<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/NCT03304288</url>
  </required_header>
  <id_info>
    <org_study_id>81670116</org_study_id>
    <nct_id>NCT03304288</nct_id>
  </id_info>
  <brief_title>The Combination of Low-dose Rituximab and ATRA as the Treatment of Steroid-resistant/Relapse Immune Thrombocytopenia</brief_title>
  <official_title>The Combination of Low-dose Rituximab and All-trans Retinoic Acid as the Treatment of Steroid-resistant/Relapse Immune Thrombocytopenia: a Multicenter, Randomized, Open-label Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Peking University People's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Beijing Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Navy General Hospital, Beijing</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beijing Tongren Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Peking University People's Hospital</source>
  <oversight_info>
    <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>
      Randomized, open-label, multicentre study to assess the efficacy and safety of the&#xD;
      combination of low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Immune thrombocytopenia (ITP) is a severe bleeding disorder. Approximately 2/3 of patients&#xD;
      achieve remission from first-line therapies. However, the underlying mechanism of&#xD;
      steroid-resistant or relapsed ITP is not well understood; thus, treatment remains a great&#xD;
      challenge. Rituximab has been shown to partly improve the complete remission rate of ITP.&#xD;
      All-trans retinoic acid (ATRA) has an immunomodulatory effect on haematopoiesis, making it a&#xD;
      possible treatment option.&#xD;
&#xD;
      A multicentre prospective study was performed in non-splenectomized ITP patients who were&#xD;
      either resistant to a standard dose of corticosteroids or had relapsed. Patients were&#xD;
      randomized to the low-dose rituximab+ATRA and the low-dose rituximab monotherapy groups.&#xD;
      Platelet count, bleeding and other symptoms were evaluated before and after treatment.&#xD;
      Interim analysis was scheduled at 50% through recruitment. Adverse events are also recorded&#xD;
      throughout the study, in order to assess the efficacy and safety of the combination of&#xD;
      low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">October 11, 2017</start_date>
  <completion_date type="Anticipated">February 28, 2021</completion_date>
  <primary_completion_date type="Actual">January 15, 2021</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>overall response</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Year 1</time_frame>
    <description>The number of participants (responders) with platelet count &gt;=30x10^9/L and at least a 2-fold increase in the baseline count (PR) or a platelet count &gt;=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>sustained response</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Year 1</time_frame>
    <description>The number of participants that can maintain the platelet count &gt; 30 x 109/L, an absence of bleeding events, and without requirement for any other ITP-specific treatment for 6 consecutive months after achievement of response. Interim analysis was scheduled at 50% through recruitment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>complete response</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Year 1</time_frame>
    <description>The number of participants (responders) with platelet count&gt;=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>time to response</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Year 1</time_frame>
    <description>Time to response was defined as the time from starting treatment to the time to achieve the response. Interim analysis was scheduled at 50% through recruitment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of response</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Year 1</time_frame>
    <description>Duration of response was measured from the achievement of response to the loss of response. Interim analysis was scheduled at 50% through recruitment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>incidence of adverse events</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Year 1</time_frame>
    <description>All patients were assessed for adverse events every week during the first 4 weeks of treatment, and at 2-weeks interval for the following 5 months, and monthly thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Interim analysis was scheduled at 50% through recruitment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Initial response</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Week 4</time_frame>
    <description>The number of patients who achieve response at 4 weeks following treatment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">168</enrollment>
  <condition>Immune Thrombocytopenia</condition>
  <arm_group>
    <arm_group_label>low-dose rituximab &amp; ATRA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>rituximab 100mg once weekly for 6 weeks and oral all-trance retinoid acid 20mg/m^2 qd for 12 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>low-dose rituximab</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>rituximab 100mg once weekly for 6 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Low-dose rituximab was used in combination with ATRA or as the monotherapy</description>
    <arm_group_label>low-dose rituximab</arm_group_label>
    <arm_group_label>low-dose rituximab &amp; ATRA</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>All-trans retinoic acid</intervention_name>
    <description>ATRA was used in combination with low-dose rituximab</description>
    <arm_group_label>low-dose rituximab &amp; ATRA</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ITP confirmed by excluding other supervened causes of thrombocytopenia;&#xD;
&#xD;
          -  Platelet count of less than 30×10^9/L at enrollment;&#xD;
&#xD;
          -  Patients who did not achieve a sustained response to treatment with full dose&#xD;
             corticosteroids for a minimum duration of 4 weeks or who relapsed during&#xD;
             steroid-tapering or after its discontinuation;&#xD;
&#xD;
          -  ECOG&lt;2.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Secondary immune thrombocytopenia (e.g., patients with HIV, HCV, Helicobacter pylori&#xD;
             infection or patients with systemic lupus erythematosus)&#xD;
&#xD;
          -  Congestive heart failure&#xD;
&#xD;
          -  Severe arrhythmia&#xD;
&#xD;
          -  Nursing or pregnant women&#xD;
&#xD;
          -  Aspartate aminotransferase and alanine transaminase levels ≥ 3×the upper limit of the&#xD;
             normal threshold criteria&#xD;
&#xD;
          -  Creatinine or serum bilirubin levels each 1•5 times or more than the normal range&#xD;
&#xD;
          -  Active or previous malignancy&#xD;
&#xD;
          -  Patients with other diseases were undergoing treatment with immunosuppressants&#xD;
&#xD;
          -  Patients with ITP had received rituximab&#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>Xiao-hui Zhang, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Peking University Insititute of Hematology, Peking University People's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Peking University Insititute of Hematology, Peking University People's Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100044</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Navy General Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100048</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beijing Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100730</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beijing Tongren Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>October 3, 2017</study_first_submitted>
  <study_first_submitted_qc>October 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 9, 2017</study_first_posted>
  <last_update_submitted>January 16, 2021</last_update_submitted>
  <last_update_submitted_qc>January 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Peking University People's Hospital</investigator_affiliation>
    <investigator_full_name>Xiao-hui Zhang</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>all-trans retinoid acid</keyword>
  <keyword>rituximab</keyword>
  <keyword>steroid-resistant</keyword>
  <keyword>refractory</keyword>
  <keyword>low-dose</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thrombocytopenia</mesh_term>
    <mesh_term>Purpura, Thrombocytopenic, Idiopathic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Tretinoin</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/NCT03304288
org study id: 81670116
nct id: NCT03304288
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Randomized, open-label, multicentre study to assess the efficacy and safety of the
      combination of low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.
