<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/NCT04470804</url>
  </required_header>
  <id_info>
    <org_study_id>PRCA-2</org_study_id>
    <nct_id>NCT04470804</nct_id>
  </id_info>
  <brief_title>Sirolimus Treatment for Newly Diagnosed Primary Acquired PRCA</brief_title>
  <acronym>PRCA</acronym>
  <official_title>Sirolimus Treatment for Newly Diagnosed Primary Acquired Pure Red Cell Aplasia: a Single Center Prospective Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bing Han</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Peking Union Medical College Hospital</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pure red cell aplasia (PRCA) is a kind of anemia characterized by severe reticulocytopenia&#xD;
      and obvious bone marrow erythroblastic cells decreased. Cyclosporine A and /or steroids are&#xD;
      the first line therapy but some patients were refractory or intolerance to the treatment. The&#xD;
      effects of the second line therapy are also not satisfactory and sometimes not available. The&#xD;
      investigators aim to explore the efficacy and side-effect of sirolimus for newly diagnosed&#xD;
      primary acquired PRCA.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pure red cell aplasia (PRCA) is a rare normocytic normochromic anemia with reticulocytopenia,&#xD;
      characterized by a reduction of erythroid precursors from the bone marrow, could be divided&#xD;
      into congenital and acquired PRCA according to pathogenesis. Congenital PRCA, also known as&#xD;
      Diamond-Blackfan syndrome, has been associated with pathogenic variant in GATA1 and TSR2 and&#xD;
      gene encode ribosomal proteins. Acquired PRCA can be a primary disease which is usually&#xD;
      mediated by immunology, or secondary to other diseases, such as lymphoproliferative diseases,&#xD;
      autoimmune diseases, thymoma, infection, or drugs. The first line therapy of acquired PRCA is&#xD;
      Cyclosporine A (CsA) and steroids, the second line therapy are anti-CD20, anti-human&#xD;
      thymocyte immunoglobulin, immunosuppressive drugs like cyclophosphamide, bone marrow&#xD;
      transplantation. Unfortunately, some patients did not response or tolerate the above&#xD;
      treatments.&#xD;
&#xD;
      Sirolimus (rapamycin) is an agent produced by the bacterium Streptomyces hygroscopicus,&#xD;
      inhibits the mammalian target of rapamycin (mTOR). mTOR is a serine/threonine kinase that&#xD;
      regulates cell growth, proliferation, metabolism and survival in eukaryotic cells, and is&#xD;
      identified as two interacting complex, mTORC1 and mTORC2. Sirolimus primarily inhibits&#xD;
      mTORC1, has been approved for prevent organ transplant rejection, especially in renal&#xD;
      transplantation. Sirolimus also promises to treat autoimmune, degenerative and&#xD;
      hyperproliferative disorders. Recently, sirolimus has been reported to be effective and well&#xD;
      tolerated for many immune-mediated cytopenias, such as autoimmune lymphoproliferative&#xD;
      syndrome, immune thrombocytopenia, EVANS syndrome, etc. Some case reports and our previous&#xD;
      retrospective study showed that sirolimus was effective for refractory/relapse PRCA with good&#xD;
      tolerance. However, due to the rare occurrence of PRCA and good response rate to CsA, there&#xD;
      are very few studies of sirolimus on newly diagnosed PRCA so far.&#xD;
&#xD;
      In this study, It is anticipated to evaluate the efficacy and safety of sirolimus versus CsA&#xD;
      in patients with newly diagnosed PRCA . The side-effects will be documented and plasma&#xD;
      concentration of sirolimus will be monitored. Furthermore, an interim analysis will be&#xD;
      performed to assess the treatment efficacy and safety of sirolimus versus CsA in primary PRCA&#xD;
      patients when a total of 56 eligible participants finished the designed treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2020</start_date>
  <completion_date type="Actual">July 31, 2022</completion_date>
  <primary_completion_date type="Actual">July 30, 2022</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hemoglobin level</measure>
    <time_frame>6 months</time_frame>
    <description>Hemoglobin level in g/L</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hemoglobin level</measure>
    <time_frame>2 years</time_frame>
