xml: <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/NCT05983952</url>
    </required_header>
    <id_info>
      <org_study_id>03CD38APS</org_study_id>
      <nct_id>NCT05983952</nct_id>
    </id_info>
    <brief_title>Anti-CD38 Antibody Treating APS With Thrombocytopenia</brief_title>
    <official_title>A Prospective, One-arm and Open Clinical Study to Assess Safety and Efficacy of Anti-CD38 Antibody in the Treatment of Antiphospholipid Syndrome With Secondary Thrombocytopenia</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Institute of Hematology &amp; Blood Diseases Hospital, China</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Institute of Hematology &amp; Blood Diseases Hospital, China</source>
    <oversight_info>
      <has_dmc>Yes</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>
        To evaluate the safety and efficacy of anti-CD38 antibody in the treatment of&#xD;
        antiphospholipid syndrome with secondary thrombocytopenia in patients who have not responded&#xD;
        adequately or relapsed after first-line treatment and at least one second-line therapy&#xD;
        including rituximab and/or TPO-RA.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The anti-phospholipid syndrome (APS) is a systemic autoimmune disorder characterized by&#xD;
        recurrent thrombosis and/or obstetrical morbidity along with persistent anti-phospholipid&#xD;
        antibodies (APLA), including lupus anticoagulant (LA), anti-β2-glycoprotein I (anti-β2GPI)&#xD;
        and/or anti-cardiolipin (aCL) antibodies. APS is one of the most common acquired&#xD;
        thrombophilias, and unlike most of the genetic thrombophilias, ise associated with both&#xD;
        venous and arterial thrombosis. The deep veins of the lower extremities and the cerebral&#xD;
        arterial circulation are the most commonly affected venous and arterial sites, respectively.&#xD;
        It has been posited that &quot;two hits&quot; are necessary to trigger a thrombotic event in&#xD;
        antiphospholipid syndrome. This hypothesis argues that antiphospholipid antibodies provide&#xD;
        the first hit by creating a generalized procoagulant state, which conspires with a second hit&#xD;
        (often cryptic and potentially the result of subclinical vascular injury, stasis, or&#xD;
        inflammation) that triggers thrombosis. The evidence that IgG antibodies targeting domain I&#xD;
        of β2GPI contribute to the prothrombotic state of antiphospholipid syndrome is convincing.&#xD;
        Meanwhile, data also support roles for other isotypes of aβ2GPI, antibodies that target&#xD;
        heterotypic complexes of phospholipids and phospholipid binding proteins, and antibodies that&#xD;
        target phospholipids directly. Given that most mechanistic studies have focused on either&#xD;
        polyclonal IgG fractions isolated from patients with antiphospholipid syndrome or IgG&#xD;
        anti-β2GPI, researchers unfortunately could not build a nuanced model of how diverse species&#xD;
        of antiphospholipid antibodies conspire to cause various manifestations of antiphospholipid&#xD;
        syndrome.&#xD;
  &#xD;
        The Sapporo classification criteria for APS were first proposed in 1999, and updated at the&#xD;
        Eleventh International Congress on Antiphospholipid Antibodies in Sydney in 2006.Patient must&#xD;
        have both clinical and laboratory criteria to meet a diagnosis of APS. Clinical criteria&#xD;
        include either objectively confirmed venous, arterial or small vessel thrombosis, or&#xD;
        obstetric morbidity including the unexplained death of one or more morphologically normal&#xD;
        fetuses at or beyond the 10th week of gestation, the premature birth of one or more&#xD;
        morphologically normal neonates before the 34th week of gestation, and/or three or more&#xD;
        unexplained, consecutive spontaneous abortions before the 10th week of gestation. Since these&#xD;
        clinical manifestations are prevalent in the general population and may have a multifactorial&#xD;
        etiology, laboratory investigations are central to the diagnosis of APS. The updated Sydney&#xD;
        classification scheme also requires specific laboratory criteria: a lupus anticoagulant&#xD;
        detected according to guidelines published by the International Society on Thrombosis and&#xD;
