Red Blood Cell - IMProving trAnsfusions for Chronically Transfused Recipients (RBC-IMPACT)

Red Blood Cell - IMProving trAnsfusions for Chronically Transfused Recipients (RBC-IMPACT)

Red Blood Cell - IMProving trAnsfusions for Chronically Transfused recipients (RBC-IMPACT) is an observational cohort study to assess donor, component, and recipient factors that contribute to RBC efficacy in chronically and episodically transfused patients. The objective of the study is to determine how specific genetic and non-genetic factors in donors and recipients may impact RBC survival after transfusion - in short, what factors on both the donor and recipient side may improve the efficacy of the transfusion.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease; Thalassemia; Pediatric Cancer
• Intervention / Treatment: Biological: Red Blood Cell (RBC) Transfusion

Detailed Description

Sickle cell disease (SCD) and thalassemia are genetic disorders inducing anemia of differing pathophysiology. A primary therapy for preventing certain SCD complications (e.g., stroke) and for thalassemia major is regular red blood cell (RBC) transfusion, coupled with iron chelation to prevent the complications of transfusion-induced iron overload. For patients with pediatric hematology-oncology diagnoses with chemotherapy-induced aplasia, RBC transfusion is also common, but the degree of transfusion-induced iron overload and its implications for these patients is incompletely understood. Because iron-related tissue toxicity is a major cause of morbidity and mortality in regularly transfused patients, developing strategies to minimize iron loading and iron toxicity is a key objective of this proposal (study Aim #2), stemming from the objective to optimize RBC unit characteristics that patients with SCD and thalassemia receive beyond RBC phenotype matching for Rh C, E and K antigens (study Aim #1). The study will enroll patients with SCD, thalassemia or pediatric oncologic diagnoses receiving eligible transfusion at 6 hospital sites in the United States, as well as patients with SCD at 5 hemocenters in Brazil.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Kathy Chapman, MT; Phone Number: 301-738-3697; Email: KathyChapman@westat.com
• Study Contact Backup: Name: Holly Sawyer, MPH; Phone Number: 254-630-5647; Email: HollySawyer@westat.com

Study Locations

• Brazil
  • Rio De Janeiro, Brazil, 20211-030
    • Recruiting
    • HEMORIO - Rio De Janeiro
    • Contact: Luiz Amorim, MD, PhD; Email: luizamorimfilho@gmail.com
  • São Paulo, Brazil, 05403-000
    • Recruiting
    • Childrens Institute and Adult Clinics at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
    • Contact: Carla Dinardo, MD, PhD; Email: caludinardo@gmail.com
    • Contact: Miriam Park, MD, PhD; Email: parkmiriam0@gmail.com
  • Amazonas
    • Manaus, Amazonas, Brazil, 69050-001
      • Recruiting
      • HEMOAM - Amazonas
      • Contact: Nelson A Fraiji, MD, PhD; Email: nfraiji@hemoam.am.gov.br
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30622-020
      • Recruiting
      • HEMOMINAS - Minas Gerais
      • Contact: André Belisário, PhD; Email: andrebelisario@yahoo.com.br
  • Pernambuco
    • Recife, Pernambuco, Brazil, 52011-000
      • Recruiting
      • HEMOPE - Pernambuco
      • Contact: Paulo Loureiro, MD, PhD; Email: paula.loureiro10@gmail.com
      • Contact: Dahra Teles, MD; Email: dahra.teles@gmail.com
• United States
  • California
    • Oakland, California, United States, 94609
      • Recruiting
      • UCSF Benioff Children's Hospital
      • Contact: Shannon Kelly, MD; Email: shannon.kelly@ucsf.edu
    • San Francisco, California, United States, 94118
      • Recruiting
      • Vitalant Research Institute
      • Contact: Brian Custer, PhD, MPH; Email: bcuster@vitalant.org
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: John Manis, MD; Email: john.manis@childrens.harvard.edu
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • Weill Cornell Medical Collection (WCMC)/New York Presbyterian Hospital (NYPH)
      • Contact: Melissa Cushing, MD; Email: mec2013@med.cornell.edu
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center/New York Presbyterian Hospital (NYPH)
      • Contact: Eldad A Hod, MD; Email: eh2217@cumc.columbia.edu
    • New York, New York, United States, 10065
      • Recruiting
      • New York Blood Center (NYBC)
      • Contact: Bruce Sachais, MD, PhD; Email: bsachais@nybc.org
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Children's Wisconsin
      • Contact: Brian Branchford, MD; Email: bbranchford@versiti.org
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Froedtert Hospital
      • Contact: Lisa Baumann Kreuziger, MD, MS; Email: lisakreuziger@versiti.org
    • Milwaukee, Wisconsin, United States, 53233
      • Recruiting
      • Versiti Wisconsin, Inc.
      • Contact: Alan Mast, MD, PhD; Email: aemast@versiti.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All transfused patients with sickle cell disease (in the U.S or Brazil) and thalassemia on simple chronic transfusion (or partial manual exchange transfusion) from hospitals affiliated with REDS-IV-P Domestic hubs or Brazil hemocenters. (Aim #1)