    <description>Hemoglobin level in g/L</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Overall response</measure>
    <time_frame>1 year</time_frame>
    <description>complete response plus partial response</description>
  </other_outcome>
  <other_outcome>
    <measure>Complete response</measure>
    <time_frame>1 year</time_frame>
    <description>Hemoglobin &gt;120 g/L in males or Hemoglobin &gt;110 g/L in females, and lasting for at least 2 months</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">56</enrollment>
  <condition>Pure Red Cell Aplasia, Acquired</condition>
  <arm_group>
    <arm_group_label>Sirolimus on newly diagnosed primary acquired PRCA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A prospective research of the sirolimus efficiency on newly diagnosed primary acquired PRCA patients. Sirolimus dosage: 2mg QD with plasma concentration 4-15ng/mL. Medication time should last at least 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyclosporine A on newly diagnosed primary acquired PRCA</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cyclosporine A (CsA) efficiency on newly diagnosed primary acquired PRCA patients. CsA dosage: 4mg/kg QD. Medication time should last at least 6 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sirolimus</intervention_name>
    <description>Sirolimus treats in experimental group</description>
    <arm_group_label>Sirolimus on newly diagnosed primary acquired PRCA</arm_group_label>
    <other_name>Sirolimus Tablets</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclosporine A</intervention_name>
    <description>Cyclosporine A uses for active comparator group.</description>
    <arm_group_label>Cyclosporine A on newly diagnosed primary acquired PRCA</arm_group_label>
    <other_name>Cyclosporine A Tablets</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. age &gt;18 years old.&#xD;
&#xD;
          2. hemoglobin (Hb) &lt;90 g/L before treatment.&#xD;
&#xD;
          3. no history of immunosuppression therapy prior to sirolimus or CsA treatment.&#xD;
&#xD;
          4. adequate hepatic functions with alanine transaminase (ALT)/aspartate. transaminase&#xD;
             (AST) levels within 3 times of the normal upper limit and total bilirubin levels&#xD;
             within 2 times of the normal upper limit.&#xD;
&#xD;
          5. documented patient consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. diagnosis of secondary aPRCA.&#xD;
&#xD;
          2. history of treatment with immunosuppression therapy before enrollment.&#xD;
&#xD;
          3. history of leukemia, stem cell transplantation, or treatment-related myelodysplastic&#xD;
             syndromes (MDS).&#xD;
&#xD;
          4. creatinine/transaminase ≥ 3 normal upper limit.&#xD;
&#xD;
          5. complicated with active or uncontrolled infections or uncontrolled cardiovascular&#xD;
             disease.&#xD;
&#xD;
          6. presence of other diseases that may cause anemia.&#xD;
&#xD;
          7. presence of malignancies.&#xD;
&#xD;
          8. pregnant and lactating women.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>88 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bing Han, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Peking Union Medical College Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Peking Union Medical College Hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100730</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <results_reference>
    <citation>Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, Manno CS, Casper J, Grupp SA, Teachey DT. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016 Jan 7;127(1):17-28. doi: 10.1182/blood-2015-07-657981. Epub 2015 Oct 26.</citation>
    <PMID>26504182</PMID>
  </results_reference>
  <results_reference>
    <citation>Li J, Wang Z, Dai L, Cao L, Su J, Zhu M, Yu Z, Bai X, Ruan C. Effects of rapamycin combined with low dose prednisone in patients with chronic immune thrombocytopenia. Clin Dev Immunol. 2013;2013:548085. doi: 10.1155/2013/548085. Epub 2013 Dec 2.</citation>
    <PMID>24363761</PMID>
  </results_reference>
  <results_reference>
    <citation>Means RT Jr. Pure red cell aplasia. Blood. 2016 Nov 24;128(21):2504-2509. doi: 10.1182/blood-2016-05-717140.</citation>
    <PMID>27881371</PMID>
  </results_reference>
  <results_reference>
