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Isoagglutinins in the Development of IVIG-associated Hemolysis

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ClinicalTrials.gov Identifier: NCT02259478
Recruitment Status : Completed
First Posted : October 8, 2014
Last Update Posted : March 14, 2017
Sponsor:
Collaborators:
University Health Network, Toronto
Sunnybrook Health Sciences Centre
Mount Sinai Hospital, New York
The Hospital for Sick Children
St. Michael's Hospital, Toronto
Women's College Hospital
Information provided by (Responsible Party):
Jacob Pendergrast, Toronto Transfusion Medicine Collaborative

Brief Summary:
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.

Condition or disease
Immunoglobulins, Intravenous Hemolysis

Detailed Description:

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.


Study Type : Observational
Actual Enrollment : 144 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Elucidation of the Mechanism of IVIG-Associated Hemolysis
Study Start Date : October 2014
Actual Primary Completion Date : October 2016
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources




Primary Outcome Measures :
  1. Hemolysis [ Time Frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion ]
    Definition and grading of hemolysis adopted from the Canadian IVIG Hemolysis Pharmacovigilance Group


Secondary Outcome Measures :
  1. Adverse transfusion reaction [ Time Frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion ]
    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)

  2. Descriptive analysis of risk factors [ Time Frame: From initiation of IVIG therapy to 5-10 days after the completion of last IVIG infusion ]

    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:

    1. Cytokine panel profiling
    2. C3, C4, ferritin and CRP levels
    3. Monocyte monolayer assay using patient monocytes and implicated lot of IVIG against AET-treated group A1, B, and O red cells
    4. Tests of eluted IgG antibody for subtype.
    5. ABO zygosity (PCR) and/or by Flow
    6. FcR polymorphisms by PCR
    7. Secretor status by PCR


Biospecimen Retention:   Samples With DNA
Whole blood samples will be collected immediately prior and following a course of IVIG therapy, and then again 5-10 days later


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Ages Eligible for Study:   3 Months and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
All orders for IVIG received by the UHN Blood Transfusion Service will be reviewed by the study coordinator to identify potential study participants
Criteria

Inclusion Criteria:

  • cumulative dose within a 28-day period equal or greater to 2 g/kg body weight, adjusted for lean body mass
  • non-O blood group
  • willing to provide blood samples immediately prior to, immediately after the completion of, and 5-10 days after the course of IVIG therapy
  • Able to provide informed consent, either themselves or through a surrogate decision-maker

Exclusion Criteria:

  • evidence of active bleeding or hemolytic anemia at time of enrolment (patients with chronic, stable anemia will be eligible following review by the principle investigator)
  • concurrently prescribed transfusion therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02259478


Locations
Canada, Ontario
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada, M4N 3M5
St. Michael's Hospital
Toronto, Ontario, Canada, M5B 1W8
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Mount Sinai Hospital
Toronto, Ontario, Canada, M5G 2C4
University Health Network
Toronto, Ontario, Canada, M5G 2C4
Women's College Hospital
Toronto, Ontario, Canada
Sponsors and Collaborators
Toronto Transfusion Medicine Collaborative
University Health Network, Toronto
Sunnybrook Health Sciences Centre
Mount Sinai Hospital, New York
The Hospital for Sick Children
St. Michael's Hospital, Toronto
Women's College Hospital
Investigators
Principal Investigator: Don Branch, PhD Canadian Blood Services

Responsible Party: Jacob Pendergrast, Consultant in Transfusion Medicine, Toronto Transfusion Medicine Collaborative
ClinicalTrials.gov Identifier: NCT02259478     History of Changes
Other Study ID Numbers: 14-8191-CE
First Posted: October 8, 2014    Key Record Dates
Last Update Posted: March 14, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Jacob Pendergrast, Toronto Transfusion Medicine Collaborative:
Intravenous Immunoglobulin (IVIG)
Hemolysis
Transfusion Medicine
Pharmacovigilance

Additional relevant MeSH terms:
Hemolysis
Pathologic Processes