<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/NCT02213653</url>
  </required_header>
  <id_info>
    <org_study_id>FERASE</org_study_id>
    <nct_id>NCT02213653</nct_id>
  </id_info>
  <brief_title>Randomized Study Evaluating Agents Stimulants Erythropoiesis (ASE) Associated With Ferric Carboxymaltose (Ferinject ®) in Concomitant or Sequential Patients Treated for Cancer and With Anemia Associated With Functional Iron Deficiency</brief_title>
  <official_title>Phase IV Randomized Study Evaluating Agents Stimulants Erythropoiesis (ASE) Associated With Ferric Carboxymaltose (Ferinject ®) in Concomitant or Sequential Patients Treated for Cancer and With Anemia Associated With Functional Iron Deficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Francois Baclesse</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospira, now a wholly owned subsidiary of Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Roche Pharma AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Vifor Pharma</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Centre Francois Baclesse</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Anemia in patients with cancer is a common problem associated with an impaired quality of&#xD;
      life.&#xD;
&#xD;
      Treatment with erythropoiesis stimulating agents (ESA) allows an increase in hemoglobin&#xD;
      levels in 40-70% of patients and decreased transfusion requirements.&#xD;
&#xD;
      Absolute or functional iron deficiency is also common with about 30% of cancer patients with&#xD;
      all histologies combined iron deficiency and anemia.&#xD;
&#xD;
      Several studies have shown the benefits of the combination of intravenous iron to&#xD;
      erythropoiesis-stimulating agents in improving hemoglobin. However, none of them, to the&#xD;
      investigators knowledge, has not been specifically performed on a population of patients with&#xD;
      functional iron deficiency.&#xD;
&#xD;
      In addition, in clinical practice, this association is not carried out in particular because&#xD;
      there is no dosage or consensus sequence for the administration of iron associated with ESAs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      - Iron Deficiency and Cancer The literature review therefore presents uncertainties do not&#xD;
      allow the routine application of intravenous iron associated with ESAs. The SOR also conclude&#xD;
      that IV iron is &quot;consider&quot; if iron deficiency.&#xD;
&#xD;
      These uncertainties are the heterogeneity of the study populations, contradictory results and&#xD;
      the use of patterns intravenous iron binding and non-standardized.&#xD;
&#xD;
      The investigators focus in this study in patients with chemotherapy-induced anemia with&#xD;
      functional iron deficiency is a cause of lack of response to ESA. Indeed, patients with true&#xD;
      iron deficiency seems to justify a routine iron supplementation. In contrast, patients&#xD;
      without iron deficiency do not warrant formal way of initiating such treatment (although the&#xD;
      literature is contradictory).&#xD;
&#xD;
      This study aims to evaluate, in patients with chemotherapy-induced anemia and functional iron&#xD;
      deficiency, the efficacy and safety of the combination epoietin zeta + Iron in concomitant&#xD;
      intravenous or sequential.&#xD;
&#xD;
      Because data RCP (Summary of Product Characteristics), ease of use, its safety profile, the&#xD;
      ability to achieve higher doses of iron with a lower frequency and with better adherence, the&#xD;
      ferric carboxymaltose was chosen as an intravenous iron. One specialty is available, the&#xD;
      Ferinject ® (Laboratoires VIFOR Pharma).&#xD;
&#xD;
      The erythropoiesis-stimulating agent chosen in this study is epoietin zeta.&#xD;
&#xD;
      - Hepcidin and iron Hepcidin is a peptide hormone of 25 amino acids produced by the liver and&#xD;
      considered as the central regulator of iron homeostasis in the body.&#xD;
&#xD;
      It works by controlling intestinal iron absorption and iron reuse by the reticuloendothelial&#xD;
      system. Hepcidin acts by preventing the export of iron enterocytes, intestinal site of&#xD;
      absorption of dietary iron, and macrophages, iron recycling site of hemoglobin, by binding to&#xD;
      ferroportin present at the membrane these cells and by inducing its internalization and&#xD;
      degradation.&#xD;
&#xD;
      Accordingly, hepcidin can be considered a hyposidérémiante hormone. The hepcidin rate is&#xD;
      increased by the iron thereby limiting its accumulation and tissue damage associated with&#xD;
