<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/NCT01667263</url>
  </required_header>
  <id_info>
    <org_study_id>U1111-1132-6877</org_study_id>
    <secondary_id>Z111107058811024</secondary_id>
    <nct_id>NCT01667263</nct_id>
  </id_info>
  <brief_title>The Combination of ATRA and Danazol as Second-line Treatment in Adult Immune Thrombocytopenia</brief_title>
  <official_title>The Combination of Oral All-trans Retinoic Acid and Danazol vs Danazol as Second-line Treatment in Adult 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 Municipal Science &amp; Technology Commission</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beijing Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Qilu Hospital of Shandong University</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>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Randomized, open-label, multicentre study to compare the efficacy and safety of ATRA plus&#xD;
      danazol with danazol monotherapy in patients with corticosteroid-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;
      corticosteroid-resistant or relapsed ITP is not well understood; thus, treatment remains a&#xD;
      great challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on&#xD;
      haematopoiesis, making it a 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 ATRA+danazol and danazol monotherapy group. Platelet count, bleeding and other&#xD;
      symptoms were evaluated before and after treatment. Adverse events are also recorded&#xD;
      throughout the study, in order to compare the efficacy and safety of ATRA plus danazol with&#xD;
      danazol monotherapy in patients with corticosteroid-resistant/relapsed ITP.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2012</start_date>
  <completion_date type="Actual">February 1, 2017</completion_date>
  <primary_completion_date type="Actual">July 1, 2016</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>the sustained platelet response at the 12-month follow-up</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Month 12</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 12-month follow-up.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>overall response</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of Month 12</time_frame>
    <description>The number of participants with platelet count &gt;=30×10^9/L at least once and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>primary response rate at 4 weeks</measure>
    <time_frame>From the start of study treatment (Day 1) up to week 4 of treatment</time_frame>
    <description>The number of participants with platelet count &gt;=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 4 of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>primary response rate at 8 weeks</measure>
    <time_frame>From the start of study treatment (Day 1) up to week 8 of treatment</time_frame>
    <description>The number of participants with platelet count &gt;=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 8 of treatment</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 month 12</time_frame>
    <description>Time to response was defined as the time from starting treatment to the time to achieve the response.</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 month 12</time_frame>
    <description>Duration of response was measured from the achievement of response to the loss of response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>reduction in bleeding symptoms</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of month 12</time_frame>
    <description>Changes of bleeding after treatment. Bleeding was defined in accordance with the WHO bleeding scale (0, no bleeding; 1, petechiae; 2, mild blood loss; 3, gross blood loss; and 4, debilitating blood loss).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>safety</measure>
    <time_frame>From the start of study treatment (Day 1) up to the end of follow-up</time_frame>
    <description>All patients were assessed for safety every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">130</enrollment>
  <condition>Autoimmune Thrombocytopenia</condition>
  <arm_group>
    <arm_group_label>All-trans retinoic acid ＆Danazol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Danazol 400mg po and ATRA 10mg bid po</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Danazol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Danazol 400mg po</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>All-trans retinoic acid</intervention_name>
    <arm_group_label>All-trans retinoic acid ＆Danazol</arm_group_label>
    <other_name>Retinoid acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Danazol</intervention_name>
    <arm_group_label>All-trans retinoic acid ＆Danazol</arm_group_label>
    <arm_group_label>Danazol</arm_group_label>
    <other_name>Danocrine</other_name>
    <other_name>Cleregil</other_name>
    <other_name>Danol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Primary immune thrombocytopenia (ITP) confirmed by excluding other supervened causes&#xD;
