under the concentration-time curve of time 0 to infinity (AUC0-∞) of anakinra
time frame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
description: Pharmacokinetics study
measure: Plasma clearance after administration (CL/F) of anakinra
time frame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
description: Pharmacokinetics study
arm group label: Anakinra
arm group type: Experimental
description: One daily subcutaneous injection of a fixed dose of 100 mg will be administered at a fixed time by a nurse during a five day period
intervention type: Drug
intervention name: Anakinra
description: One daily subcutaneous injection of a fixed dose of 100 mg will be administered at a fixed time during a five day period
arm group label: Anakinra
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pascal Richette
role: Principal Investigator
affiliation: Groupe Hospitalier Lariboisière - Paris
last name: Pascal Guggenbuhl
role: Principal Investigator
affiliation: Rennes University Hospital
facility: 
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Rheumatic Diseases
mesh term: Hemochromatosis
mesh term: Collagen Diseases
mesh term: Hemosiderosis
mesh term: Interleukin 1 Receptor Antagonist Protein