      iron overload. Inversely, the rate is reduced hepcidin during increased iron as anemia needs,&#xD;
      hypoxia, pregnancy or other situations of iron deficiency.&#xD;
&#xD;
      Moreover, hepcidin is strongly induced by inflammation. Thus, in pathological situations such&#xD;
      as cancer, high levels of hepcidin explain well enough inflammatory anemia characterized by&#xD;
      anemia, iron retention at storage proteins such as ferritin but also at the level of the&#xD;
      reticuloendothelial system endothelial and a decrease in intestinal iron absorption.&#xD;
&#xD;
      Despite its importance in the pathophysiology of anemia of inflammation and a fortiori with&#xD;
      iron deficiency anemia functional hepcidin is not measured in clinical routine. There is not,&#xD;
      to the investigators knowledge, prospective data on its blood levels in situations of iron&#xD;
      deficiency anemia in cancer patients functional and data on changes in hepcidin levels&#xD;
      induced by treatment with intravenous iron or with erythropoietin.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <start_date>April 2013</start_date>
  <completion_date type="Actual">November 2014</completion_date>
  <primary_completion_date type="Actual">November 2014</primary_completion_date>
  <phase>Phase 4</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with hematopoietic response at 10 weeks.</measure>
    <time_frame>The rate of hematopoietic response will be evaluated 10 weeks</time_frame>
    <description>The primary objective is to evaluate the rate of hematopoietic response to 10 weeks in patients with anemia and functional iron deficiency treated epoietin zeta + carboxymaltose concomitant IV iron, by epoietin zeta + carboxymaltose IV ferric sequential or epoietin zeta alone</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of transfusion requirements</measure>
    <time_frame>The number of transfusions will be evaluated weekly Week 1-16</time_frame>
    <description>The secondary objective is to assess transfusion requirements will be evaluated throughout the study</description>
  </secondary_outcome>
  <other_outcome>
    <measure>The hematopoietic response at 6 and 16 weeks</measure>
    <time_frame>The hematopoietic response will be evaluated at 6 and 16 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>The time to achieve the therapeutic goal (hemoglobin&gt; 12g/dl or increase in hemoglobin&gt; 2g/dl)</measure>
    <time_frame>The time to achieve the therapeutic goal will be determine 6,10 and 16 weeks after treatment start</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Quality of life</measure>
    <time_frame>Quality of life will be evaluated 6,10 and 16 weeks after treatment start</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>The consumption of erythropoiesis stimulating agent</measure>
    <time_frame>The consumption of erythropoiesis stimulating agent will be evaluated 6,10 and 16 weeks after treatment start</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>The mean increase in hemoglobin concentration</measure>
    <time_frame>The mean increase in hemoglobin concentration will be evaluated weekly Week 1-16</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>The evolution of the iron status parameters</measure>
    <time_frame>The evolution of the iron status parameters will be performed at weeks 4,6,10,13 and 16</time_frame>
    <description>Ferritin, CST, soluble transferrin receptor, reticulocytes, CRP will be dosed at weeks 4,6,10,13 and 16</description>
  </other_outcome>
  <other_outcome>
    <measure>Tolerance</measure>
    <time_frame>Tolerance will be evaluated at weeks 6, 10 and 16</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Fatigue</measure>
    <time_frame>Fatigue will be evaluated 6,10 and 16 weeks after treatment start</time_frame>
    <description>Fatigue will be estimated with the generic scale FACT-G</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Solid Cancer Metastatic Disease</condition>
  <condition>Lymphoid Disease</condition>
  <arm_group>
    <arm_group_label>Concomitant iron and I.V. epoietin zeta</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Iron and I.V. epoietin zeta sequential</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Epoietin zeta</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ARM A : IV iron + epoietin zeta</intervention_name>
    <description>Epoietin zeta at a dose of 450 IU / kg per week subcutaneously&#xD;