    <citation>Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, Manno C, Rappaport E, Schwabe D, Sheen C, Sullivan KE, Zhuang H, Wechsler DS, Grupp SA. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009 Apr;145(1):101-6. doi: 10.1111/j.1365-2141.2009.07595.x. Epub 2009 Feb 4.</citation>
    <PMID>19208097</PMID>
  </results_reference>
  <results_reference>
    <citation>Long Z, Yu F, Du Y, Li H, Chen M, Zhuang J, Han B. Successful treatment of refractory/relapsed acquired pure red cell aplasia with sirolimus. Ann Hematol. 2018 Nov;97(11):2047-2054. doi: 10.1007/s00277-018-3431-5. Epub 2018 Jul 7.</citation>
    <PMID>29982851</PMID>
  </results_reference>
  <results_reference>
    <citation>Chen Z, Liu X, Chen M, Yang C, Han B. Successful sirolimus treatment of patients with pure red cell aplasia complicated with renal insufficiency. Ann Hematol. 2020 Apr;99(4):737-741. doi: 10.1007/s00277-020-03946-2. Epub 2020 Feb 6.</citation>
    <PMID>32030447</PMID>
  </results_reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 9, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>February 26, 2023</last_update_submitted>
  <last_update_submitted_qc>February 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Peking Union Medical College Hospital</investigator_affiliation>
    <investigator_full_name>Bing Han</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>sirolimus</keyword>
  <keyword>newly diagnosed pure red cell aplasia</keyword>
  <keyword>prospective study</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Red-Cell Aplasia, Pure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Temsirolimus</mesh_term>
    <mesh_term>MTOR Inhibitors</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_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/NCT04470804
org study id: PRCA-2
nct id: NCT04470804
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Pure red cell aplasia (PRCA) is a kind of anemia characterized by severe reticulocytopenia
      and obvious bone marrow erythroblastic cells decreased. Cyclosporine A and /or steroids are
      the first line therapy but some patients were refractory or intolerance to the treatment. The
      effects of the second line therapy are also not satisfactory and sometimes not available. The
      investigators aim to explore the efficacy and side-effect of sirolimus for newly diagnosed
      primary acquired PRCA.
Pure red cell aplasia (PRCA) is a rare normocytic normochromic anemia with reticulocytopenia,
      characterized by a reduction of erythroid precursors from the bone marrow, could be divided
      into congenital and acquired PRCA according to pathogenesis. Congenital PRCA, also known as
      Diamond-Blackfan syndrome, has been associated with pathogenic variant in GATA1 and TSR2 and
      gene encode ribosomal proteins. Acquired PRCA can be a primary disease which is usually
      mediated by immunology, or secondary to other diseases, such as lymphoproliferative diseases,
      autoimmune diseases, thymoma, infection, or drugs. The first line therapy of acquired PRCA is
      Cyclosporine A (CsA) and steroids, the second line therapy are anti-CD20, anti-human
      thymocyte immunoglobulin, immunosuppressive drugs like cyclophosphamide, bone marrow
      transplantation. Unfortunately, some patients did not response or tolerate the above
      treatments.

      Sirolimus (rapamycin) is an agent produced by the bacterium Streptomyces hygroscopicus,
      inhibits the mammalian target of rapamycin (mTOR). mTOR is a serine/threonine kinase that
      regulates cell growth, proliferation, metabolism and survival in eukaryotic cells, and is
      identified as two interacting complex, mTORC1 and mTORC2. Sirolimus primarily inhibits
      mTORC1, has been approved for prevent organ transplant rejection, especially in renal
      transplantation. Sirolimus also promises to treat autoimmune, degenerative and
      hyperproliferative disorders. Recently, sirolimus has been reported to be effective and well
      tolerated for many immune-mediated cytopenias, such as autoimmune lymphoproliferative
      syndrome, immune thrombocytopenia, EVANS syndrome, etc. Some case reports and our previous
      retrospective study showed that sirolimus was effective for refractory/relapse PRCA with good
      tolerance. However, due to the rare occurrence of PRCA and good response rate to CsA, there
      are very few studies of sirolimus on newly diagnosed PRCA so far.

