<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/NCT03233776</url>
  </required_header>
  <id_info>
    <org_study_id>SC35</org_study_id>
    <nct_id>NCT03233776</nct_id>
  </id_info>
  <brief_title>Anakinra: Safety and Efficacy in the Management of Fever During Neutropenia and Mucositis in ASCT</brief_title>
  <acronym>AFFECT-1</acronym>
  <official_title>Safety and Efficacy of Interleukin-1 Inhibitor Anakinra for the Amelioration of Fever During Neutropenia and Mucositis in Patients With Multiple Myeloma Receiving an Autologous Stem Cell Transplantation After High-dose Melphalan</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Radboud University Medical Center</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Oral and intestinal mucositis are major risk factors for the occurrence of fever during&#xD;
      neutropenia and bloodstream infections after intensive chemo- and radiotherapy. These&#xD;
      complications often require dose reductions or cause delay of treatment, and thereby&#xD;
      interfere with optimal anticancer treatment. Currently, there are no effective strategies to&#xD;
      prevent or treat mucositis and the related complications.&#xD;
&#xD;
      The pro-inflammatory cytokine interleukin-1β (IL-1β) has shown pivotal in the pathogenesis of&#xD;
      mucositis and recently, it has been established in murine models that IL-1 inhibition&#xD;
      significantly ameliorates chemotherapy-induced intestinal mucositis.&#xD;
&#xD;
      In this phase IIa study the safety, maximum tolerated dose and efficacy of anakinra, a&#xD;
      recombinant human IL-1 receptor antagonist, will be determined in adult patients with&#xD;
      multiple myeloma who receive high-dose melphalan (HDM) in the preparation for an autologous&#xD;
      hematopoietic stem cell transplantation (ASCT) and are at high risk for experiencing&#xD;
      mucositis and fever during neutropenia (FN). After establishing the optimal dose, a pivotal&#xD;
      double-blind randomized placebo-controlled multicenter phase IIb trial will be planned to&#xD;
      establish efficacy.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 21, 2017</start_date>
  <completion_date type="Actual">August 1, 2020</completion_date>
  <primary_completion_date type="Actual">May 7, 2019</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>Sequential Assignment</intervention_model>
    <intervention_model_description>3+3 design</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Establish the maximum tolerated dose of anakinra (MTD, 100, 200 or 300 mg).</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
    <description>In this study, using a traditional 3+3 design, 3 doses of anakinra will be examined: 100, 200 and 300 mg. The first cohort of patients will start with 100 mg. Escalation to the next dose cohort(s) is based on the occurrence of dose limiting toxicities (DLTs). The definition of a DLT is: an opportunistic infection, a SUSAR, severe non-hematological toxicity grade 3-4, or the occurrence of primary graft failure or prolonged neutropenia (neutrophils have not been &gt;0.5 x10^9/l on one single day, assessed on day +21, and counting from day 0).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of fever during neutropenia</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of mucositis-related fever</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily mean CRP level</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical mucositis as determined by the daily mouth and gut scores</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days with fever (≥ 38.5° C)</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of bloodstream infections i.e. bacteremia</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay in days</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of systemic antimicrobial agents (incidence and duration)</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of analgesic drugs (incidence and duration)</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of total parenteral nutrition (TPN) (incidence and duration)</measure>
    <time_frame>Day of admission (day -2) until discharge. Maximum period: +30 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year</time_frame>
    <description>Quality of life according to the EORTC QLQ-C30</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fatigue severity</measure>
    <time_frame>Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year</time_frame>
    <description>Severity of fatigue as the score measured by the validated FACIT-Fatigue scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Short term overall survival</measure>
    <time_frame>+100 days and +1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Anakinra</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dosage form: intravenous. Dosage: either 100 mg, 200 mg or 300 mg. Frequency: once daily. Duration: 15 days (day -2 until day +12).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra</intervention_name>
    <description>Subjects will be treated with a daily dose of anakinra, intravenously, starting on day -2, until day +12 (day 0 is day of SCT). Predefined doses are 100 mg , 200 mg and 300 mg.</description>
