<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/NCT04447053</url>
  </required_header>
  <id_info>
    <org_study_id>10743-SUBTLE</org_study_id>
    <nct_id>NCT04447053</nct_id>
  </id_info>
  <brief_title>Sequential Belimumab and T-cell Based Therapy in SLE</brief_title>
  <official_title>Sequential Belimumab Followed by T-cell Based Therapy in the Treatment of Systemic Lupus Erythematosus (SUBTLE) - a Preliminary Proof-of-concept Mechanistic Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National University Hospital, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>National University Hospital, Singapore</source>
  <oversight_info>
    <has_dmc>No</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>
      Systemic lupus erythematosus (SLE) is a disease in which the immune system (the bodily system&#xD;
      that fights infection) attacks the body's own cells and tissues, causing inflammation and&#xD;
      organ damage if not promptly and appropriately managed. Autoantibodies (specific proteins&#xD;
      produced by the immune system which participate in attacking self tissues and organs) are the&#xD;
      hallmarks of SLE which are produced by a specific type of white blood cells called B cells.&#xD;
      Belimumab (Benlysta®) is a monoclonal antibody against the B cells by blocking the action of&#xD;
      BLyS, a protein that prolongs the longevity and enhances the functions of B cells and is&#xD;
      found to be elevated in patients with SLE, was approved by the FDA to treat patients with&#xD;
      SLE. This study aims to study the effects of Belimumab on T cells, another specific type of&#xD;
      white blood cells which also play a crucial role in SLE, in patients with SLE. In this trial,&#xD;
      80 adult patients with SLE will be recruited, 40 of them will be assigned to receive&#xD;
      intravenous (IV) Belimumab with standard of care therapy (SOC), and 40 to receive SOC only.&#xD;
      After 48 weeks of exposure to Belimumab + SOC and SOC alone, the phenotype and functions of T&#xD;
      cells will be studied and compared.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 8, 2021</start_date>
  <completion_date type="Anticipated">May 20, 2025</completion_date>
  <primary_completion_date type="Anticipated">May 20, 2025</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Comparing the ratio of Treg/Teff in Belimumab + SOC arm with SOC-only arm</measure>
    <time_frame>Baseline, week 4, week 12, week 24, week 36, week 48 and week 60</time_frame>
    <description>The enumeration of T-cell subsets by multi-color flow cytometry including Th1 (CD4+Tbet+), Th2 (CD4+GATA3+), Th17 (CD4+RoRgamat+) and Treg (CD4+CD25+FoxP3+) cells, as well as CD19+CD20+ B cells after staining with respective fluorescent-conjugated antibodies.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Identifying and comparing the TCR sequence of the variable regions (CDR1, CDR2 and CDR3) and their RNA expression profile before and after 48 weeks of Belimumab therapy</measure>
    <time_frame>up to week 48</time_frame>
    <description>TCR sequencing and RNA expression with the use of the state-of-the-art 10x Genomic nano-droplet technology.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To compare the numeric difference in other T cell subsets (Th1, Th2 and Th17) between the 2 arms</measure>
    <time_frame>Baseline, week 4, week 12, week 24, week 36, week 48 and week 60</time_frame>
    <description>The enumeration of T-cell subsets by multi-color flow cytometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To compare the potential improvement of cognitive function between the 2 arms</measure>
    <time_frame>Baseline and week 52</time_frame>
    <description>The use of the computerized Automated Neuropsychological Assessment Matrix (ANAM) which serves as an initial screening tool to pick up subtle cognitive dysfunction in healthy populations and serial assessments to track the progress of cognitive dysfunction in SLE patients over time.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Systemic Lupus Erythematosus</condition>
  <arm_group>
    <arm_group_label>Belimumab + SOC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be administered Belimumab, 10mg/kg, intravenously (IV) (together with SOC) in 1 hour on days 0, 14, and 28, and then every 28 days (4 weeks) until week 48.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SOC only</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients will receive SOC based on the discretion of attending physicians in accordance with the clinical disease manifestations of SLE and NUH practice of the treatment of SLE.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Belimumab Injection [Benlysta]</intervention_name>
    <description>Belimumab, IV infusion, 10mg/kg on days 0, 14, 28 then every 28 days until week 48.</description>
    <arm_group_label>Belimumab + SOC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 21&#xD;
&#xD;
          2. Able to understand the details of the trial and willing to give written informed&#xD;
             consent and comply with the requirements of the study protocol.&#xD;
&#xD;
          3. Patients who fulfill the classification criteria (SLICC 2012 or ACR 1997) for SLE and&#xD;
             have active disease (SELENA-SLEDAI ≥ 6).&#xD;
&#xD;
          4. Patients whose sera are positive for ANA (titre ≥ 1:80) or anti-dsDNA (&gt;100U/L based&#xD;
             on NUH standard laboratory cut-off).&#xD;
&#xD;
          5. Patients who are on stable dose of prednisolone (0-40mg/day) and/or non-steroidal&#xD;
             anti-inflammatory, antimalarial or immunosuppressive drugs for at least 30 days before&#xD;
             first study dose.&#xD;
&#xD;
          6. Females of child-bearing potential and non-sterilized males with female partners of&#xD;
             child-bearing potential may participate this trial only if they use a reliable means&#xD;
             of contraception.&#xD;