      In this study, It is anticipated to evaluate the efficacy and safety of sirolimus versus CsA
      in patients with newly diagnosed PRCA . The side-effects will be documented and plasma
      concentration of sirolimus will be monitored. Furthermore, an interim analysis will be
      performed to assess the treatment efficacy and safety of sirolimus versus CsA in primary PRCA
      patients when a total of 56 eligible participants finished the designed treatment.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Hemoglobin level
time frame: 6 months
description: Hemoglobin level in g/L
measure: Hemoglobin level
time frame: 2 years
description: Hemoglobin level in g/L
measure: Overall response
time frame: 1 year
description: complete response plus partial response
measure: Complete response
time frame: 1 year
description: Hemoglobin >120 g/L in males or Hemoglobin >110 g/L in females, and lasting for at least 2 months
arm group label: Sirolimus on newly diagnosed primary acquired PRCA
arm group type: Experimental
description: A prospective research of the sirolimus efficiency on newly diagnosed primary acquired PRCA patients. Sirolimus dosage: 2mg QD with plasma concentration 4-15ng/mL. Medication time should last at least 6 months
arm group label: Cyclosporine A on newly diagnosed primary acquired PRCA
arm group type: Active Comparator
description: Cyclosporine A (CsA) efficiency on newly diagnosed primary acquired PRCA patients. CsA dosage: 4mg/kg QD. Medication time should last at least 6 months
intervention type: Drug
intervention name: Sirolimus
description: Sirolimus treats in experimental group
arm group label: Sirolimus on newly diagnosed primary acquired PRCA
other name: Sirolimus Tablets
intervention type: Drug
intervention name: Cyclosporine A
description: Cyclosporine A uses for active comparator group.
arm group label: Cyclosporine A on newly diagnosed primary acquired PRCA
other name: Cyclosporine A Tablets
criteria: 
gender: All
minimum age: 18 Years
maximum age: 88 Years
healthy volunteers: No
last name: Bing Han, PhD
role: Principal Investigator
affiliation: Peking Union Medical College Hospital
facility: 
country: China
citation: Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, Manno CS, Casper J, Grupp SA, Teachey DT. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016 Jan 7;127(1):17-28. doi: 10.1182/blood-2015-07-657981. Epub 2015 Oct 26.
PMID: 26504182
citation: Li J, Wang Z, Dai L, Cao L, Su J, Zhu M, Yu Z, Bai X, Ruan C. Effects of rapamycin combined with low dose prednisone in patients with chronic immune thrombocytopenia. Clin Dev Immunol. 2013;2013:548085. doi: 10.1155/2013/548085. Epub 2013 Dec 2.
PMID: 24363761
citation: Means RT Jr. Pure red cell aplasia. Blood. 2016 Nov 24;128(21):2504-2509. doi: 10.1182/blood-2016-05-717140.
PMID: 27881371
citation: Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, Manno C, Rappaport E, Schwabe D, Sheen C, Sullivan KE, Zhuang H, Wechsler DS, Grupp SA. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009 Apr;145(1):101-6. doi: 10.1111/j.1365-2141.2009.07595.x. Epub 2009 Feb 4.
PMID: 19208097
citation: Long Z, Yu F, Du Y, Li H, Chen M, Zhuang J, Han B. Successful treatment of refractory/relapsed acquired pure red cell aplasia with sirolimus. Ann Hematol. 2018 Nov;97(11):2047-2054. doi: 10.1007/s00277-018-3431-5. Epub 2018 Jul 7.
PMID: 29982851
citation: Chen Z, Liu X, Chen M, Yang C, Han B. Successful sirolimus treatment of patients with pure red cell aplasia complicated with renal insufficiency. Ann Hematol. 2020 Apr;99(4):737-741. doi: 10.1007/s00277-020-03946-2. Epub 2020 Feb 6.
PMID: 32030447
responsible party type: Sponsor-Investigator
investigator affiliation: Peking Union Medical College Hospital
investigator full name: Bing Han
investigator title: Professor
mesh term: Red-Cell Aplasia, Pure
mesh term: Cyclosporine
mesh term: Sirolimus
mesh term: Temsirolimus
mesh term: MTOR Inhibitors
mesh term: Cyclosporins
sharing ipd: No