<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/NCT03770273</url>
  </required_header>
  <id_info>
    <org_study_id>190027</org_study_id>
    <secondary_id>19-I-0027</secondary_id>
    <nct_id>NCT03770273</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in People With Indolent Systemic Mastocytosis</brief_title>
  <official_title>A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in Subjects With Indolent Systemic Mastocytosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Mast cells help the body fight disease and heal wounds. People with indolent systemic&#xD;
      mastocytosis (ISM) make too many mast cells. This causes pain, tiredness, digestive problems,&#xD;
      and other symptoms. Researchers think the drug sarilumab could help.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To see if sarilumab is a safe and effective treatment for people with ISM.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Adults ages 18-75 with ISM who are enrolled in NIH study 02-I-0277&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
        -  Questionnaires&#xD;
&#xD;
        -  Bone marrow removed by a needle inserted into the hip bone&#xD;
&#xD;
        -  Ultrasound of the abdomen&#xD;
&#xD;
        -  Photographs of the skin&#xD;
&#xD;
      Participants will repeat some screening tests at study visits.&#xD;
&#xD;
      Participants will have a baseline visit in the hospital for 3 days. They will:&#xD;
&#xD;
        -  Be assigned to get either the study drug or a placebo. They will not know which one they&#xD;
           get.&#xD;
&#xD;
        -  Have a skin punch biopsy: An instrument will remove a small piece of skin.&#xD;
&#xD;
        -  Get their first drug dose injected under their skin&#xD;
&#xD;
      Participants will keep a side effect and medication diary during the study.&#xD;
&#xD;
      Participants will visit the clinic to get a drug dose every 2 weeks, for a total of 8 doses.&#xD;
&#xD;
      Participants will have a visit 2 weeks after their final dose. It will last up to 2 days.&#xD;
&#xD;
      Participants will have another visit 12 weeks later.&#xD;
&#xD;
      Participants may then continue this study for 1 more year. Those who continue will get&#xD;
      sarilumab, even if they previously got the placebo, every 2 weeks. They will have visits&#xD;
      every 6 weeks, and then every 3 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Systemic mastocytosis is a disorder caused by clonal mast cell proliferation and release of&#xD;
      mast cell mediators including tryptase. As a result, mast cell numbers may increase and&#xD;
      affect target organs including the dermis (maculopapular cutaneous mastocytosis/urticaria&#xD;
      pigmentosa, flushing), gastrointestinal tract (abdominal pain, diarrhea), skeletal system&#xD;
      (osteoporosis), hematological system (anemia, thrombocytopenia), and spleen and liver&#xD;
      (organomegaly). Patients with indolent (non-aggressive) systemic mastocytosis (ISM) are not&#xD;
      candidates for cytoreductive therapy and are generally treated with symptomatic therapy that&#xD;
      only partly decreases symptoms. There is, however, a documented association between severity&#xD;
      of mastocytosis and elevated serum levels of interleukin (IL)-6. Furthermore, mast cells have&#xD;
      been shown to double their rate of division and exhibit increased reactivity and release of&#xD;
      mediators when cultured in the presence of IL-6. In addition, in an animal model of&#xD;
      mastocytosis, anti-IL-6 has been shown to slow disease progression. In this study, adults&#xD;
      with ISM will thus be randomized and treated with sarilumab, a recombinant monoclonal&#xD;
      antibody directed against the IL-6 receptor, or receive placebo. Sarilumab is marketed in the&#xD;
      United States as Kevzara (Sanofi/Genzyme [Cambridge, MA, USA ]) and is approved by the Food&#xD;
      and Drug Administration for the treatment of rheumatoid arthritis. Binding of sarilumab to&#xD;
      the IL-6 receptor inhibits IL-6-associated human mast cell signaling and proliferation with a&#xD;
      resultant decrease in proliferation and reactivity (decreased mediator release), and&#xD;
      therefore is a rational choice for the treatment of ISM.&#xD;
&#xD;
      In this study, participants will be randomized with approximately half of the participants&#xD;
      receiving study drug, which will be administered at 200 mg via subcutaneous (SC) injection&#xD;
