<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/NCT03269292</url>
  </required_header>
  <id_info>
    <org_study_id>AIHA in assiut</org_study_id>
    <nct_id>NCT03269292</nct_id>
  </id_info>
  <brief_title>Clinical Characteristics and Treatment Outcomes of Patients With Autoimmune Hemolytic Anemia</brief_title>
  <official_title>Clinical Characteristics and Treatment Outcomes of Patients With Autoimmune Hemolytic Anemia in Assiut University Hospital</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</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>
      Autoimmune hemolytic anemia is characterized by shortened red blood cell survival and a&#xD;
      positive Coombs test. The responsible autoantibodies may be either warm reactive or cold&#xD;
      reactive. The rate of hemolysis and the severity of the anemia may vary from mild to severe&#xD;
      and life-threatening. Diagnosis is made in the laboratory by the findings of anemia,&#xD;
      reticulocytosis, a positive Coombs test, and specific serologic tests. The prognosis is&#xD;
      generally good but renal failure and death sometimes occur, especially in cases mediated by&#xD;
      drugs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hemolysis is the premature destruction of erythrocytes. A hemolytic anemia will develop if&#xD;
      bone marrow activity cannot compensate for the erythrocyte loss. The severity of the anemia&#xD;
      depends on whether the onset of hemolysis is gradual or abrupt and on the extent of&#xD;
      erythrocyte destruction Hemolysis can be due to hereditary and acquired disorders. Acquired&#xD;
      causes of hemolysis include immune disorders, Toxic chemicals and drugs, Antiviral agents and&#xD;
      Physical damage .&#xD;
&#xD;
      Autoimmune hemolytic anemia (AIHA) exhibits two important characteristics: shortened red&#xD;
      blood cell (RBC) survival and presence of autoantibodies directed toward autologous RBCs,&#xD;
      usually demonstrated by a positive direct antiglobulin (Coombs) test (DAT). AIHA is&#xD;
      classified by the temperature at which autoantibodies bind optimally to RBCs. In warm&#xD;
      antibody AIHA, which constitutes about 80-90% of adult cases, hemolysis is mediated by&#xD;
      antibodies which bind to RBCs at 37 °C (98.6 °F. In cryopathic hemolytic syndromes,&#xD;
      cold-reactive autoantibodies exhibit affinity for RBCs optimally at temperatures below body&#xD;
      temperature. In adults, most of the cold-reactive antibodies are agglutinins of the&#xD;
      immunoglobulin M (IgM) isotype. In children, cold hemolysins (generally IgG) are most common.&#xD;
      Unusual patients with mixed AIHA exhibit both cold-reactive and warm-reactive autoantibodies&#xD;
      .&#xD;
&#xD;
      Each of these types of AIHA may be sub-classified based on the presence or absence of&#xD;
      underlying diseases. In the absence of an underlying disease, the AIHA is termed primary or&#xD;
      idiopathic. When AIHA occurs as a manifestation or complication of another disease, the term&#xD;
      secondary AIHA is used. Chronic lymphocytic leukemia (CLL) and lymphomas account for about&#xD;
      half of all secondary AIHA cases. Systemic lupus erythematosus (SLE) and other autoimmune&#xD;
      diseases also account for a large number of secondary AIHA cases. Certain drugs also mediate&#xD;
      immune injury to RBCs. Three mechanisms are recognized and two of these involve elements of&#xD;
      autoimmunity, in which autoantibodies recognize and bind to specific RBC epitopes in concert&#xD;
      with drugs or their metabolites or in which the autoantibody binds to RBC epitopes without&#xD;
      the presence of drug&#xD;
&#xD;
      Diagnosis The signs and symptoms of AIHA are nonspecific and common to all types of anemia .&#xD;
      The primary symptoms include exertional dyspnea, dyspnea at rest, varying degrees of fatigue,&#xD;
      and signs and symptoms of the hyperdynamic state, such as bounding pulses, palpitations…etc&#xD;
&#xD;
      The laboratory findings of drug-induced AIHA may resemble those of warm antibody AIHA or a&#xD;
      cryopathic hemolytic syndrome, depending on the mechanism of the autoantibody induction and&#xD;
      the target antigen. A high index of suspicion on the part of the clinician and discussions&#xD;
      with blood bank personnel can usually reveal the role of the drug.&#xD;
&#xD;
      complete blood count Peripheral blood smear : This test can detect an anemia, pancytopenia,&#xD;
      and infections. Along with the differential count, a complete blood count can help diagnose&#xD;
      hematologic malignancies and other hematological disorders. The platelet count usually is&#xD;
      normal in most hemolytic anemias.&#xD;
&#xD;
      An increased reticulocyte count represents increased RBC production and is a criterion for&#xD;
      hemolysis but is not specific for hemolysis. Thrombocytopenia associated with positive direct&#xD;
      coombs test occur in evans syndrome .&#xD;
&#xD;
      Serum lactate dehydrogenase (LDH) study : Serum LDH elevation is a criterion for hemolysis,&#xD;
      but is not specific&#xD;
&#xD;
      Serum haptoglobin : A low serum haptoglobin level is a criterion for moderate-to-severe&#xD;
      hemolysis.&#xD;
&#xD;
      Indirect bilirubin : Unconjugated bilirubin is a criterion for hemolysis, but it is not&#xD;
      specific , the level of indirect bilirubin usually is less than 3 mg/dL.&#xD;
&#xD;
      Direct antiglobulin test (DAT):&#xD;
&#xD;
      The DAT result is usually positive in autoimmune hemolytic anemia (AIHA), but it may&#xD;
      occasionally be negative in this disorder. DAT-negative AIHAs have been reviewed. From 5-10%&#xD;
      of all AIHAs are DAT negative. The polybrene test can detect DAT-negative AIHA.&#xD;
&#xD;
      Treatment all of the drugs used in the treatment of AIHA are largely or partly directed&#xD;
      against the patient's natural immune system, which may, in turn, extensively derail the&#xD;
      immune system due to treatment. .The first-line therapy for warm AIHA are corticosteroids,&#xD;
      which are effective in 70-85% of patients and should be slowly tapered over a time period of&#xD;
      6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is&#xD;
      splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to&#xD;
      20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the&#xD;
      immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil).&#xD;
      Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and&#xD;
      alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with&#xD;
      rituximab evolves, it is likely that this drug will be located at an earlier point in therapy&#xD;
      of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some&#xD;
      cases. In coronary artery disease , rituximab is now recommended as first-line treatment&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Actual">January 24, 2021</completion_date>
  <primary_completion_date type="Actual">January 24, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline in hemoglobin</measure>
    <time_frame>three week from baseline</time_frame>
    <description>Efficacy endpoint assesment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>frequency of drug-related side effects</measure>
    <time_frame>three week from base line</time_frame>
    <description>safety endpoint</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Dose of steroid treatment</measure>
    <time_frame>at 3 weeks, three months, six month, one year from baseline</time_frame>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">150</enrollment>
  <condition>Autoimmune Hemolytic Anemia</condition>
  <arm_group>
    <arm_group_label>warm autoimmune hemolytic anemia</arm_group_label>
    <description>corticosteroid either oral form or intravenous followed by oral</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        patients above 18 years or more diagnosed AIHA at Assiut university hospital&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        patients diagnosed warm auto Immune hemolytic anemia primary or secondary(CLL, Lymphoma,&#xD;
        rheumatoid arthritis&#xD;
&#xD;
        , SLE,Drug-induced )&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. All types of congenital hemolytic anemia&#xD;
&#xD;
          2. Microangiopathic hemolytic anemia ( Thrombotic thrombocytopenic purpura (TTP) ,&#xD;
             Hemolytic-uremic syndrome (HUS) , Disseminated intravascular coagulation (DIC) )&#xD;
&#xD;
          3. Alloimmune hemolytic anemia&#xD;
&#xD;
          4. pregnancy&#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>Essam Abdel Monem El-beih, professor</last_name>
    <role>Study Director</role>
    <affiliation>Assiut University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>wael ahmed abbas, professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assiut University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Assiut University Hospital</name>
      <address>
        <city>Assiut</city>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <results_reference>
    <citation>Packman CH. The Clinical Pictures of Autoimmune Hemolytic Anemia. Transfus Med Hemother. 2015 Sep;42(5):317-24. doi: 10.1159/000440656. Epub 2015 Sep 11.</citation>
    <PMID>26696800</PMID>
  </results_reference>
  <results_reference>
    <citation>Dhingra KK, Jain D, Mandal S, Khurana N, Singh T, Gupta N. Evans syndrome: a study of six cases with review of literature. Hematology. 2008 Dec;13(6):356-60. doi: 10.1179/102453308X343518.</citation>
    <PMID>19055865</PMID>
  </results_reference>
  <results_reference>
    <citation>Garratty G. Immune hemolytic anemia associated with negative routine serology. Semin Hematol. 2005 Jul;42(3):156-64. doi: 10.1053/j.seminhematol.2005.04.005.</citation>
    <PMID>16041665</PMID>
  </results_reference>
  <results_reference>
    <citation>Kamesaki T, Oyamada T, Omine M, Ozawa K, Kajii E. Cut-off value of red-blood-cell-bound IgG for the diagnosis of Coombs-negative autoimmune hemolytic anemia. Am J Hematol. 2009 Feb;84(2):98-101. doi: 10.1002/ajh.21336.</citation>
    <PMID>19105232</PMID>
  </results_reference>
  <results_reference>
    <citation>Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014 Oct;99(10):1547-54. doi: 10.3324/haematol.2014.114561.</citation>
    <PMID>25271314</PMID>
  </results_reference>
  <results_reference>
    <citation>Michel M. [Characteristics of warm autoimmune hemolytic anemia and Evans syndrome in adults]. Presse Med. 2008 Sep;37(9):1309-18. doi: 10.1016/j.lpm.2008.01.026. Epub 2008 Jul 17. French.</citation>
    <PMID>18644324</PMID>
  </results_reference>
  <results_reference>
    <citation>Salama A. Treatment Options for Primary Autoimmune Hemolytic Anemia: A Short Comprehensive Review. Transfus Med Hemother. 2015 Sep;42(5):294-301. doi: 10.1159/000438731. Epub 2015 Aug 10.</citation>
    <PMID>26696797</PMID>
  </results_reference>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>August 28, 2017</study_first_submitted>
  <study_first_submitted_qc>August 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 31, 2017</study_first_posted>
  <last_update_submitted>April 11, 2021</last_update_submitted>
  <last_update_submitted_qc>April 11, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Ehab A. Abdelmenam</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia</mesh_term>
    <mesh_term>Anemia, Hemolytic</mesh_term>
    <mesh_term>Anemia, Hemolytic, Autoimmune</mesh_term>
    <mesh_term>Hemolysis</mesh_term>
  </condition_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/NCT03269292
org study id: AIHA in assiut
nct id: NCT03269292
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Autoimmune hemolytic anemia is characterized by shortened red blood cell survival and a
      positive Coombs test. The responsible autoantibodies may be either warm reactive or cold
      reactive. The rate of hemolysis and the severity of the anemia may vary from mild to severe
      and life-threatening. Diagnosis is made in the laboratory by the findings of anemia,
      reticulocytosis, a positive Coombs test, and specific serologic tests. The prognosis is
      generally good but renal failure and death sometimes occur, especially in cases mediated by
      drugs.
Hemolysis is the premature destruction of erythrocytes. A hemolytic anemia will develop if
      bone marrow activity cannot compensate for the erythrocyte loss. The severity of the anemia
      depends on whether the onset of hemolysis is gradual or abrupt and on the extent of
      erythrocyte destruction Hemolysis can be due to hereditary and acquired disorders. Acquired
      causes of hemolysis include immune disorders, Toxic chemicals and drugs, Antiviral agents and
      Physical damage .

