<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/NCT02259478</url>
  </required_header>
  <id_info>
    <org_study_id>14-8191-CE</org_study_id>
    <nct_id>NCT02259478</nct_id>
  </id_info>
  <brief_title>Isoagglutinins in the Development of IVIG-associated Hemolysis</brief_title>
  <official_title>Elucidation of the Mechanism of IVIG-Associated Hemolysis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Toronto Transfusion Medicine Collaborative</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sunnybrook Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mount Sinai Hospital, New York</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Hospital for Sick Children</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Unity Health Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Women's College Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Toronto Transfusion Medicine Collaborative</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients at high risk of IVIG-associated hemolysis (defined as receipt of a 28-day cumulative&#xD;
      dose of ≥ 2 g/kg, adjusted for ideal body weight, and non-O blood group) will be&#xD;
      prospectively monitored using a standardized protocol for signs of hemolysis, and will be&#xD;
      undergo additional testing for variables that have been hypothesized to increase the risk of&#xD;
      hemolysis. The goal of the study is to define the incidence and dynamics of IVIG-mediated&#xD;
      hemolysis and identify patient and product-related factors that may predict which patients&#xD;
      are especially at risk.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All IVIG orders received by the blood transfusion service at participating sites will be&#xD;
      screened for patient eligibility. All non-O blood group patients receiving a cumulative&#xD;
      28-day dose of IVIG ≥ 2 g/kg will be approached for enrolment. Exclusion criteria include the&#xD;
      presence of an alternate cause of anemia, including blood loss, other drug-induced hemolysis,&#xD;
      anemia associated with chemotherapy for cancer, or hemolysis associated with an underlying&#xD;
      disease or participation in another ongoing study. Patients receiving repeated courses of&#xD;
      therapy will be eligible for re-enrollment a maximum of 6 times. There are otherwise no&#xD;
      exclusions on the basis of age, diagnosis, concurrent treatment, or specific brand of product&#xD;
      received. Enrolment will occur at multiple Canadian health care facilities.&#xD;
&#xD;
      Upon enrolment,case report forms documenting the participant's previous medical history, IVIG&#xD;
      treatments and adverse reactions, and concurrent medication use will be collected. Laboratory&#xD;
      testing for hemolysis will be performed at baseline, immediately following the completed&#xD;
      high-dose cycle (usually administered over 1-2 days), and then again at 5-10 days&#xD;
      post-infusion. IVIG associated. Hemolysis will be defined and graded as per the criteria of&#xD;
      the Canadian IVIG Pharmacovigilance Group. The pathophysiology of IVIG-associated hemolysis&#xD;
      will be characterized by tracking changes in serum complement levels, performing extended&#xD;
      cytokine profiling, and conducting mononuclear phagocyte activity assays using patient&#xD;
      monocytes. Secretor gene status, ABO zygosity and FcR polymorphisms will also be determined.&#xD;
      A predictive model incorporating both patient factors (eg., blood group, total dose&#xD;
      prescribed, presence of pre-infusion inflammation) and product factors (eg., specific lot&#xD;
      number) will then be developed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">October 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Hemolysis</measure>
    <time_frame>From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion</time_frame>
    <description>Definition and grading of hemolysis adopted from the Canadian IVIG Hemolysis Pharmacovigilance Group</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse transfusion reaction</measure>
    <time_frame>From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion</time_frame>
    <description>Any patient symptom reported during or within 10 days of an IVIG infusion will be considered as a possible adverse transfusion reaction. Symptoms deemed to most likely indicate an adverse reaction include the development of fever, chills or rigours; allergic reactions (urticaria, angioedema or anaphylaxis); pain reactions (including headache); respiratory symptoms (cough, shortness of breath); and signs suggestive of anemia or hemolysis (pallor, fatigue, red-coloured urine, jaundice)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Descriptive analysis of risk factors</measure>
    <time_frame>From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion</time_frame>
    <description>Additional secondary outcomes will include a descriptive analysis of information collected on the initial case report form such as patient demographics, medical history, dose and lot of IVIG administered, infusion rate, patient blood group, and concurrent medications. In addition, patient samples will be sent for additional testing aimed at elucidating the mechanism of IVIG-mediated hemolysis. These include:&#xD;
Cytokine panel profiling&#xD;
C3, C4, ferritin and CRP levels&#xD;
Monocyte monolayer assay using patient monocytes and implicated lot of IVIG against AET-treated group A1, B, and O red cells&#xD;
Tests of eluted IgG antibody for subtype.&#xD;
ABO zygosity (PCR) and/or by Flow&#xD;
FcR polymorphisms by PCR&#xD;
Secretor status by PCR</description>
  </secondary_outcome>
  <enrollment type="Actual">144</enrollment>
  <condition>Immunoglobulins, Intravenous</condition>
  <condition>Hemolysis</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood samples will be collected immediately prior and following a course of IVIG&#xD;
      therapy, and then again 5-10 days later&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        All orders for IVIG received by the UHN Blood Transfusion Service will be reviewed by the&#xD;
        study coordinator to identify potential study participants&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  cumulative dose within a 28-day period equal or greater to 2 g/kg body weight,&#xD;
             adjusted for lean body mass&#xD;
&#xD;
          -  non-O blood group&#xD;
&#xD;
          -  willing to provide blood samples immediately prior to, immediately after the&#xD;
             completion of, and 5-10 days after the course of IVIG therapy&#xD;
&#xD;
          -  Able to provide informed consent, either themselves or through a surrogate&#xD;