      once every 2 weeks (Q2W) for a total of 16 weeks. The other participants will receive a&#xD;
      placebo administered via SC injection Q2W for 16 weeks. Participants will return for a&#xD;
      follow-up visit 2 weeks after the final dose (treatment peak), and then again 12 weeks later.&#xD;
      Evaluations at study visits will include quality of life and symptom assessments and&#xD;
      measurement of serum tryptase levels. Bone marrow examination will be performed at the onset&#xD;
      and conclusion of the study. After the week 28 visit, all participants will have the option&#xD;
      to continue sarilumab for 52 more weeks, at 200 mg administered via SC injections.&#xD;
      Participants will continue to be monitored on a regular basis for safety concerns, as&#xD;
      instructed in the study drug s package insert.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 19, 2019</start_date>
  <completion_date type="Actual">July 31, 2023</completion_date>
  <primary_completion_date type="Actual">July 31, 2023</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mastocytosis Quality of Life Questionnaire (MC-QoL)</measure>
    <time_frame>16 weeks post study drug initiation</time_frame>
    <description>QoL at 16 weeks post-initiation of study drug/placebo using the Mastocytosis Quality of Life Questionnaire (MC-QoL)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Frequency and Severity of AE's</measure>
    <time_frame>day 0 through week 28</time_frame>
    <description>frequency and severity of adverse events during the randomized double-blinded placebo-controlled treatment period</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Reductions in use of medicines and reduction in serum Tryptase</measure>
    <time_frame>Day 0 through Week 28</time_frame>
    <description>Reduction in use of medicines for symptomatic relief, reduction in serum levels of tryptase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Questionnaires MC-Qol, MSAS, SCORMA, MQLQ, MSAF</measure>
    <time_frame>Day 0 through Week 28</time_frame>
    <description>Percent improvement in QoL using MC-Qol, scoring of mastocytosis index (SCORMA), and Memorial Symptom Assessment Scale (MSAS) and the Mastocytosis Quality of Life Questionnaire (MQLQ), and the mastocytosis Symptom Assessment Form (MSAF)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mast cells in bone marrow and allelic frequency of D816V</measure>
    <time_frame>Day 0 and Week 16 for bone marrow and Day 0, week 16 and week 28 for D816V allelic Frequency</time_frame>
    <description>Reduction of percentage infiltrating mast cells in bone marrow. Decrease in the allelic frequency of D816V using PCR</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Indolent Systemic Mastocytosis</condition>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>8 SC injections of placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>sarilumab</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>8 SC injections of 200 mg/1.14 ml of sarilumab over 16 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>sarilumab</intervention_name>
    <description>sarilumab is a fully human anti-IL-6R(number sign) monoclonal antibody that binds membrane-bound and soluble human IL-6R and has been shown to inhibit IL-6 signaling</description>
    <arm_group_label>sarilumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Participants must meet all of the following criteria to be enrolled in this study:&#xD;
&#xD;
          1. Male or female participant greater than or equal to 18 and &lt; 75 years of age at&#xD;
             screening.&#xD;
&#xD;
          2. Enrolled on NIAID protocol 02-I-0277.&#xD;
&#xD;
          3. Documented pathologic diagnosis of ISM.&#xD;
&#xD;
          4. MC-QoL score of at least 25% (which suggests participant is at least somewhat affected&#xD;
             by all McQoL questions).&#xD;
&#xD;
          5. Willing and able to undergo a bone marrow biopsy and aspirate.&#xD;
&#xD;
          6. Absolute neutrophil count (ANC) greater than or equal to 2000/mL.&#xD;
&#xD;
          7. Hemoglobin greater than or equal to 12.0 g/dL (males), greater than or equal to 11&#xD;
             g/dL (females).&#xD;
&#xD;
          8. Platelet count greater than or equal to 150,000/microliters.&#xD;
&#xD;
          9. Alanine transaminase (ALT) and aspartate transaminase (AST) &lt; 1.5 times the upper&#xD;
             limit of normal (ULN).&#xD;
&#xD;
         10. Willing to allow storage of blood and bone marrow for future use in medical research.&#xD;