        Hemostasis (ISTH), anticardiolipin (aCL) antibodies (IgG or IgM) exceeding 40 IgG or IgM&#xD;
        antiphospholipid units, or anti-β2GPI antibodies (IgG or IgM) at levels exceeding the 99th&#xD;
        percentile, measured by enzyme-linked immunosorbent assay (ELISA). To minimize the risk of&#xD;
        making a diagnosis based on transient ntiphospholipid antibodies, the recommendations are to&#xD;
        perform assays on two separate occasions, at least twelve weeks apart.The major changes made&#xD;
        in the 2006 revision of the Sapporo criteria were that anti-β2GPI antibody was included for&#xD;
        the first time and a recommendation was made to classify patients into those with only one&#xD;
        positive APLA and those with two or three positive APLA, based on accumulating information&#xD;
        suggesting that positivity in more than a single assay was associated with higher thrombotic&#xD;
        risk.&#xD;
  &#xD;
        Thrombocytopenia occurs in APS with a frequency ranging from 20% to 50%, and the estimated&#xD;
        bleeding risk associated with it is much lower than the thrombotic risk associated with aPL.&#xD;
        In some patients with a confirmed APS diagnosis, secondary immune thrombocytopenia (ITP) may&#xD;
        lead to severe thrombocytopenia with consequent major bleeding. At the same time, the&#xD;
        presence of antiphospholipid antibodies (aPL) in patients with a diagnosis of primary ITP has&#xD;
        been reported in several studies, although with some specific characteristics especially&#xD;
        related to the variety of antigenic targets. Even though it does not enter the APS defining&#xD;
        criteria, thrombocytopenia should be regarded as a warning sign of a &quot;high risk&quot; APS and thus&#xD;
        thoroughly evaluated. The presence of aPL in patients with ITP should be assessed as well to&#xD;
        stratify the risk of paradoxical thrombosis. In detail, besides the high hemorrhagic risk in&#xD;
        secondary thrombocytopenia, patients with a co-diagnosis of APS or only antibodies are also&#xD;
        at risk of arterial and venous thrombosis. The pathogenesis of thrombocytopenia in&#xD;
        antiphospholipid antibody-positive patients is not fully understood. However, based on&#xD;
        currently available data, four different pathogenesis hypothesis were proposed, including&#xD;
        secondary Immune thrombocytopenia, decreased platelet production, increased platelet pooling&#xD;
        and increased platelet consumption. The APS associated thrombocytopenia treatment guidelines&#xD;
        can be drawn lessons from the treatment strategies of ITP. Conventional treatment of adult&#xD;
        APS associated thrombocytopenia includes first-line glucocorticoid and immunoglobulin&#xD;
        therapy. B-cell targeted drugs are effective in the treatment of APS. Studies have found that&#xD;
        rituximab can improve the clinical manifestations (including thrombocytopenia) and&#xD;
        serological indicators in the late stage of APS treatment. Splenectomy is reserved for&#xD;
        refractory patients who present with severe bleeding symptoms and are resistant to&#xD;
        glucocorticoids and immunosuppressants. Plasmapheresis can be used in patients with CAPS when&#xD;
        severe thrombocytopenia occurs. Thrombopoietin receptor agonists may increase the risk of&#xD;
        thrombosis in APS patients and should be used with caution. When thrombosis coexists with&#xD;
        bleeding events associated with thrombocytopenia, if platelet counts reach safe levels (&amp;gt;&#xD;
        50×109/L), glucocorticoid combined with anticoagulant therapy is recommended. It is difficult&#xD;
        to treat APS patients with severe thrombocytopenia and severe bleeding. It has been reported&#xD;
        in previous literature that platelets can be significantly increased in some patients after&#xD;
        treatment with hormones or rituximab, immunosuppressants, etc., but it is easy to relapse and&#xD;
        difficult to maintain. The decrease of aPL is not obvious and it is difficult to completely&#xD;
        remove. It is a difficult point in the treatment of hematology.&#xD;
  &#xD;
        Anti-CD38 antibody, which targets plasma cells, has been used in multiple myeloma in a number&#xD;
