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Age of Blood in Sickle Cell Transfusion

Primary Purpose

Sickle Cell Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Transfusion
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring Transfusion

Eligibility Criteria

16 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • age 16 to 60 years
  • Hemoglobin SS/Hemoglobin Sβ-thalassemia^0
  • on chronic red cell transfusion therapy
  • outpatient at the time of transfusion

Exclusion criteria:

  • history of reactions to transfusion therapy that cannot be adequately managed by antihistamines
  • ≥ 2 red cell alloantibodies
  • participation in another therapeutic trial for SCD
  • pregnant
  • HIV positive
  • uncontrolled inter-current illness, or psychiatric illness/social situations that would limit compliance with study requirements.

Sites / Locations

  • Emory UniversityRecruiting
  • University of North Carolina at Chapel HillRecruiting
  • Versiti Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

≤10 day Blood

≥30 day Blood

Arm Description

Subjects in this group will receive only blood stored ≤10 days for 3 consecutive transfusion events.

Subjects in this group will receive only blood stored ≥30 days for 3 consecutive transfusion events.

Outcomes

Primary Outcome Measures

Proportion of biochemically old red cell units
The investigators will compare the transfusions provided to the two groups (the proportion of biochemically old units when stored ≥30 days compared to when stored ≤10 days) using a Fisher exact test at an alpha of 0.05. Power: With a total sample size of 40 patients (20 in each group), the investigators will have at least 80% power (α=0.05) to detect a difference of at least 47% between the two randomized groups for biochemically old red cell units (close to a 100% difference is expected). The investigators will compare the secondary endpoints plasma free hemoglobin, heme, and NTBI and also PS, PE, and microparticle concentrations using a two sided two sample t-test at an alpha of 0.05.