&#xD;
          7. Females of child-bearing potential must have a negative serum pregnancy test within&#xD;
             three weeks prior to baseline.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. They have severe active nephritis and/or active CNS lupus and/or other autoimmune&#xD;
             diseases e.g. RA, mixed connective tissue disease, scleroderma, dermatomyositis and&#xD;
             polymyositis.&#xD;
&#xD;
          2. They are pregnant.&#xD;
&#xD;
          3. They have had previous treatment with any B-cell and T-cell targeted biologic therapy,&#xD;
             intravenous (IV) cyclophosphamide within 6 months of enrolment, intravenous&#xD;
             immunoglobulins or prednisolone (&gt;100mg/day) within 3 months.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anselm Mak</last_name>
    <role>Principal Investigator</role>
    <affiliation>National University Hospital, Singapore</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Anselm Mak</last_name>
    <phone>+6567722598</phone>
    <email>mdcam@nsu.edu.sg</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Nien Yee Kow</last_name>
    <phone>+6566015194</phone>
    <email>mdckown@nus.edu.sg</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National University Hospital</name>
      <address>
        <city>SIngapore</city>
        <country>Singapore</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anselm Mak</last_name>
      <phone>+6567722598</phone>
      <email>mdcam@nus.edu.sg</email>
    </contact>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>June 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>June 19, 2023</last_update_submitted>
  <last_update_submitted_qc>June 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lupus Erythematosus, Systemic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Belimumab</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/NCT04447053
org study id: 10743-SUBTLE
nct id: NCT04447053
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Systemic lupus erythematosus (SLE) is a disease in which the immune system (the bodily system
      that fights infection) attacks the body's own cells and tissues, causing inflammation and
      organ damage if not promptly and appropriately managed. Autoantibodies (specific proteins
      produced by the immune system which participate in attacking self tissues and organs) are the
      hallmarks of SLE which are produced by a specific type of white blood cells called B cells.
      Belimumab (Benlysta®) is a monoclonal antibody against the B cells by blocking the action of
      BLyS, a protein that prolongs the longevity and enhances the functions of B cells and is
      found to be elevated in patients with SLE, was approved by the FDA to treat patients with
      SLE. This study aims to study the effects of Belimumab on T cells, another specific type of
      white blood cells which also play a crucial role in SLE, in patients with SLE. In this trial,
      80 adult patients with SLE will be recruited, 40 of them will be assigned to receive
      intravenous (IV) Belimumab with standard of care therapy (SOC), and 40 to receive SOC only.
      After 48 weeks of exposure to Belimumab + SOC and SOC alone, the phenotype and functions of T
      cells will be studied and compared.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Comparing the ratio of Treg/Teff in Belimumab + SOC arm with SOC-only arm
time frame: Baseline, week 4, week 12, week 24, week 36, week 48 and week 60
description: The enumeration of T-cell subsets by multi-color flow cytometry including Th1 (CD4+Tbet+), Th2 (CD4+GATA3+), Th17 (CD4+RoRgamat+) and Treg (CD4+CD25+FoxP3+) cells, as well as CD19+CD20+ B cells after staining with respective fluorescent-conjugated antibodies.
measure: Identifying and comparing the TCR sequence of the variable regions (CDR1, CDR2 and CDR3) and their RNA expression profile before and after 48 weeks of Belimumab therapy
time frame: up to week 48
description: TCR sequencing and RNA expression with the use of the state-of-the-art 10x Genomic nano-droplet technology.
measure: To compare the numeric difference in other T cell subsets (Th1, Th2 and Th17) between the 2 arms
time frame: Baseline, week 4, week 12, week 24, week 36, week 48 and week 60
description: The enumeration of T-cell subsets by multi-color flow cytometry.
measure: To compare the potential improvement of cognitive function between the 2 arms
time frame: Baseline and week 52
description: The use of the computerized Automated Neuropsychological Assessment Matrix (ANAM) which serves as an initial screening tool to pick up subtle cognitive dysfunction in healthy populations and serial assessments to track the progress of cognitive dysfunction in SLE patients over time.
arm group label: Belimumab + SOC
arm group type: Experimental
description: Patients will be administered Belimumab, 10mg/kg, intravenously (IV) (together with SOC) in 1 hour on days 0, 14, and 28, and then every 28 days (4 weeks) until week 48.
arm group label: SOC only
arm group type: No Intervention
description: Patients will receive SOC based on the discretion of attending physicians in accordance with the clinical disease manifestations of SLE and NUH practice of the treatment of SLE.
intervention type: Drug
intervention name: Belimumab Injection [Benlysta]
description: Belimumab, IV infusion, 10mg/kg on days 0, 14, 28 then every 28 days until week 48.
arm group label: Belimumab + SOC
criteria: 
gender: All
minimum age: 21 Years
maximum age: 70 Years
healthy volunteers: No
last name: Anselm Mak
role: Principal Investigator
affiliation: National University Hospital, Singapore
last name: Anselm Mak
phone: +6567722598
email: mdcam@nsu.edu.sg
last name: Nien Yee Kow
phone: +6566015194
email: mdckown@nus.edu.sg
facility: 
status: Recruiting
contact: 
country: Singapore
responsible party type: Sponsor
mesh term: Lupus Erythematosus, Systemic
mesh term: Belimumab