        of clinical studies and has shown good therapeutic effects. In addition, the clinical trials&#xD;
        of anti-CD38 antibody analogues such as fizumatumumab in the treatment of autoimmune diseases&#xD;
        including membranous nephropathy and systemic lupus erythematosus (SLE) are also being&#xD;
        carried out simultaneously. A case report of anti-CD38 antibody in the treatment of APS has&#xD;
        been reported abroad, and it has been found that it can significantly reduce the titer of&#xD;
        antiphospholipid antibodies. In the process of treating ITP patients with antiphospholipid&#xD;
        antibodies, investigators found that anti-CD38 antibody could not only rapidly increase&#xD;
        platelet count, but also significantly reduce the titer of antiphospholipid antibodies, which&#xD;
        may have a significant therapeutic effect on APS.Therefore, the use of daratumumab to clear&#xD;
        APS with secondary thrombocytopenia may be effective and represents a new therapeutic&#xD;
        strategy.&#xD;
  &#xD;
        Therefore, the investigators designed this clinical trial to evaluate the safety and efficacy&#xD;
        of anti-CD38 antibody in the treatment of antiphospholipid syndrome with secondary&#xD;
        thrombocytopenia.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Anticipated">August 2023</start_date>
    <completion_date type="Anticipated">August 2025</completion_date>
    <primary_completion_date type="Anticipated">August 2025</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>To evaluate the efficacy after CM313 treatment within 8 weeks</measure>
      <time_frame>8 weeks</time_frame>
      <description>Proportion of subjects with a platelet count ≥ 50 × 10^9/L within 8 weeks after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Safety of anti-CD38 antibody</measure>
      <time_frame>24 weeks</time_frame>
      <description>Incidence, severity, and relationship of treatment emergent adverse events after anti-CD38 antibody treatment</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Response rate of treatment</measure>
      <time_frame>12 weeks</time_frame>
      <description>Including: 1. Proportion of subjects with a platelet count ≥ 50 × 10^9/L at week 2, week 4, week 6，week 8，week 10 and week 12 in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period; 2. Proportion of subjects achieving platelet counts ≥ 50×10^9/L at least once in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the first 12 weeks; 3. Proportion of subjects whose platelet counts ≥ 30×10^9/L and at least two times of baseline platelet count in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids within 8 weeks（two consecutive measurements at least 7 days apart）.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Duration from treatment initiation to platelet count ≥50×10^9/L</measure>
      <time_frame>12 weeks</time_frame>
      <description>Duration from treatment initiation to platelet count ≥50×10^9/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Duration of platelet response</measure>
      <time_frame>24 weeks</time_frame>
      <description>The longest duration for which the subject sustained a platelet count ≥50×109/L</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>platelet count ≥50×10^9/L ≥75% tests</measure>
      <time_frame>24 weeks</time_frame>
      <description>Proportion of subjects with platelet count ≥50×10^9/L in ≥ 75% of the total number of tests</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Measurements of platelet count at each visit time point</measure>
      <time_frame>24 weeks</time_frame>
      <description>Platelet count at each visit time point</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Emergency treatment</measure>
      <time_frame>24 weeks</time_frame>
      <description>Percentage of subjects who received emergency treatment</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Number of subjects with clinically significant bleeding as assessed using the world health organization (WHO) bleeding scale</measure>
      <time_frame>24 weeks</time_frame>
      <description>Changes of the subjects' numbers in WHO bleeding score after Anti-CD38 antibody treatment according to the reported World Health Organization's Bleeding Scale. The WHO Bleeding Scale is a measure of bleeding severity with the following grades: grade 0 = no bleeding, grade 1= petechiae, grade 2= mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Occurrence of thrombosis</measure>