Chronically transfused patients with sickle cell disease or thalassemia, and patients with pediatric oncology diagnoses with hypo-proliferative bone marrow receiving care at hospitals affiliated with REDS-IV-P Domestic hubs or Brazil hemocenters (for SCD only). (Aim #2).

Description

Inclusion Criteria (Aim #1):

• Well-characterized transfusion-dependent form of SCD or thalassemia (including Hemoglobin E-thalassemia and sickle-beta thalassemia) on chronic simple transfusion therapy or partial manual exchange
• On a regular simple RBC transfusion schedule, including partial manual exchange (i.e., 1-3 units scheduled every 2-6 weeks and on a minimum 6-month chronic transfusion trial; for partial manual exchange, the phlebotomy must be completed before the transfusion is started without a back and forth between rounds of phlebotomy and transfusion)
• Seen at any participating domestic hub hospital (i.e., Columbia University Irving Medical Center/Morgan Stanley Children's Hospital of New York, Weill Cornell Medical Center/Komansky Children's Hospital, Boston Children's Hospital, Froedtert & Medical College of Wisconsin/Children's Wisconsin, University of California San Francisco, Benioff Children's Hospital Oakland) or enrolled in the Brazil REDS-IV-P sickle cell disease cohort and seen at any participating Brazil hemocenter (i.e., Childrens Institute and Adult Clinics at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP, HEMOAM - Amazonas, HEMOMINAS - Minas Gerais, HEMOPE -Pernambuco, and HEMORIO - Rio de Janeiro)

Exclusion Criteria (Aim #1):

• Institutionalization or imprisonment
• Foster care
• Weight <11 kg

Inclusion criteria (Aim #2):

• Either included in Aim #1 (consented patient with SCD or thalassemia) or patient with pediatric oncologic diagnosis under care in a pediatric hematology/oncology service with anemia due to chemotherapy or primary/secondary hypo-proliferative bone marrow requiring a RBC transfusion (including HSCT)
• [In domestic study only] Age ≤21 years old (many pediatric services include care of patients up to age 21, therefore the protocol will not limit by age but instead on whether they are seen in a pediatric service)
• Planned transfusion of RBC from an aliquot or unit from a single donor
• Seen at any participating domestic hub hospital (i.e., Columbia University Irving Medical Center/Morgan Stanley Children's Hospital of New York, Weill Cornell Medical Center/Komansky Children's Hospital, Boston Children's Hospital, Froedtert & Medical College of Wisconsin/Children's Wisconsin, University of California San Francisco, Benioff Children's Hospital Oakland) or at any REDS-IV-P participating Brazil hemocenter (i.e., Childrens Institute and Adult Clinics at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP, HEMOAM - Amazonas, HEMOMINAS - Minas Gerais, HEMOPE -Pernambuco, and HEMORIO - Rio de Janeiro).