             of thrombocytopenia;&#xD;
&#xD;
          -  Platelet count of less than 30×109/L at enrolment&#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;
          -  18 years older.&#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;
          -  Unable to do blood routine test for the sake of time, distance, economic issues or&#xD;
             other reasons.&#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 People's Hospital, Peking University Insititute of Hematology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beijing Hospital, Ministry of Health</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100044</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peking University People's Hospital, Peking University Insititute of Hematology</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100044</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>
    <facility>
      <name>PLA Navy General Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Qilu Hospital, Shandong University</name>
      <address>
        <city>Jinan</city>
        <state>Shandong</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Zhang X, Fu H, Xu L, Liu D, Wang J, Liu K, Huang X. Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes. Biol Blood Marrow Transplant. 2011 Feb;17(2):274-80. doi: 10.1016/j.bbmt.2010.09.007. Epub 2010 Sep 18.</citation>
    <PMID>20854919</PMID>
  </reference>
  <reference>
    <citation>Nozaki Y, Tamaki C, Yamagata T, Sugiyama M, Ikoma S, Kinoshita K, Funauchi M. All-trans-retinoic acid suppresses interferon-gamma and tumor necrosis factor-alpha; a possible therapeutic agent for rheumatoid arthritis. Rheumatol Int. 2006 Jul;26(9):810-7. doi: 10.1007/s00296-005-0076-1. Epub 2005 Nov 15.</citation>
    <PMID>16292516</PMID>
  </reference>
  <reference>
    <citation>Sakakura M, Wada H, Tawara I, Nobori T, Sugiyama T, Sagawa N, Shiku H. Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura. Thromb Res. 2007;120(2):187-93. doi: 10.1016/j.thromres.2006.09.008. Epub 2006 Oct 24.</citation>
    <PMID>17067661</PMID>
  </reference>
  <reference>
    <citation>Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008 Mar 1;111(5):2505-15. doi: 10.1182/blood-2007-07-102798.</citation>
    <PMID>18299451</PMID>
  </reference>
  <reference>
    <citation>Wing K, Larsson P, Sandstrom K, Lundin SB, Suri-Payer E, Rudin A. CD4+ CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology. 2005 Aug;115(4):516-25. doi: 10.1111/j.1365-2567.2005.02186.x.</citation>
    <PMID>16011520</PMID>
  </reference>
  <reference>
    <citation>Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kuhne T, Ruggeri M, George JN. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12.</citation>
    <PMID>19005182</PMID>
  </reference>
  <reference>
    <citation>LIU Wen-bin, WANG Zhao-yue, CAO Li-juan, ZHAO Xiao-juan, ZHU Ming-qing, BAI Xia, RUAN Chang-geng.Therapeutic Effect and Mechanism of All-trans-retinoic Acid Treatment in Refractory Idiopathic Thrombocytopenic Purpura.Suzhou University Journal of Medical Science.2009;3 476-479.</citation>
  </reference>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>August 15, 2012</study_first_submitted>
  <study_first_submitted_qc>August 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 17, 2012</study_first_posted>
  <last_update_submitted>September 3, 2017</last_update_submitted>
  <last_update_submitted_qc>September 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2017</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 retinoic acid</keyword>
  <keyword>primary immune thrombocytopenia</keyword>
  <keyword>corticosteroid-resistant</keyword>
  <keyword>refractory</keyword>
  <keyword>danazol</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>Tretinoin</mesh_term>
    <mesh_term>Danazol</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/NCT01667263
org study id: U1111-1132-6877
secondary id: Z111107058811024
nct id: NCT01667263
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
Randomized, open-label, multicentre study to compare the efficacy and safety of ATRA plus
      danazol with danazol monotherapy in patients with corticosteroid-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
      corticosteroid-resistant or relapsed ITP is not well understood; thus, treatment remains a
      great challenge. 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 ATRA+danazol and danazol monotherapy group. Platelet count, bleeding and other
      symptoms were evaluated before and after treatment. Adverse events are also recorded
      throughout the study, in order to compare the efficacy and safety of ATRA plus danazol with
      danazol monotherapy in patients with corticosteroid-resistant/relapsed ITP.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: the sustained platelet response at the 12-month follow-up
time frame: From the start of study treatment (Day 1) up to the end of Month 12
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 12-month follow-up.