      Autoimmune hemolytic anemia (AIHA) exhibits two important characteristics: shortened red
      blood cell (RBC) survival and presence of autoantibodies directed toward autologous RBCs,
      usually demonstrated by a positive direct antiglobulin (Coombs) test (DAT). AIHA is
      classified by the temperature at which autoantibodies bind optimally to RBCs. In warm
      antibody AIHA, which constitutes about 80-90% of adult cases, hemolysis is mediated by
      antibodies which bind to RBCs at 37 °C (98.6 °F. In cryopathic hemolytic syndromes,
      cold-reactive autoantibodies exhibit affinity for RBCs optimally at temperatures below body
      temperature. In adults, most of the cold-reactive antibodies are agglutinins of the
      immunoglobulin M (IgM) isotype. In children, cold hemolysins (generally IgG) are most common.
      Unusual patients with mixed AIHA exhibit both cold-reactive and warm-reactive autoantibodies
      .

      Each of these types of AIHA may be sub-classified based on the presence or absence of
      underlying diseases. In the absence of an underlying disease, the AIHA is termed primary or
      idiopathic. When AIHA occurs as a manifestation or complication of another disease, the term
      secondary AIHA is used. Chronic lymphocytic leukemia (CLL) and lymphomas account for about
      half of all secondary AIHA cases. Systemic lupus erythematosus (SLE) and other autoimmune
      diseases also account for a large number of secondary AIHA cases. Certain drugs also mediate
      immune injury to RBCs. Three mechanisms are recognized and two of these involve elements of
      autoimmunity, in which autoantibodies recognize and bind to specific RBC epitopes in concert
      with drugs or their metabolites or in which the autoantibody binds to RBC epitopes without
      the presence of drug

      Diagnosis The signs and symptoms of AIHA are nonspecific and common to all types of anemia .
      The primary symptoms include exertional dyspnea, dyspnea at rest, varying degrees of fatigue,
      and signs and symptoms of the hyperdynamic state, such as bounding pulses, palpitations…etc

      The laboratory findings of drug-induced AIHA may resemble those of warm antibody AIHA or a
      cryopathic hemolytic syndrome, depending on the mechanism of the autoantibody induction and
      the target antigen. A high index of suspicion on the part of the clinician and discussions
      with blood bank personnel can usually reveal the role of the drug.

      complete blood count Peripheral blood smear : This test can detect an anemia, pancytopenia,
      and infections. Along with the differential count, a complete blood count can help diagnose
      hematologic malignancies and other hematological disorders. The platelet count usually is
      normal in most hemolytic anemias.