Secondary Outcome Measures

Full Information

First Posted
October 5, 2018
Last Updated
April 17, 2023
Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT03704922
Brief Title
Age of Blood in Sickle Cell Transfusion
Official Title
Age of Blood in Sickle Cell Transfusion -The Effects of Phosphotidylserine Expression on Older Red Cell Units in Adults With Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 4, 2017 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
March 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The Investigators hypothesize that older red cell units trigger phagocytosis and activation of circulating macrophages with a downstream immunomodulatory cascade and release of excess Non Transferrin Bound Iron(NTBI) that leads to increased rates of infection in adults with Sickle Cell Disease(SCD). To test this hypothesis, the study staff will perform a randomized prospective clinical trial. In aim 1, the study staff will determine the biochemical differences between ≥30 day-old versus ≤10 day-old units. In aim 2, the study staff will determine the physiologic effects of the transfused blood in a patient with SCD. Lastly, in aim 3, the study staff will explore the clinical implications of receiving older red cells over a 3 month period.
Detailed Description
The Investigators assembled a multidisciplinary investigative team to examine the potential effects of older red cell units in adults with Sickle Cell Disease(SCD). Study staff have preliminary data that show: 1) there is equipoise among blood bank directors about the effects of older units in adults with SCD, 2) in our institution, many adults are administered older units, 3) older units activate macrophages and 4) this physiology promoted by older units is associated with an increased risk of infection. Our team is now poised to take the next investigative step: a prospective, randomized study. In Milwaukee, 1/3 of units transfused to adults with SCD are >30 days old, but nation-wide some restrict the transfusion of older units. About four hundred adults receive care in the Adult Sickle Cell Clinic at Froedtert Hospital in Milwaukee, about 23 of who receive chronic outpatient transfusions for chronic pain or stroke prophylaxis. Transfusions are administered to adults regardless of storage age, except in the case of red cell exchange, for which there is a policy to use less than 14 day old units. In a 3-year retrospective review of transfusions administered to adults with SCD, 627 units were given via simple transfusion over 281 outpatient encounters. The overall median unit storage age was 22 days (range: 2-42 days), and 25% of the units transfused were stored 33 days or longer. To determine the opinions and policies of other hospital blood bank directors about the use of older red cell units for patients with SCD, study staff conducted a nation-wide survey (n=90). While only 23% of respondents had a storage age restriction policy for patients with SCD, 31% thought that older units were not as effective as younger units, and 65% believed that evidence-based policies were needed Adults with SCD may be susceptible to the effects of an older unit's physiology because they are prone to infection, inflamed, and poorly equipped to handle excess iron. In a cohort of 40 steady-state adults with SCD, the investigators specifically measured markers of inflammation and iron excess. High sensitivity C-reactive protein, a marker of systemic inflammation, was found to be markedly elevated (median 5.6 mg/L, range 0.4-60 mg/L; reference range <1.0 mg/L), as was ferritin, a marker of iron stores (median 2,969 ng/ml, range 20-12,300 ng/ml; reference range 13-400 ng/ml). Forty chronically-transfused adults with SCD will be randomized in a double-blind fashion to receive ≥30 day-old or ≤10 day-old units for, at most, 3 consecutive outpatient transfusions. Subjects will be randomized in blocks of 5 and stratified by age: at least 10 subjects from each of the age ranges 16-30 and 31-60 years will be enrolled. Pre-transfusion, sterile samples will be extracted from red cell units. Patient peripheral blood will be also obtained 1 month before randomization, immediately pre-transfusion, and 2 and 24 hours post-transfusion. Hemoglobin will be measured pre-transfusion, 2 and 24 hours post-transfusion, and 2 weeks post transfusion. Participants will complete standardized diaries daily to document symptoms of infection, SCD pain, medications and Emergency Department(ED) or hospital use. Diaries will be collected and participants will be assessed with each transfusion encounter and 4 weeks after the last transfusion. To ensure compliance, coordinators will contact subjects weekly to complete the diaries. Study staff will evaluate red cells pre- and post-transfusion for Phosphatidylserine(PE), Phosphatidylethanolamine (PS), and microparticles as above for all blood samples. White cells will be isolated with established separation techniques. The white cell populations of interest will be defined by their location on a forward scatter/side scatter plot and their positivity using key fluorochrome-labeled identity markers (macrophages: CD14, neutrophils: CD16). Once the cell populations of interest are identified, the cells will be evaluated for various markers of activation. The plasma fraction from each patient and red cell unit will be diverted to determine concentrations of free heme/hemoglobin, cytokines, and NTBI, respectively.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
Transfusion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
≤10 day Blood
Arm Type
Experimental
Arm Description
Subjects in this group will receive only blood stored ≤10 days for 3 consecutive transfusion events.
Arm Title
≥30 day Blood
Arm Type
Experimental
Arm Description
Subjects in this group will receive only blood stored ≥30 days for 3 consecutive transfusion events.
Intervention Type
Biological
Intervention Name(s)
Transfusion
Intervention Description
Red cell units for transfusion
Primary Outcome Measure Information:
Title
Proportion of biochemically old red cell units
Description
The investigators will compare the transfusions provided to the two groups (the proportion of biochemically old units when stored ≥30 days compared to when stored ≤10 days) using a Fisher exact test at an alpha of 0.05. Power: With a total sample size of 40 patients (20 in each group), the investigators will have at least 80% power (α=0.05) to detect a difference of at least 47% between the two randomized groups for biochemically old red cell units (close to a 100% difference is expected). The investigators will compare the secondary endpoints plasma free hemoglobin, heme, and NTBI and also PS, PE, and microparticle concentrations using a two sided two sample t-test at an alpha of 0.05.
Time Frame
through third transfusion, an average of 18 weeks
Other Pre-specified Outcome Measures:
Title
Change in the concentration of CD62L positive circulating monocytes
Description
Change in CD62Lcirculating monocyte/macrophage MFI at 2 hours post-transfusion compared to the subject pre-transfusion. The investigators will compare the two groups using a two sample two-sided t-test of the log at an alpha of 0.05. Power: In addition, we will use a general(ized) linear model to include biochemically old units transfused, regardless of unit age, as a covariate in our analysis. Other co-variates will include free heme, cell free hemoglobin, and NTBI from the transfused unit. We will similarly compare secondary activation endpoints: activation markers for neutrophils and measured cytokine concentrations. Lastly, as an exploratory aim, we will evaluate the in vivo change in recipient red cell PE/PS positivity at 2 and 24 hours post transfusion. When possible, donor and recipient red cells will be differentiated in S-antigen negative patients who are by chance provided S-positive heterozygous or homozygous donor red cells.
Time Frame
through third transfusion, an average of 18 weeks
Title
Percentage of infections in adults
Description
The primary endpoint is the percentage of infections in adults who receive ≥30 day-old units as compared to ≤10 day-old units. The presence of an indwelling catheter will be used as a key co-variate in this analysis. The investigators will further explore the relationship of blood age and transfusion of biochemically old red cell units on the change in Hb and HbS% over time, daily pain scores, opioid use and dose, ED and hospitalization rate, infection symptoms, new alloantibody formation, and antibiotic use during the 3-month study period. The investigators will compare groups using a Fisher exact test. Power: A difference of 20% will be of clinical interest. The investigators do not expect to have adequate power for this pilot study but at an alpha of 0.05 with 20 subjects in each group the investigators will be able to detect a difference of 47% between the proportions.
Time Frame
through fourth transfusion, an average of 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: age 16 to 60 years have diagnosis of sickle cell disease receiving outpatient red cell transfusion therapy outpatient at the time of transfusion Exclusion criteria: history of reactions to transfusion therapy that cannot be adequately managed by antihistamines do not have crossmatch compatible red cells participation in another therapeutic trial for SCD pregnant HIV positive uncontrolled inter-current illness, or psychiatric illness/social situations that would limit compliance with study requirements.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Matthew Karafin, MD
Phone
414-937-6809
Email
MKarafin@Versiti.org
First Name & Middle Initial & Last Name or Official Title & Degree
David Wichlan
Phone
919-966-6876
Email
david_wichlan@med.unc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jane Little, MD
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Matthew Karafin, MD, MS
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hailly Butler, RN
Phone
404-712-8895
Email
hailly.butler@emory.edu
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Wichlan
Phone
919-966-6876
Email
david_wichlan@med.unc.edu
Facility Name
Versiti Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Individual Site Status
Completed

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
IPD Sharing Time Frame
beginning 9 to 36 months following publication
IPD Sharing Access Criteria
IRB, IEC, or REB approval and an executed data use/sharing agreement with UNC.

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Age of Blood in Sickle Cell Transfusion

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