Carboxymaltose ferric (Ferinject ®) at week 1; Intravenous infusion not exceeding 1000 mg (administered once if weight&gt; 50 kg, 500 mg twice otherwise, with an interval of one week between each administration).&#xD;
Renewable with a minimum of 4 weeks depending on the iron status (if CST &lt;20% and absence of serum ferritin&gt; 800) in the same manner as week 1.</description>
    <arm_group_label>Concomitant iron and I.V. epoietin zeta</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ARM B: IV iron + epoietin zeta sequence</intervention_name>
    <description>Epoietin zeta at a dose of 450 IU / kg per week subcutaneously started in week 7&#xD;
carboxymaltose ferric (Ferinject ®) at week 1&#xD;
Intravenous infusion not exceeding 1000 mg (administered once if weight&gt; 50 kg, 500 mg twice otherwise, with an interval of one week between each administration).&#xD;
Renewable with a minimum of 4 weeks depending on the iron status (if CST &lt;20% and absence of serum ferritin&gt; 800) in the same manner as week 1.</description>
    <arm_group_label>Iron and I.V. epoietin zeta sequential</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ARM C : single epoietin zeta</intervention_name>
    <description>Epoietin zeta at a dose of 450 IU / kg per week subcutaneously begun in week 1</description>
    <arm_group_label>Epoietin zeta</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient&gt; 18 years;&#xD;
&#xD;
          -  Metastatic or locally advanced non-curable undergoing chemotherapy or lymphoid disease&#xD;
             for which chemotherapy is indicated solid cancerous disease;&#xD;
&#xD;
          -  Patient for which there are at least 3 cycles or 3 months of chemotherapy;&#xD;
&#xD;
          -  Haemoglobin between 8.5 and 11 g / dL;&#xD;
&#xD;
          -  Functional martial deficiency defined by a coefficient of transferrin saturation and&#xD;
             serum ferritin ≤ 20% between 100 and 800 mg / L;&#xD;
&#xD;
          -  Life expectancy&gt; 3 months;&#xD;
&#xD;
          -  ECOG ≤ 2.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Documented hemochromatosis ;&#xD;
&#xD;
          -  AST and / or ALT&gt; 2.5N;&#xD;
&#xD;
          -  Renal impairment with Cockcroft clearance &lt;30 mL / min;&#xD;
&#xD;
          -  Vitamin B12 deficiency or folate;&#xD;
&#xD;
          -  Hemolysis;&#xD;
&#xD;
          -  Infectious disease being untreated;&#xD;
&#xD;
          -  Haemorrhagic syndrome related or not with the tumor;&#xD;
&#xD;
          -  Hypersensitivity to Ferinject ® or any of the excipients;&#xD;
&#xD;
          -  Land atopic asthma or eczema known&#xD;
&#xD;
          -  Contraindication to EPO;&#xD;
&#xD;
          -  Taking a supplement to oral iron;&#xD;
&#xD;
          -  Treatment with EPO within 6 months prior to study entry;&#xD;
&#xD;
          -  No transfusion of packed red cells within 15 days before enrollment or randomization&#xD;
             in the study;&#xD;
&#xD;
          -  Participation in another clinical trial;&#xD;
&#xD;
          -  Psychiatric pathology can disrupt the course of treatment or prevent the&#xD;
             interpretation of results;&#xD;
&#xD;
          -  Pregnant or lactating women;&#xD;
&#xD;
          -  Persons deprived of liberty;&#xD;
&#xD;
          -  Major subject to a measure of legal protection or unable to consent.&#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>Emmanuel SEVIN, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre François Baclesse</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHU</name>
      <address>
        <city>Caen</city>
        <zip>14000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre François Baclesse</name>
      <address>
        <city>Caen</city>
        <zip>14076</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>April 2015</verification_date>
  <study_first_submitted>July 31, 2014</study_first_submitted>
  <study_first_submitted_qc>August 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 11, 2014</study_first_posted>
  <last_update_submitted>April 28, 2015</last_update_submitted>
  <last_update_submitted_qc>April 28, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 29, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Functional iron deficiency</keyword>
  <keyword>Metastatic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Anemia, Iron-Deficiency</mesh_term>
    <mesh_term>Iron Deficiencies</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Iron</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/NCT02213653
org study id: FERASE
nct id: NCT02213653
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
Anemia in patients with cancer is a common problem associated with an impaired quality of
      life.