      <time_frame>24 weeks</time_frame>
      <description>Assessment of the occurrence of thrombosis during the study period</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Measurements of antiphospholipid antibody</measure>
      <time_frame>24 weeks</time_frame>
      <description>Measurements of the level of antiphospholipid antibody during the study period</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>platelet count ≥50×10^9/L at least once</measure>
      <time_frame>8 weeks</time_frame>
      <description>Percentage of subjects with a platelet count ≥50×109/L at least once 8 weeks after the first dose</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>platelet count ≥30×10^9/L and at least 2-fold from baseline on at least one occasion</measure>
      <time_frame>8 weeks</time_frame>
      <description>The percentage of subjects with a platelet count ≥30×10^9/L and at least 2-fold from baseline 8 weeks after the first dose on at least one occasion</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Measurements of various subsets of immunocompetent cells</measure>
      <time_frame>24 weeks</time_frame>
      <description>To assess the changes of the percentage of B cell subsets，regulatory B cells（Breg），regulatory T cells (Treg)，supressor T cells（Ts），monocyte subcets, helper T cells（Th）subsets and the functionally-polarized CD4+ T cell subsets, etc. in peripheral blood mononuclear cells（PBMCs）before and after anti-CD38 antibody therapy, and to compare with the healthy controls.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">10</enrollment>
    <condition>Antiphospholipid Syndrome</condition>
    <condition>Thrombocytopenia</condition>
    <arm_group>
      <arm_group_label>Intervention（Anti-CD38 antibody）</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>10 enrolled subjects: once a week x 8 doses</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Anti-CD38 antibody Injection</intervention_name>
      <description>intravenous Anti-CD38 antibody administration&#xD;
  This study adopts a prospective, single arm, open design method. Ten subjects were enrolled in the study and were treated with Anti-CD38 antibody (16mg/kg/w) for 8 weeks.&#xD;
  The first stage is the main research stage (d1-w8), which is the core treatment period. The subjects will receive intravenous infusion of 16mg/kg Anti-CD38 antibody once a week for 8 weeks to observe the safety and efficacy during treatment.&#xD;
  The second stage (w9-w24) is the stage of withdrawal from the visit, mainly to observe the safety and continuous efficacy of Anti-CD38 antibody after treatment.</description>
      <arm_group_label>Intervention（Anti-CD38 antibody）</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age 18 and above, male or female.&#xD;
  &#xD;
            -  Conform to the diagnostic criteria of antiphospholipid syndrome (APS).&#xD;
  &#xD;
            -  Failure to achieve response or relapse after corticosteroid therapy, and at least one&#xD;
               second-line therapy including rituximab, CSA or CTX etc., or those who cannot chose&#xD;
               other second-line therapy.&#xD;
  &#xD;
            -  Platelet count of &lt;30 X 10^9/L.&#xD;
  &#xD;
            -  With normal hepatic and renal functions.&#xD;
  &#xD;
            -  ECOG physical state score ≤ 2 points.&#xD;
  &#xD;
            -  Cardiac function of the New York Society of Cardiac Function ≤ 2.&#xD;
  &#xD;
            -  Signed and dated written informed consent&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Received any treatment of anti-CD38 antibody drug&#xD;
  &#xD;
            -  Uncontrollable primary diseases of important organs, such as malignant tumors, liver&#xD;
               failure, heart failure, renal failure and other diseases;&#xD;
  &#xD;
            -  HIV positive;&#xD;
  &#xD;
            -  Accompanied by uncontrollable active infection, including hepatitis B, hepatitis C,&#xD;
               cytomegalovirus, EB virus and syphilis positive;&#xD;
  &#xD;
            -  Accompanied by extensive and severe bleeding, such as hemoptysis, upper&#xD;
               gastrointestinal hemorrhage, intracranial hemorrhage, etc.;&#xD;
  &#xD;
            -  At present, there are heart diseases, arrhythmias that need treatment or hypertension&#xD;