Immune thrombocytopenia (ITP) is a severe bleeding disorder. Approximately 2/3 of patients
      achieve remission from first-line therapies. However, the underlying mechanism of
      steroid-resistant or relapsed ITP is not well understood; thus, treatment remains a great
      challenge. Rituximab has been shown to partly improve the complete remission rate of ITP.
      All-trans retinoic acid (ATRA) has an immunomodulatory effect on haematopoiesis, making it a
      possible treatment option.

      A multicentre prospective study was performed in non-splenectomized ITP patients who were
      either resistant to a standard dose of corticosteroids or had relapsed. Patients were
      randomized to the low-dose rituximab+ATRA and the low-dose rituximab monotherapy groups.
      Platelet count, bleeding and other symptoms were evaluated before and after treatment.
      Interim analysis was scheduled at 50% through recruitment. Adverse events are also recorded
      throughout the study, in order to assess the efficacy and safety of the combination of
      low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: overall response
time frame: From the start of study treatment (Day 1) up to the end of Year 1
description: The number of participants (responders) with platelet count >=30x10^9/L and at least a 2-fold increase in the baseline count (PR) or a platelet count >=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment.
measure: sustained response
time frame: From the start of study treatment (Day 1) up to the end of Year 1
description: The number of participants that can maintain the platelet count > 30 x 109/L, an absence of bleeding events, and without requirement for any other ITP-specific treatment for 6 consecutive months after achievement of response. Interim analysis was scheduled at 50% through recruitment.
measure: complete response
time frame: From the start of study treatment (Day 1) up to the end of Year 1
description: The number of participants (responders) with platelet count>=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment.
measure: time to response
time frame: From the start of study treatment (Day 1) up to the end of Year 1
description: Time to response was defined as the time from starting treatment to the time to achieve the response. Interim analysis was scheduled at 50% through recruitment.
measure: duration of response
time frame: From the start of study treatment (Day 1) up to the end of Year 1
description: Duration of response was measured from the achievement of response to the loss of response. Interim analysis was scheduled at 50% through recruitment.
measure: incidence of adverse events
time frame: From the start of study treatment (Day 1) up to the end of Year 1
description: All patients were assessed for adverse events every week during the first 4 weeks of treatment, and at 2-weeks interval for the following 5 months, and monthly thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Interim analysis was scheduled at 50% through recruitment.
measure: Initial response
time frame: From the start of study treatment (Day 1) up to the end of Week 4
description: The number of patients who achieve response at 4 weeks following treatment
arm group label: low-dose rituximab & ATRA
arm group type: Experimental
description: rituximab 100mg once weekly for 6 weeks and oral all-trance retinoid acid 20mg/m^2 qd for 12 weeks.
arm group label: low-dose rituximab
arm group type: Active Comparator
description: rituximab 100mg once weekly for 6 weeks
intervention type: Drug
intervention name: Rituximab
description: Low-dose rituximab was used in combination with ATRA or as the monotherapy
arm group label: low-dose rituximab
arm group label: low-dose rituximab & ATRA
intervention type: Drug
intervention name: All-trans retinoic acid
description: ATRA was used in combination with low-dose rituximab
arm group label: low-dose rituximab & ATRA
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Xiao-hui Zhang, Professor
role: Principal Investigator
affiliation: Peking University Insititute of Hematology, Peking University People's Hospital
facility: 
facility: 
facility: 
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Peking University People's Hospital
investigator full name: Xiao-hui Zhang
investigator title: Professor
mesh term: Thrombocytopenia
mesh term: Purpura, Thrombocytopenic, Idiopathic
mesh term: Rituximab
mesh term: Tretinoin