      Treatment with erythropoiesis stimulating agents (ESA) allows an increase in hemoglobin
      levels in 40-70% of patients and decreased transfusion requirements.

      Absolute or functional iron deficiency is also common with about 30% of cancer patients with
      all histologies combined iron deficiency and anemia.

      Several studies have shown the benefits of the combination of intravenous iron to
      erythropoiesis-stimulating agents in improving hemoglobin. However, none of them, to the
      investigators knowledge, has not been specifically performed on a population of patients with
      functional iron deficiency.

      In addition, in clinical practice, this association is not carried out in particular because
      there is no dosage or consensus sequence for the administration of iron associated with ESAs.
- Iron Deficiency and Cancer The literature review therefore presents uncertainties do not
      allow the routine application of intravenous iron associated with ESAs. The SOR also conclude
      that IV iron is "consider" if iron deficiency.

      These uncertainties are the heterogeneity of the study populations, contradictory results and
      the use of patterns intravenous iron binding and non-standardized.

      The investigators focus in this study in patients with chemotherapy-induced anemia with
      functional iron deficiency is a cause of lack of response to ESA. Indeed, patients with true
      iron deficiency seems to justify a routine iron supplementation. In contrast, patients
      without iron deficiency do not warrant formal way of initiating such treatment (although the
      literature is contradictory).

      This study aims to evaluate, in patients with chemotherapy-induced anemia and functional iron
      deficiency, the efficacy and safety of the combination epoietin zeta + Iron in concomitant
      intravenous or sequential.

      Because data RCP (Summary of Product Characteristics), ease of use, its safety profile, the
      ability to achieve higher doses of iron with a lower frequency and with better adherence, the
      ferric carboxymaltose was chosen as an intravenous iron. One specialty is available, the
      Ferinject ® (Laboratoires VIFOR Pharma).

      The erythropoiesis-stimulating agent chosen in this study is epoietin zeta.

      - Hepcidin and iron Hepcidin is a peptide hormone of 25 amino acids produced by the liver and
      considered as the central regulator of iron homeostasis in the body.

      It works by controlling intestinal iron absorption and iron reuse by the reticuloendothelial
      system. Hepcidin acts by preventing the export of iron enterocytes, intestinal site of
      absorption of dietary iron, and macrophages, iron recycling site of hemoglobin, by binding to
      ferroportin present at the membrane these cells and by inducing its internalization and
      degradation.

      Accordingly, hepcidin can be considered a hyposidérémiante hormone. The hepcidin rate is
      increased by the iron thereby limiting its accumulation and tissue damage associated with
      iron overload. Inversely, the rate is reduced hepcidin during increased iron as anemia needs,
      hypoxia, pregnancy or other situations of iron deficiency.

      Moreover, hepcidin is strongly induced by inflammation. Thus, in pathological situations such
      as cancer, high levels of hepcidin explain well enough inflammatory anemia characterized by
      anemia, iron retention at storage proteins such as ferritin but also at the level of the
      reticuloendothelial system endothelial and a decrease in intestinal iron absorption.