&#xD;
         11. Willing to allow genetic testing on biospecimens.&#xD;
&#xD;
         12. Able to provide informed consent.&#xD;
&#xD;
         13. Participants who can become pregnant must agree to use adequate contraception when&#xD;
             engaging in sexual activities that can result in pregnancy. Adequate contraception&#xD;
             must be used consistently, beginning at least 1 month before the beginning of dosing&#xD;
             and lasting until 3 months after the final dose of study drug. Acceptable methods of&#xD;
             contraception include the following:&#xD;
&#xD;
               -  Hormonal contraception (non-oral only).&#xD;
&#xD;
               -  Male or female condom with spermicide.&#xD;
&#xD;
               -  Diaphragm or cervical cap with a spermicide.&#xD;
&#xD;
               -  Intrauterine device.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
        Individuals meeting any of the following criteria will be excluded from study&#xD;
        participation:&#xD;
&#xD;
          1. Any abnormality that would be scored as a Grade 4 toxicity on the Common Terminology&#xD;
             Criteria for Adverse Events (CTCAE) version 5.0. Only clinically significant lab&#xD;
             results will deem the subject ineligible&#xD;
&#xD;
          2. Infected with HIV or has other known immunodeficiency.&#xD;
&#xD;
          3. Has an active infection, including localized infection.&#xD;
&#xD;
          4. Active diverticulitis.&#xD;
&#xD;
          5. Active or chronic viral hepatitis.&#xD;
&#xD;
          6. Active or latent tuberculosis.&#xD;
&#xD;
          7. Use of any other anti-IL-6 or anti-IL-6R agent within 1 year prior to the date&#xD;
             informed consent was obtained.&#xD;
&#xD;
          8. Use of cytoreductive therapy for mastocytosis within 1 year prior to the date informed&#xD;
             consent was obtained.&#xD;
&#xD;
          9. Known lymphoma or advanced and metastatic solid tumors on active therapy (including&#xD;
             chemotherapy) within 1 year prior to the date informed consent was obtained&#xD;
&#xD;
         10. Use of chemotherapy within 1 year prior to the date informed consent was obtained.&#xD;
&#xD;
         11. Receipt of any marketed (eg, omalizumab) or investigational biologic or monoclonal&#xD;
             antibody reported to affect mast cell activation within 5 half-lives prior to date&#xD;
             informed consent was obtained.&#xD;
&#xD;
         12. Receipt of intravenous (IV) immunoglobulin within 30 days prior to the date informed&#xD;
             consent was obtained.&#xD;
&#xD;
         13. Receipt of live attenuated vaccines within 30 days prior to the date informed consent&#xD;
             was obtained.&#xD;
&#xD;
         14. History of alcohol or drug/abuse within 12 months prior to date informed consent was&#xD;
             obtained.&#xD;
&#xD;
         15. Is allergic to any component of the sarilumab formulation.&#xD;
&#xD;
         16. Pregnant or breastfeeding.&#xD;
&#xD;
         17. Any condition that, in the opinion of the investigator, contraindicates participation&#xD;
             in this study.&#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>Hirsh D Komarow, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Allergy and Infectious Diseases (NIAID)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-I-0027.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>August 24, 2023</verification_date>
  <study_first_submitted>December 7, 2018</study_first_submitted>
  <study_first_submitted_qc>December 7, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>August 25, 2023</last_update_submitted>
  <last_update_submitted_qc>August 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cytokine</keyword>
  <keyword>Monoclonal Therapy</keyword>
  <keyword>Interleukin-6</keyword>
  <keyword>Mast Cell</keyword>
  <keyword>Bone Marrow</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mastocytosis</mesh_term>
    <mesh_term>Mastocytosis, Systemic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03770273
org study id: 190027
secondary id: 19-I-0027
nct id: NCT03770273
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Mast cells help the body fight disease and heal wounds. People with indolent systemic
      mastocytosis (ISM) make too many mast cells. This causes pain, tiredness, digestive problems,
      and other symptoms. Researchers think the drug sarilumab could help.