             decision-maker&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  evidence of active bleeding or hemolytic anemia at time of enrolment (patients with&#xD;
             chronic, stable anemia will be eligible following review by the principle&#xD;
             investigator)&#xD;
&#xD;
          -  concurrently prescribed transfusion therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Don Branch, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Canadian Blood Services</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Michael's Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5B 1W8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Hospital for Sick Children</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Health Network</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Women's College Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>August 29, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 8, 2014</study_first_posted>
  <last_update_submitted>March 10, 2017</last_update_submitted>
  <last_update_submitted_qc>March 10, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 14, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Toronto Transfusion Medicine Collaborative</investigator_affiliation>
    <investigator_full_name>Jacob Pendergrast</investigator_full_name>
    <investigator_title>Consultant in Transfusion Medicine</investigator_title>
  </responsible_party>
  <keyword>Intravenous Immunoglobulin (IVIG)</keyword>
  <keyword>Hemolysis</keyword>
  <keyword>Transfusion Medicine</keyword>
  <keyword>Pharmacovigilance</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemolysis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</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/NCT02259478
org study id: 14-8191-CE
nct id: NCT02259478
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
Patients at high risk of IVIG-associated hemolysis (defined as receipt of a 28-day cumulative
      dose of ≥ 2 g/kg, adjusted for ideal body weight, and non-O blood group) will be
      prospectively monitored using a standardized protocol for signs of hemolysis, and will be
      undergo additional testing for variables that have been hypothesized to increase the risk of
      hemolysis. The goal of the study is to define the incidence and dynamics of IVIG-mediated
      hemolysis and identify patient and product-related factors that may predict which patients
      are especially at risk.
All IVIG orders received by the blood transfusion service at participating sites will be
      screened for patient eligibility. All non-O blood group patients receiving a cumulative
      28-day dose of IVIG ≥ 2 g/kg will be approached for enrolment. Exclusion criteria include the
      presence of an alternate cause of anemia, including blood loss, other drug-induced hemolysis,
      anemia associated with chemotherapy for cancer, or hemolysis associated with an underlying
      disease or participation in another ongoing study. Patients receiving repeated courses of
      therapy will be eligible for re-enrollment a maximum of 6 times. There are otherwise no
      exclusions on the basis of age, diagnosis, concurrent treatment, or specific brand of product
      received. Enrolment will occur at multiple Canadian health care facilities.

      Upon enrolment,case report forms documenting the participant's previous medical history, IVIG
      treatments and adverse reactions, and concurrent medication use will be collected. Laboratory
      testing for hemolysis will be performed at baseline, immediately following the completed
      high-dose cycle (usually administered over 1-2 days), and then again at 5-10 days
      post-infusion. IVIG associated. Hemolysis will be defined and graded as per the criteria of
      the Canadian IVIG Pharmacovigilance Group. The pathophysiology of IVIG-associated hemolysis
      will be characterized by tracking changes in serum complement levels, performing extended
      cytokine profiling, and conducting mononuclear phagocyte activity assays using patient
      monocytes. Secretor gene status, ABO zygosity and FcR polymorphisms will also be determined.
      A predictive model incorporating both patient factors (eg., blood group, total dose
      prescribed, presence of pre-infusion inflammation) and product factors (eg., specific lot
      number) will then be developed.
observational model: Case-Control
time perspective: Prospective
measure: Hemolysis
time frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion
description: Definition and grading of hemolysis adopted from the Canadian IVIG Hemolysis Pharmacovigilance Group
measure: Adverse transfusion reaction
time frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion
description: Any patient symptom reported during or within 10 days of an IVIG infusion will be considered as a possible adverse transfusion reaction. Symptoms deemed to most likely indicate an adverse reaction include the development of fever, chills or rigours; allergic reactions (urticaria, angioedema or anaphylaxis); pain reactions (including headache); respiratory symptoms (cough, shortness of breath); and signs suggestive of anemia or hemolysis (pallor, fatigue, red-coloured urine, jaundice)
measure: Descriptive analysis of risk factors
time frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion
description: Additional secondary outcomes will include a descriptive analysis of information collected on the initial case report form such as patient demographics, medical history, dose and lot of IVIG administered, infusion rate, patient blood group, and concurrent medications. In addition, patient samples will be sent for additional testing aimed at elucidating the mechanism of IVIG-mediated hemolysis. These include:
Cytokine panel profiling
C3, C4, ferritin and CRP levels
Monocyte monolayer assay using patient monocytes and implicated lot of IVIG against AET-treated group A1, B, and O red cells
Tests of eluted IgG antibody for subtype.
ABO zygosity (PCR) and/or by Flow
FcR polymorphisms by PCR
Secretor status by PCR
Whole blood samples will be collected immediately prior and following a course of IVIG
      therapy, and then again 5-10 days later
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 3 Months
maximum age: N/A
healthy volunteers: No
last name: Don Branch, PhD
role: Principal Investigator
affiliation: Canadian Blood Services
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Toronto Transfusion Medicine Collaborative
investigator full name: Jacob Pendergrast
investigator title: Consultant in Transfusion Medicine
mesh term: Hemolysis
sharing ipd: Yes