      Despite its importance in the pathophysiology of anemia of inflammation and a fortiori with
      iron deficiency anemia functional hepcidin is not measured in clinical routine. There is not,
      to the investigators knowledge, prospective data on its blood levels in situations of iron
      deficiency anemia in cancer patients functional and data on changes in hepcidin levels
      induced by treatment with intravenous iron or with erythropoietin.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients with hematopoietic response at 10 weeks.
time frame: The rate of hematopoietic response will be evaluated 10 weeks
description: The primary objective is to evaluate the rate of hematopoietic response to 10 weeks in patients with anemia and functional iron deficiency treated epoietin zeta + carboxymaltose concomitant IV iron, by epoietin zeta + carboxymaltose IV ferric sequential or epoietin zeta alone
measure: Number of transfusion requirements
time frame: The number of transfusions will be evaluated weekly Week 1-16
description: The secondary objective is to assess transfusion requirements will be evaluated throughout the study
measure: The hematopoietic response at 6 and 16 weeks
time frame: The hematopoietic response will be evaluated at 6 and 16 weeks
measure: The time to achieve the therapeutic goal (hemoglobin> 12g/dl or increase in hemoglobin> 2g/dl)
time frame: The time to achieve the therapeutic goal will be determine 6,10 and 16 weeks after treatment start
measure: Quality of life
time frame: Quality of life will be evaluated 6,10 and 16 weeks after treatment start
measure: The consumption of erythropoiesis stimulating agent
time frame: The consumption of erythropoiesis stimulating agent will be evaluated 6,10 and 16 weeks after treatment start
measure: The mean increase in hemoglobin concentration
time frame: The mean increase in hemoglobin concentration will be evaluated weekly Week 1-16
measure: The evolution of the iron status parameters
time frame: The evolution of the iron status parameters will be performed at weeks 4,6,10,13 and 16
description: Ferritin, CST, soluble transferrin receptor, reticulocytes, CRP will be dosed at weeks 4,6,10,13 and 16
measure: Tolerance
time frame: Tolerance will be evaluated at weeks 6, 10 and 16
measure: Fatigue
time frame: Fatigue will be evaluated 6,10 and 16 weeks after treatment start
description: Fatigue will be estimated with the generic scale FACT-G
arm group label: Concomitant iron and I.V. epoietin zeta
arm group type: Experimental
arm group label: Iron and I.V. epoietin zeta sequential
arm group type: Experimental
arm group label: Epoietin zeta
arm group type: Active Comparator
intervention type: Drug
intervention name: ARM A : IV iron + epoietin zeta
description: Epoietin zeta at a dose of 450 IU / kg per week subcutaneously
Carboxymaltose ferric (Ferinject ®) at week 1; Intravenous infusion not exceeding 1000 mg (administered once if weight> 50 kg, 500 mg twice otherwise, with an interval of one week between each administration).
Renewable with a minimum of 4 weeks depending on the iron status (if CST <20% and absence of serum ferritin> 800) in the same manner as week 1.
arm group label: Concomitant iron and I.V. epoietin zeta
intervention type: Drug
intervention name: ARM B: IV iron + epoietin zeta sequence
description: Epoietin zeta at a dose of 450 IU / kg per week subcutaneously started in week 7
carboxymaltose ferric (Ferinject ®) at week 1
Intravenous infusion not exceeding 1000 mg (administered once if weight> 50 kg, 500 mg twice otherwise, with an interval of one week between each administration).
Renewable with a minimum of 4 weeks depending on the iron status (if CST <20% and absence of serum ferritin> 800) in the same manner as week 1.
arm group label: Iron and I.V. epoietin zeta sequential
intervention type: Drug
intervention name: ARM C : single epoietin zeta
description: Epoietin zeta at a dose of 450 IU / kg per week subcutaneously begun in week 1
arm group label: Epoietin zeta
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Emmanuel SEVIN, MD
role: Principal Investigator
affiliation: Centre François Baclesse
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Anemia, Iron-Deficiency
mesh term: Iron Deficiencies
mesh term: Iron