    <arm_group_label>Anakinra</arm_group_label>
    <other_name>Kineret</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged ≥ 18 years&#xD;
&#xD;
          -  Diagnosed with multiple myeloma&#xD;
&#xD;
          -  Scheduled to receive an autologous SCT after myeloablative therapy with high-dose&#xD;
             melphalan&#xD;
&#xD;
          -  Managed with a central venous catheter (triple- or quadruple lumen)&#xD;
&#xD;
          -  Is able and willing to participate&#xD;
&#xD;
          -  Has provided written informed consent&#xD;
&#xD;
          -  Has a negative tuberculosis Quantiferon test&#xD;
&#xD;
          -  Has negative serology for active hepatitis B and C&#xD;
&#xD;
          -  Has negative serology for HIV&#xD;
&#xD;
          -  Has no known hypersensitivity to Escherichia coli derived products or any components&#xD;
             of anakinra&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for&#xD;
             the duration of study participation (during treatment with study medication), and for&#xD;
             30 days after the last dose.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to understand the nature and extent of the trial and the procedures required&#xD;
&#xD;
          -  Enrolment in any other investigational treatment study or use of an investigational&#xD;
             agent during the stem cell transplantation (this means studies in multiple myeloma&#xD;
             regarding induction or maintenance treatment are permitted).&#xD;
&#xD;
          -  Women who are pregnant or nursing&#xD;
&#xD;
          -  Diagnosed with amyloidosis or light-chain deposition disease&#xD;
&#xD;
          -  ALT or AST greater than 2.0 x upper limit of normal (ULN) of the local laboratories&#xD;
             values.&#xD;
&#xD;
          -  Bilirubin levels greater than 2.0 x upper limit of normal (ULN) of the local&#xD;
             Laboratories values, except for benign non-malignant indirect hyperbilirubinemia such&#xD;
             as Gilbert syndrome&#xD;
&#xD;
          -  Impaired renal function with eGFR &lt;40 ml/min&#xD;
&#xD;
          -  Received a live vaccine during the 3 months prior to baseline visit&#xD;
&#xD;
          -  Recent use of IL-1 antagonist, such as anakinra, rilonacept or canakinumab, within&#xD;
             three months prior to baseline visit&#xD;
&#xD;
          -  Treatment with TNFα inhibiting agents (such as etanercept, adalimumab, infliximab,&#xD;
             certolizumab and golimumab).&#xD;
&#xD;
          -  Uncontrolled bacterial or viral infections, or fungal infections, at the start of&#xD;
             therapy&#xD;
&#xD;
          -  Documented colonization with highly resistant microorganisms (HRMOs, in Dutch:&#xD;
             BRMO's), prior to registration, or detected during screening procedures&#xD;
&#xD;
          -  Documented colonization with methicillin-resistant Staphylococcus aureus (MRSA), prior&#xD;
             to registration&#xD;
&#xD;
          -  Subjects who are not able to receive antibacterial prophylaxis with quinolones&#xD;
             (because of hypersensitivity)&#xD;
&#xD;
          -  Subjects with an active solid malignancy prior to registration, with the exception of&#xD;
             cutaneous basal or squamous cell carcinomas&#xD;
&#xD;
          -  History of mycobacterial infection.&#xD;
&#xD;
          -  Subjects with intrinsic disorders of the gastro-intestinal (GI) tract, including, but&#xD;
             not limited to: Crohn's disease, ulcerative colitis, celiac disease, short bowel&#xD;
             syndrome.&#xD;
&#xD;
          -  Subject has any concurrent medical or psychiatric condition or disease that is likely&#xD;
             to interfere with the study procedures or results, or that in the opinion of the&#xD;
             investigator, would constitute a hazard for participating in this study.&#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>Nicole Blijlevens, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboud University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Radboud university medical center</name>
      <address>
        <city>Nijmegen</city>
        <zip>6525 GA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>July 19, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>November 23, 2020</last_update_submitted>
  <last_update_submitted_qc>November 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Anakinra</keyword>
  <keyword>Mucositis</keyword>
  <keyword>Hematopoietic stem cell transplantation</keyword>
  <keyword>Febrile neutropenia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
    <mesh_term>Mucositis</mesh_term>
    <mesh_term>Neutropenia</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/NCT03233776
org study id: SC35
nct id: NCT03233776
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Oral and intestinal mucositis are major risk factors for the occurrence of fever during
      neutropenia and bloodstream infections after intensive chemo- and radiotherapy. These
      complications often require dose reductions or cause delay of treatment, and thereby
      interfere with optimal anticancer treatment. Currently, there are no effective strategies to
      prevent or treat mucositis and the related complications.