               that researchers judge is poorly controlled;&#xD;
  &#xD;
            -  Patients with thrombotic diseases such as pulmonary embolism, thrombosis and&#xD;
               atherosclerosis;&#xD;
  &#xD;
            -  Those who have received allogeneic stem cell transplantation or organ transplantation&#xD;
               in the past;&#xD;
  &#xD;
            -  Patients with mental disorders who cannot normally obtain informed consent and conduct&#xD;
               trials and follow-up;&#xD;
  &#xD;
            -  Patients whose toxic symptoms caused by pre-trial treatment have not disappeared;&#xD;
  &#xD;
            -  Other serious diseases that may limit the subject's participation in this test (such&#xD;
               as diabetes; Severe cardiac insufficiency; Myocardial obstruction or unstable&#xD;
               arrhythmia or unstable angina pectoris in recent 6 months; Gastric ulcer, etc.);&#xD;
  &#xD;
            -  Patients with septicemia or other irregular severe bleeding;&#xD;
  &#xD;
            -  Pregnant women, suspected pregnancies (positive pregnancy test for human chorionic&#xD;
               gonadotropin in urine at screening) and lactating patients.&#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>Lei Zhang, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Chinese Academy of Medical Science and Blood Disease Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Yunfei Chen, MD</last_name>
      <phone>+8618502220788</phone>
      <email>chenyunfei@ihcams.ac.cn</email>
    </overall_contact>
    <location>
      <facility>
        <name>Chinese Academy of Medical Science and Blood Disease Hospital</name>
        <address>
          <city>Tianjin</city>
          <state>Tianjin</state>
          <zip>300020</zip>
          <country>China</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Yunfei Chen, MD</last_name>
        <phone>+86-22-23909009</phone>
        <email>chenyunfei@ihcams.ac.cn</email>
      </contact>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 31, 2023</study_first_submitted>
    <study_first_submitted_qc>July 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 9, 2023</study_first_posted>
    <last_update_submitted>August 9, 2023</last_update_submitted>
    <last_update_submitted_qc>August 9, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Institute of Hematology &amp; Blood Diseases Hospital, China</investigator_affiliation>
      <investigator_full_name>Zhang Lei, MD</investigator_full_name>
      <investigator_title>vice Director of Thrombosis and Hemostasis Center</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Thrombocytopenia</mesh_term>
      <mesh_term>Antiphospholipid Syndrome</mesh_term>
      <mesh_term>Syndrome</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Antibodies</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Researchers qualified can request the dataset, including de-identified individual subject data. Data may be requested from PI from 12 months 36 months after study completion.</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_time_frame>12 months to 36 months after study completion</ipd_time_frame>
      <ipd_access_criteria>Upon request to PI</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05983952
  org study id: 03CD38APS
  nct id: NCT05983952
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  To evaluate the safety and efficacy of anti-CD38 antibody in the treatment of
        antiphospholipid syndrome with secondary thrombocytopenia in patients who have not responded
        adequately or relapsed after first-line treatment and at least one second-line therapy
        including rituximab and/or TPO-RA.
  The anti-phospholipid syndrome (APS) is a systemic autoimmune disorder characterized by
        recurrent thrombosis and/or obstetrical morbidity along with persistent anti-phospholipid
        antibodies (APLA), including lupus anticoagulant (LA), anti-β2-glycoprotein I (anti-β2GPI)
        and/or anti-cardiolipin (aCL) antibodies. APS is one of the most common acquired
        thrombophilias, and unlike most of the genetic thrombophilias, ise associated with both
        venous and arterial thrombosis. The deep veins of the lower extremities and the cerebral
        arterial circulation are the most commonly affected venous and arterial sites, respectively.