Exclusion criteria (Aim #2):

• Institutionalization or imprisonment
• Foster care
• Current active auto-immune hemolytic anemia based on positive direct antiglobulin test (DAT) with laboratory evidence of hemolysis and increased transfusion requirement
• [In domestic study only] Microangiopathic hemolytic anemia
• Weight <18 kg

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sickle cell disease (SCD); Patients with SCD who are chronically transfused (in the U.S. and Brazil)	Biological: Red Blood Cell (RBC) Transfusion; Simple RBC transfusion or partial manual exchange
Thalassemia; Patients with thalassemia who are chronically transfused in the U.S.	Biological: Red Blood Cell (RBC) Transfusion; Simple RBC transfusion or partial manual exchange
Pediatric Hematology-Oncology; Patients in U.S. with pediatric oncologic diagnoses with hypo-proliferative bone marrow requiring single unit red blood cell transfusion	Biological: Red Blood Cell (RBC) Transfusion; Simple RBC transfusion or partial manual exchange
Blood Donors; Allogenic blood donors in the US (estimated: 10,200) and allogenic blood donors in Brazil (estimated: 2,100) with extended donation genotyping using an investigational hematology array.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hemoglobin A or Hemoglobin Level per day (RBC Survival)	Change in hemoglobin A or hemoglobin level per day in between subsequent transfusion episodes, for sickle cell disease and thalassemia cohorts, respectively	Baseline (immediately pre-) to post-transfusion over 2 years
Change in Serum Iron Level	For all groups participating, change in serum iron measured from immediately prior to 2 hours post-transfusion	Baseline (immediately before) and 2-hours after transfusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin Increment	Hemoglobin increment [defined as Hb/HbA(post-transfusion)visit(i) - Hb/HbA(pre-transfusion)visit(i)] is associated with "RBC survival"	Baseline (immediately pre-) to post-transfusion, over 2 years
Hemolysis Parameter Increment	Includes serum iron, indirect bilirubin, or plasma free hemoglobin	Baseline (immediately pre-) to post-transfusion or 2-hours post-transfusion, over 2 years
Hepcidin Level	Hepcidin level at time of transfusion is a predictor of change in iron parameters (i.e., transferrin saturation, serum iron) following transfusion	Baseline (immediately before) to 2 hours after transfusion
Non-Transferrin-Bound Iron (NTBI) Level	NTBI levels in patients with pediatric oncologic diagnoses with aplasia are elevated at baseline and increase following transfusion	Baseline (immediately before) to 2 hours after transfusion
Number of Clinical Complications	Increased NTBI, serum iron, or transferrin saturation following transfusion is associated with increased risk of clinical adverse effects (i.e., new infections, SCD complications)	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Alloimmunization	Rate of new alloantibody formation	2 years
4-hydroxynonenal [4-HNE]	Recipient oxidative stress pre-transfusion is associated with "RBC survival"	2 years
Type I interferon (i.e., MxA protein assay) and other cytokines (i.e., IL-6, MCP-1, IFNgamma)	Recipient inflammation pre-transfusion is associated with "RBC survival"	2 years
Number of Transfusion Reactions	Transfusion reactions are associated with "RBC survival"	2 years

Collaborators and Investigators

• Sponsor: Westat
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Eldad A Hod, MD, Columbia University; Principal Investigator: Brian Custer, PhD, MPH, Vitalant Research Institute

Publications and helpful links

Helpful Links

• REDS-IV-P public website

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2022
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: February 10, 2022
• First Submitted That Met QC Criteria: February 10, 2022
• First Posted (Actual): February 24, 2022

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 7, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Genetic; Pediatric; Observational; Oncology; Red Blood Cell; Thalassemia; Sickle Cell Disease; Transfusion; RBC survival; Non-genetic; Blood donor
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Thalassemia
• Other Study ID Numbers: 75N92019D00032; 75N92019D00033 (Other Grant/Funding Number: National Heart, Lung and Blood Institute); 75N92019D00034 (Other Grant/Funding Number: National Heart, Lung and Blood Institute); 75N92019D00035 (Other Grant/Funding Number: National Heart, Lung and Blood Institute); 75N92019D00036 (Other Grant/Funding Number: National Heart, Lung and Blood Institute); 75N92019D00037 (Other Grant/Funding Number: National Heart, Lung and Blood Institute); 75N92019D00038 (Other Grant/Funding Number: National Heart, Lung and Blood Institute)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified public use datasets will be created and delivered to NHLBI at the end of the study (and end of the REDS-IV-P program) and will be made available indefinitely for future analysis
• IPD Sharing Time Frame: At the end of the REDS-IV-P program, estimated in March 2026, the public use data sets will be available and will be available indefinitely for future analytic use.
• IPD Sharing Access Criteria: Public use datasets will be posted to NIH/NHLBI data repository systems.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No