measure: overall response
time frame: From the start of study treatment (Day 1) up to the end of Month 12
description: The number of participants with platelet count >=30×10^9/L at least once and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy
measure: primary response rate at 4 weeks
time frame: From the start of study treatment (Day 1) up to week 4 of treatment
description: The number of participants with platelet count >=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 4 of treatment
measure: primary response rate at 8 weeks
time frame: From the start of study treatment (Day 1) up to week 8 of treatment
description: The number of participants with platelet count >=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 8 of treatment
measure: time to response
time frame: From the start of study treatment (Day 1) up to the end of month 12
description: Time to response was defined as the time from starting treatment to the time to achieve the response.
measure: duration of response
time frame: From the start of study treatment (Day 1) up to the end of month 12
description: Duration of response was measured from the achievement of response to the loss of response.
measure: reduction in bleeding symptoms
time frame: From the start of study treatment (Day 1) up to the end of month 12
description: Changes of bleeding after treatment. Bleeding was defined in accordance with the WHO bleeding scale (0, no bleeding; 1, petechiae; 2, mild blood loss; 3, gross blood loss; and 4, debilitating blood loss).
measure: safety
time frame: From the start of study treatment (Day 1) up to the end of follow-up
description: All patients were assessed for safety every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
arm group label: All-trans retinoic acid ＆Danazol
arm group type: Experimental
description: Danazol 400mg po and ATRA 10mg bid po
arm group label: Danazol
arm group type: Active Comparator
description: Danazol 400mg po
intervention type: Drug
intervention name: All-trans retinoic acid
arm group label: All-trans retinoic acid ＆Danazol
other name: Retinoid acid
intervention type: Drug
intervention name: Danazol
arm group label: All-trans retinoic acid ＆Danazol
arm group label: Danazol
other name: Danocrine
other name: Cleregil
other name: Danol
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 People's Hospital, Peking University Insititute of Hematology
facility: 
facility: 
facility: 
facility: 
facility: 
country: China
citation: Zhang X, Fu H, Xu L, Liu D, Wang J, Liu K, Huang X. Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes. Biol Blood Marrow Transplant. 2011 Feb;17(2):274-80. doi: 10.1016/j.bbmt.2010.09.007. Epub 2010 Sep 18.
PMID: 20854919
citation: Nozaki Y, Tamaki C, Yamagata T, Sugiyama M, Ikoma S, Kinoshita K, Funauchi M. All-trans-retinoic acid suppresses interferon-gamma and tumor necrosis factor-alpha; a possible therapeutic agent for rheumatoid arthritis. Rheumatol Int. 2006 Jul;26(9):810-7. doi: 10.1007/s00296-005-0076-1. Epub 2005 Nov 15.
PMID: 16292516
citation: Sakakura M, Wada H, Tawara I, Nobori T, Sugiyama T, Sagawa N, Shiku H. Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura. Thromb Res. 2007;120(2):187-93. doi: 10.1016/j.thromres.2006.09.008. Epub 2006 Oct 24.
PMID: 17067661
citation: Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008 Mar 1;111(5):2505-15. doi: 10.1182/blood-2007-07-102798.
PMID: 18299451
citation: Wing K, Larsson P, Sandstrom K, Lundin SB, Suri-Payer E, Rudin A. CD4+ CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology. 2005 Aug;115(4):516-25. doi: 10.1111/j.1365-2567.2005.02186.x.
PMID: 16011520
citation: Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kuhne T, Ruggeri M, George JN. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12.
PMID: 19005182
citation: LIU Wen-bin, WANG Zhao-yue, CAO Li-juan, ZHAO Xiao-juan, ZHU Ming-qing, BAI Xia, RUAN Chang-geng.Therapeutic Effect and Mechanism of All-trans-retinoic Acid Treatment in Refractory Idiopathic Thrombocytopenic Purpura.Suzhou University Journal of Medical Science.2009;3 476-479.
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: Tretinoin
mesh term: Danazol