        It has been posited that "two hits" are necessary to trigger a thrombotic event in
        antiphospholipid syndrome. This hypothesis argues that antiphospholipid antibodies provide
        the first hit by creating a generalized procoagulant state, which conspires with a second hit
        (often cryptic and potentially the result of subclinical vascular injury, stasis, or
        inflammation) that triggers thrombosis. The evidence that IgG antibodies targeting domain I
        of β2GPI contribute to the prothrombotic state of antiphospholipid syndrome is convincing.
        Meanwhile, data also support roles for other isotypes of aβ2GPI, antibodies that target
        heterotypic complexes of phospholipids and phospholipid binding proteins, and antibodies that
        target phospholipids directly. Given that most mechanistic studies have focused on either
        polyclonal IgG fractions isolated from patients with antiphospholipid syndrome or IgG
        anti-β2GPI, researchers unfortunately could not build a nuanced model of how diverse species
        of antiphospholipid antibodies conspire to cause various manifestations of antiphospholipid
        syndrome.
  
        The Sapporo classification criteria for APS were first proposed in 1999, and updated at the
        Eleventh International Congress on Antiphospholipid Antibodies in Sydney in 2006.Patient must
        have both clinical and laboratory criteria to meet a diagnosis of APS. Clinical criteria
        include either objectively confirmed venous, arterial or small vessel thrombosis, or
        obstetric morbidity including the unexplained death of one or more morphologically normal
        fetuses at or beyond the 10th week of gestation, the premature birth of one or more
        morphologically normal neonates before the 34th week of gestation, and/or three or more
        unexplained, consecutive spontaneous abortions before the 10th week of gestation. Since these
        clinical manifestations are prevalent in the general population and may have a multifactorial
        etiology, laboratory investigations are central to the diagnosis of APS. The updated Sydney
        classification scheme also requires specific laboratory criteria: a lupus anticoagulant
        detected according to guidelines published by the International Society on Thrombosis and
        Hemostasis (ISTH), anticardiolipin (aCL) antibodies (IgG or IgM) exceeding 40 IgG or IgM
        antiphospholipid units, or anti-β2GPI antibodies (IgG or IgM) at levels exceeding the 99th
        percentile, measured by enzyme-linked immunosorbent assay (ELISA). To minimize the risk of
        making a diagnosis based on transient ntiphospholipid antibodies, the recommendations are to
        perform assays on two separate occasions, at least twelve weeks apart.The major changes made
        in the 2006 revision of the Sapporo criteria were that anti-β2GPI antibody was included for
        the first time and a recommendation was made to classify patients into those with only one
        positive APLA and those with two or three positive APLA, based on accumulating information
        suggesting that positivity in more than a single assay was associated with higher thrombotic
        risk.
  
        Thrombocytopenia occurs in APS with a frequency ranging from 20% to 50%, and the estimated
        bleeding risk associated with it is much lower than the thrombotic risk associated with aPL.