      An increased reticulocyte count represents increased RBC production and is a criterion for
      hemolysis but is not specific for hemolysis. Thrombocytopenia associated with positive direct
      coombs test occur in evans syndrome .

      Serum lactate dehydrogenase (LDH) study : Serum LDH elevation is a criterion for hemolysis,
      but is not specific

      Serum haptoglobin : A low serum haptoglobin level is a criterion for moderate-to-severe
      hemolysis.

      Indirect bilirubin : Unconjugated bilirubin is a criterion for hemolysis, but it is not
      specific , the level of indirect bilirubin usually is less than 3 mg/dL.

      Direct antiglobulin test (DAT):

      The DAT result is usually positive in autoimmune hemolytic anemia (AIHA), but it may
      occasionally be negative in this disorder. DAT-negative AIHAs have been reviewed. From 5-10%
      of all AIHAs are DAT negative. The polybrene test can detect DAT-negative AIHA.

      Treatment all of the drugs used in the treatment of AIHA are largely or partly directed
      against the patient's natural immune system, which may, in turn, extensively derail the
      immune system due to treatment. .The first-line therapy for warm AIHA are corticosteroids,
      which are effective in 70-85% of patients and should be slowly tapered over a time period of
      6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is
      splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to
      20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the
      immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil).
      Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and
      alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with
      rituximab evolves, it is likely that this drug will be located at an earlier point in therapy
      of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some
      cases. In coronary artery disease , rituximab is now recommended as first-line treatment
observational model: Cohort
time perspective: Prospective
measure: Change from baseline in hemoglobin
time frame: three week from baseline
description: Efficacy endpoint assesment
measure: frequency of drug-related side effects
time frame: three week from base line
description: safety endpoint
measure: Dose of steroid treatment
time frame: at 3 weeks, three months, six month, one year from baseline
arm group label: warm autoimmune hemolytic anemia
description: corticosteroid either oral form or intravenous followed by oral
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Essam Abdel Monem El-beih, professor
role: Study Director
affiliation: Assiut University
last name: wael ahmed abbas, professor
role: Principal Investigator
affiliation: Assiut University
facility: 
country: Egypt
citation: Packman CH. The Clinical Pictures of Autoimmune Hemolytic Anemia. Transfus Med Hemother. 2015 Sep;42(5):317-24. doi: 10.1159/000440656. Epub 2015 Sep 11.
PMID: 26696800
citation: Dhingra KK, Jain D, Mandal S, Khurana N, Singh T, Gupta N. Evans syndrome: a study of six cases with review of literature. Hematology. 2008 Dec;13(6):356-60. doi: 10.1179/102453308X343518.
PMID: 19055865
citation: Garratty G. Immune hemolytic anemia associated with negative routine serology. Semin Hematol. 2005 Jul;42(3):156-64. doi: 10.1053/j.seminhematol.2005.04.005.
PMID: 16041665
citation: Kamesaki T, Oyamada T, Omine M, Ozawa K, Kajii E. Cut-off value of red-blood-cell-bound IgG for the diagnosis of Coombs-negative autoimmune hemolytic anemia. Am J Hematol. 2009 Feb;84(2):98-101. doi: 10.1002/ajh.21336.
PMID: 19105232
citation: Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014 Oct;99(10):1547-54. doi: 10.3324/haematol.2014.114561.
PMID: 25271314
citation: Michel M. [Characteristics of warm autoimmune hemolytic anemia and Evans syndrome in adults]. Presse Med. 2008 Sep;37(9):1309-18. doi: 10.1016/j.lpm.2008.01.026. Epub 2008 Jul 17. French.
PMID: 18644324
citation: Salama A. Treatment Options for Primary Autoimmune Hemolytic Anemia: A Short Comprehensive Review. Transfus Med Hemother. 2015 Sep;42(5):294-301. doi: 10.1159/000438731. Epub 2015 Aug 10.
PMID: 26696797
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Ehab A. Abdelmenam
investigator title: Principal Investigator
mesh term: Anemia
mesh term: Anemia, Hemolytic
mesh term: Anemia, Hemolytic, Autoimmune
mesh term: Hemolysis