      Objective:

      To see if sarilumab is a safe and effective treatment for people with ISM.

      Eligibility:

      Adults ages 18-75 with ISM who are enrolled in NIH study 02-I-0277

      Design:

      Participants will be screened with:

        -  Physical exam

        -  Medical history

        -  Blood and urine tests

        -  Questionnaires

        -  Bone marrow removed by a needle inserted into the hip bone

        -  Ultrasound of the abdomen

        -  Photographs of the skin

      Participants will repeat some screening tests at study visits.

      Participants will have a baseline visit in the hospital for 3 days. They will:

        -  Be assigned to get either the study drug or a placebo. They will not know which one they
           get.

        -  Have a skin punch biopsy: An instrument will remove a small piece of skin.

        -  Get their first drug dose injected under their skin

      Participants will keep a side effect and medication diary during the study.

      Participants will visit the clinic to get a drug dose every 2 weeks, for a total of 8 doses.

      Participants will have a visit 2 weeks after their final dose. It will last up to 2 days.

      Participants will have another visit 12 weeks later.

      Participants may then continue this study for 1 more year. Those who continue will get
      sarilumab, even if they previously got the placebo, every 2 weeks. They will have visits
      every 6 weeks, and then every 3 months.
Systemic mastocytosis is a disorder caused by clonal mast cell proliferation and release of
      mast cell mediators including tryptase. As a result, mast cell numbers may increase and
      affect target organs including the dermis (maculopapular cutaneous mastocytosis/urticaria
      pigmentosa, flushing), gastrointestinal tract (abdominal pain, diarrhea), skeletal system
      (osteoporosis), hematological system (anemia, thrombocytopenia), and spleen and liver
      (organomegaly). Patients with indolent (non-aggressive) systemic mastocytosis (ISM) are not
      candidates for cytoreductive therapy and are generally treated with symptomatic therapy that
      only partly decreases symptoms. There is, however, a documented association between severity
      of mastocytosis and elevated serum levels of interleukin (IL)-6. Furthermore, mast cells have
      been shown to double their rate of division and exhibit increased reactivity and release of
      mediators when cultured in the presence of IL-6. In addition, in an animal model of
      mastocytosis, anti-IL-6 has been shown to slow disease progression. In this study, adults
      with ISM will thus be randomized and treated with sarilumab, a recombinant monoclonal
      antibody directed against the IL-6 receptor, or receive placebo. Sarilumab is marketed in the
      United States as Kevzara (Sanofi/Genzyme [Cambridge, MA, USA ]) and is approved by the Food
      and Drug Administration for the treatment of rheumatoid arthritis. Binding of sarilumab to
      the IL-6 receptor inhibits IL-6-associated human mast cell signaling and proliferation with a
      resultant decrease in proliferation and reactivity (decreased mediator release), and
      therefore is a rational choice for the treatment of ISM.

      In this study, participants will be randomized with approximately half of the participants
      receiving study drug, which will be administered at 200 mg via subcutaneous (SC) injection
      once every 2 weeks (Q2W) for a total of 16 weeks. The other participants will receive a
      placebo administered via SC injection Q2W for 16 weeks. Participants will return for a
      follow-up visit 2 weeks after the final dose (treatment peak), and then again 12 weeks later.
      Evaluations at study visits will include quality of life and symptom assessments and
      measurement of serum tryptase levels. Bone marrow examination will be performed at the onset
      and conclusion of the study. After the week 28 visit, all participants will have the option
      to continue sarilumab for 52 more weeks, at 200 mg administered via SC injections.
      Participants will continue to be monitored on a regular basis for safety concerns, as
      instructed in the study drug s package insert.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Mastocytosis Quality of Life Questionnaire (MC-QoL)
time frame: 16 weeks post study drug initiation
description: QoL at 16 weeks post-initiation of study drug/placebo using the Mastocytosis Quality of Life Questionnaire (MC-QoL)
measure: Frequency and Severity of AE's
time frame: day 0 through week 28
description: frequency and severity of adverse events during the randomized double-blinded placebo-controlled treatment period
measure: Reductions in use of medicines and reduction in serum Tryptase
time frame: Day 0 through Week 28
description: Reduction in use of medicines for symptomatic relief, reduction in serum levels of tryptase
measure: Questionnaires MC-Qol, MSAS, SCORMA, MQLQ, MSAF
time frame: Day 0 through Week 28
description: Percent improvement in QoL using MC-Qol, scoring of mastocytosis index (SCORMA), and Memorial Symptom Assessment Scale (MSAS) and the Mastocytosis Quality of Life Questionnaire (MQLQ), and the mastocytosis Symptom Assessment Form (MSAF)
measure: mast cells in bone marrow and allelic frequency of D816V
time frame: Day 0 and Week 16 for bone marrow and Day 0, week 16 and week 28 for D816V allelic Frequency
description: Reduction of percentage infiltrating mast cells in bone marrow. Decrease in the allelic frequency of D816V using PCR
arm group label: placebo
arm group type: Active Comparator
description: 8 SC injections of placebo
arm group label: sarilumab
arm group type: Active Comparator
description: 8 SC injections of 200 mg/1.14 ml of sarilumab over 16 weeks
intervention type: Biological
intervention name: sarilumab
description: sarilumab is a fully human anti-IL-6R(number sign) monoclonal antibody that binds membrane-bound and soluble human IL-6R and has been shown to inhibit IL-6 signaling
arm group label: sarilumab
intervention type: Other
intervention name: Placebo
description: Placebo
arm group label: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Hirsh D Komarow, M.D.
role: Principal Investigator
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-I-0027.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Mastocytosis
mesh term: Mastocytosis, Systemic
sharing ipd: No