        In some patients with a confirmed APS diagnosis, secondary immune thrombocytopenia (ITP) may
        lead to severe thrombocytopenia with consequent major bleeding. At the same time, the
        presence of antiphospholipid antibodies (aPL) in patients with a diagnosis of primary ITP has
        been reported in several studies, although with some specific characteristics especially
        related to the variety of antigenic targets. Even though it does not enter the APS defining
        criteria, thrombocytopenia should be regarded as a warning sign of a "high risk" APS and thus
        thoroughly evaluated. The presence of aPL in patients with ITP should be assessed as well to
        stratify the risk of paradoxical thrombosis. In detail, besides the high hemorrhagic risk in
        secondary thrombocytopenia, patients with a co-diagnosis of APS or only antibodies are also
        at risk of arterial and venous thrombosis. The pathogenesis of thrombocytopenia in
        antiphospholipid antibody-positive patients is not fully understood. However, based on
        currently available data, four different pathogenesis hypothesis were proposed, including
        secondary Immune thrombocytopenia, decreased platelet production, increased platelet pooling
        and increased platelet consumption. The APS associated thrombocytopenia treatment guidelines
        can be drawn lessons from the treatment strategies of ITP. Conventional treatment of adult
        APS associated thrombocytopenia includes first-line glucocorticoid and immunoglobulin
        therapy. B-cell targeted drugs are effective in the treatment of APS. Studies have found that
        rituximab can improve the clinical manifestations (including thrombocytopenia) and
        serological indicators in the late stage of APS treatment. Splenectomy is reserved for
        refractory patients who present with severe bleeding symptoms and are resistant to
        glucocorticoids and immunosuppressants. Plasmapheresis can be used in patients with CAPS when
        severe thrombocytopenia occurs. Thrombopoietin receptor agonists may increase the risk of
        thrombosis in APS patients and should be used with caution. When thrombosis coexists with
        bleeding events associated with thrombocytopenia, if platelet counts reach safe levels (&gt;
        50×109/L), glucocorticoid combined with anticoagulant therapy is recommended. It is difficult
        to treat APS patients with severe thrombocytopenia and severe bleeding. It has been reported
        in previous literature that platelets can be significantly increased in some patients after
        treatment with hormones or rituximab, immunosuppressants, etc., but it is easy to relapse and
        difficult to maintain. The decrease of aPL is not obvious and it is difficult to completely
        remove. It is a difficult point in the treatment of hematology.
  
        Anti-CD38 antibody, which targets plasma cells, has been used in multiple myeloma in a number
        of clinical studies and has shown good therapeutic effects. In addition, the clinical trials
        of anti-CD38 antibody analogues such as fizumatumumab in the treatment of autoimmune diseases
        including membranous nephropathy and systemic lupus erythematosus (SLE) are also being
        carried out simultaneously. A case report of anti-CD38 antibody in the treatment of APS has
        been reported abroad, and it has been found that it can significantly reduce the titer of
        antiphospholipid antibodies. In the process of treating ITP patients with antiphospholipid
        antibodies, investigators found that anti-CD38 antibody could not only rapidly increase
        platelet count, but also significantly reduce the titer of antiphospholipid antibodies, which
        may have a significant therapeutic effect on APS.Therefore, the use of daratumumab to clear
        APS with secondary thrombocytopenia may be effective and represents a new therapeutic
        strategy.
  
        Therefore, the investigators designed this clinical trial to evaluate the safety and efficacy
        of anti-CD38 antibody in the treatment of antiphospholipid syndrome with secondary
        thrombocytopenia.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: To evaluate the efficacy after CM313 treatment within 8 weeks
  time frame: 8 weeks
  description: Proportion of subjects with a platelet count ≥ 50 × 10^9/L within 8 weeks after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period
  measure: Safety of anti-CD38 antibody
  time frame: 24 weeks
  description: Incidence, severity, and relationship of treatment emergent adverse events after anti-CD38 antibody treatment
  measure: Response rate of treatment
  time frame: 12 weeks
  description: Including: 1. Proportion of subjects with a platelet count ≥ 50 × 10^9/L at week 2, week 4, week 6，week 8，week 10 and week 12 in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period; 2. Proportion of subjects achieving platelet counts ≥ 50×10^9/L at least once in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the first 12 weeks; 3. Proportion of subjects whose platelet counts ≥ 30×10^9/L and at least two times of baseline platelet count in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids within 8 weeks（two consecutive measurements at least 7 days apart）.