      The pro-inflammatory cytokine interleukin-1β (IL-1β) has shown pivotal in the pathogenesis of
      mucositis and recently, it has been established in murine models that IL-1 inhibition
      significantly ameliorates chemotherapy-induced intestinal mucositis.

      In this phase IIa study the safety, maximum tolerated dose and efficacy of anakinra, a
      recombinant human IL-1 receptor antagonist, will be determined in adult patients with
      multiple myeloma who receive high-dose melphalan (HDM) in the preparation for an autologous
      hematopoietic stem cell transplantation (ASCT) and are at high risk for experiencing
      mucositis and fever during neutropenia (FN). After establishing the optimal dose, a pivotal
      double-blind randomized placebo-controlled multicenter phase IIb trial will be planned to
      establish efficacy.
allocation: N/A
intervention model: Sequential Assignment
intervention model description: 3+3 design
primary purpose: Supportive Care
masking: None (Open Label)
measure: Establish the maximum tolerated dose of anakinra (MTD, 100, 200 or 300 mg).
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
description: In this study, using a traditional 3+3 design, 3 doses of anakinra will be examined: 100, 200 and 300 mg. The first cohort of patients will start with 100 mg. Escalation to the next dose cohort(s) is based on the occurrence of dose limiting toxicities (DLTs). The definition of a DLT is: an opportunistic infection, a SUSAR, severe non-hematological toxicity grade 3-4, or the occurrence of primary graft failure or prolonged neutropenia (neutrophils have not been >0.5 x10^9/l on one single day, assessed on day +21, and counting from day 0).
measure: Incidence of fever during neutropenia
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Incidence of mucositis-related fever
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Daily mean CRP level
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Clinical mucositis as determined by the daily mouth and gut scores
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Days with fever (≥ 38.5° C)
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Incidence of bloodstream infections i.e. bacteremia
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Length of hospital stay in days
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Use of systemic antimicrobial agents (incidence and duration)
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Use of analgesic drugs (incidence and duration)
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Use of total parenteral nutrition (TPN) (incidence and duration)
time frame: Day of admission (day -2) until discharge. Maximum period: +30 days.
measure: Quality of life
time frame: Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year
description: Quality of life according to the EORTC QLQ-C30
measure: Fatigue severity
time frame: Baseline, at discharge (average: 23 days; maximum: after 30 days), +100 days, +1 year
description: Severity of fatigue as the score measured by the validated FACIT-Fatigue scale
measure: Short term overall survival
time frame: +100 days and +1 year
arm group label: Anakinra
arm group type: Experimental
description: Dosage form: intravenous. Dosage: either 100 mg, 200 mg or 300 mg. Frequency: once daily. Duration: 15 days (day -2 until day +12).
intervention type: Drug
intervention name: Anakinra
description: Subjects will be treated with a daily dose of anakinra, intravenously, starting on day -2, until day +12 (day 0 is day of SCT). Predefined doses are 100 mg , 200 mg and 300 mg.
arm group label: Anakinra
other name: Kineret
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nicole Blijlevens, MD PhD
role: Principal Investigator
affiliation: Radboud University Medical Center
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Mucositis
mesh term: Neutropenia
mesh term: Interleukin 1 Receptor Antagonist Protein