  measure: Duration from treatment initiation to platelet count ≥50×10^9/L
  time frame: 12 weeks
  description: Duration from treatment initiation to platelet count ≥50×10^9/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids
  measure: Duration of platelet response
  time frame: 24 weeks
  description: The longest duration for which the subject sustained a platelet count ≥50×109/L
  measure: platelet count ≥50×10^9/L ≥75% tests
  time frame: 24 weeks
  description: Proportion of subjects with platelet count ≥50×10^9/L in ≥ 75% of the total number of tests
  measure: Measurements of platelet count at each visit time point
  time frame: 24 weeks
  description: Platelet count at each visit time point
  measure: Emergency treatment
  time frame: 24 weeks
  description: Percentage of subjects who received emergency treatment
  measure: Number of subjects with clinically significant bleeding as assessed using the world health organization (WHO) bleeding scale
  time frame: 24 weeks
  description: Changes of the subjects' numbers in WHO bleeding score after Anti-CD38 antibody treatment according to the reported World Health Organization's Bleeding Scale. The WHO Bleeding Scale is a measure of bleeding severity with the following grades: grade 0 = no bleeding, grade 1= petechiae, grade 2= mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss.
  measure: Occurrence of thrombosis
  time frame: 24 weeks
  description: Assessment of the occurrence of thrombosis during the study period
  measure: Measurements of antiphospholipid antibody
  time frame: 24 weeks
  description: Measurements of the level of antiphospholipid antibody during the study period
  measure: platelet count ≥50×10^9/L at least once
  time frame: 8 weeks
  description: Percentage of subjects with a platelet count ≥50×109/L at least once 8 weeks after the first dose
  measure: platelet count ≥30×10^9/L and at least 2-fold from baseline on at least one occasion
  time frame: 8 weeks
  description: The percentage of subjects with a platelet count ≥30×10^9/L and at least 2-fold from baseline 8 weeks after the first dose on at least one occasion
  measure: Measurements of various subsets of immunocompetent cells
  time frame: 24 weeks
  description: To assess the changes of the percentage of B cell subsets，regulatory B cells（Breg），regulatory T cells (Treg)，supressor T cells（Ts），monocyte subcets, helper T cells（Th）subsets and the functionally-polarized CD4+ T cell subsets, etc. in peripheral blood mononuclear cells（PBMCs）before and after anti-CD38 antibody therapy, and to compare with the healthy controls.
  arm group label: Intervention（Anti-CD38 antibody）
  arm group type: Experimental
  description: 10 enrolled subjects: once a week x 8 doses
  intervention type: Drug
  intervention name: Anti-CD38 antibody Injection
  description: intravenous Anti-CD38 antibody administration
  This study adopts a prospective, single arm, open design method. Ten subjects were enrolled in the study and were treated with Anti-CD38 antibody (16mg/kg/w) for 8 weeks.
  The first stage is the main research stage (d1-w8), which is the core treatment period. The subjects will receive intravenous infusion of 16mg/kg Anti-CD38 antibody once a week for 8 weeks to observe the safety and efficacy during treatment.
  The second stage (w9-w24) is the stage of withdrawal from the visit, mainly to observe the safety and continuous efficacy of Anti-CD38 antibody after treatment.
  arm group label: Intervention（Anti-CD38 antibody）
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Lei Zhang, MD
  role: Principal Investigator
  affiliation: Chinese Academy of Medical Science and Blood Disease Hospital
  last name: Yunfei Chen, MD
  phone: +8618502220788
  email: chenyunfei@ihcams.ac.cn
  facility: 
  status: Recruiting
  contact: 
  country: China
  responsible party type: Principal Investigator
  investigator affiliation: Institute of Hematology & Blood Diseases Hospital, China
  investigator full name: Zhang Lei, MD
  investigator title: vice Director of Thrombosis and Hemostasis Center
  mesh term: Thrombocytopenia
  mesh term: Antiphospholipid Syndrome
  mesh term: Syndrome
  mesh term: Antibodies
  sharing ipd: Yes
  ipd description: Researchers qualified can request the dataset, including de-identified individual subject data. Data may be requested from PI from 12 months 36 months after study completion.
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd info type: Informed Consent Form (ICF)
  ipd time frame: 12 months to 36 months after study completion
  ipd access criteria: Upon request to PI