Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)

NCT ID: NCT04084080

Last Updated: 2025-04-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 173 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-26
• Study Completion Date: 2026-05-31

Brief Summary

The SCD-CARRE trial is a Phase 3, prospective, randomized, multicenter, controlled, parallel two-arm study aimed to determine if automated exchange blood transfusion and standard of care administered to high mortality risk adult SCD patients reduces the total number of episodes of clinical worsening of SCD requiring acute health care encounters (non-elective infusion center/ER/hospital visits) or resulting in death over 12 months as compared with standard of care.

Detailed Description

As patients with sickle cell disease (SCD) live to adulthood, the chronic impact of sustained hemolytic anemia and episodic vaso-occlusive events take their toll, with the progressive development of cardiopulmonary organ dysfunction. This culminates in the development of pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, chronic kidney disease and sudden death, all major cardiovascular complications of SCD for which there are no approved or consensus therapies. The risk of having pulmonary hypertension and diastolic heart disease can be non-invasively assessed by laboratory tests (NT-proBNP) and Doppler-echocardiography (estimated pulmonary artery systolic pressure). A recent meta-analysis of approximately 6000 patients with SCD demonstrated that patients with elevated tricuspid regurgitant jet velocity (TRV), which is an Doppler-echocardiographic measurement that estimates the pulmonary artery systolic pressure, walked an estimated 30.4 meters less in a 6 minute walk test than those without elevated TRV, and elevated TRV was associated with high mortality (hazard ratio of 4.9). In two large registry cohorts of adult patients with SCD, the investigators found that approximately 20% of the adult SCD population have high values for both biomarkers, defined as a TRV ≥ 2.5 meters per second AND a NT-proBNP ≥ 160 pg/mL, and that the 12-month mortality rate is 7.9% in this group as compared to 0.5% in patients with normal TRV or NT-proBNP values, with a risk ratio for hospitalization of 1.6. This suggests that a simple screening profile of TRV and NT-proBNP can identify about 20% of patients with SCD at the highest risk of death and hospitalization.

Given the increased mortality and early loss of functional capacity associated with cardiovascular disease in SCD adults, it is important to test effective therapeutic interventions in such patients. Red blood cell transfusions are administered by either simple or exchange transfusion, the latter removes the patients blood and replaces it with transfused red blood cells. Exchange transfusions have proven effective for acute treatment of almost all SCD complications, including severe acute chest syndrome, stroke, splenic or hepatic sequestration, and multi-organ failure, and are also used chronically for stroke prevention and recurrent acute chest syndrome. In this study the investigators hypothesize that monthly exchange transfusion will limit disease progression, improve exercise capacity, and prevent interval episodes of vaso-occlusive painful crisis and the acute chest syndrome that acutely increases pulmonary pressures and cause right heart failure.

The investigators propose to perform a clinical trial to evaluate the effects of automated exchange blood transfusion on patient morbidity and mortality, compared to standard of care among 150 adult high risk SCD patients. The trial will leverage existing coordinating center infrastructure at the University of Pittsburgh and will involve 22 experienced clinical sites. Despite the safety and wide utilization of erythrocytapheresis in adult patients with SCD, there is no consensus or quality efficacy data on its use to improve outcomes in our aging high-risk SCD patients with progressive end-organ dysfunction.

Conditions

Sickle Cell Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Exchange transfusion plus standard of care

Randomized to standard of care and automated exchange blood transfusion every 3-6 weeks for 12 months.

Group Type: EXPERIMENTAL

Red Blood Cell

Intervention Type: BIOLOGICAL

Red blood cell exchange transfusions will be performed every 3-6 weeks to maintain a target post-transfusion hemoglobin S level of \<20% and a pre-transfusion hemoglobin S of \<30%.

Standard of care

Intervention Type: OTHER

NHLBI/ASH/ATS Expert Panel recommended guidelines

Standard of care

Randomized to standard of care

Group Type: ACTIVE_COMPARATOR

Standard of care

Intervention Type: OTHER

NHLBI/ASH/ATS Expert Panel recommended guidelines

Interventions

Red Blood Cell

Red blood cell exchange transfusions will be performed every 3-6 weeks to maintain a target post-transfusion hemoglobin S level of \<20% and a pre-transfusion hemoglobin S of \<30%.

Intervention Type: BIOLOGICAL

Standard of care

NHLBI/ASH/ATS Expert Panel recommended guidelines

Intervention Type: OTHER

Other Intervention Names

Red blood cell (RBC)

Eligibility Criteria

Inclusion Criteria

• Age 18 years or older
• Diagnosis of SCD: homozygous sickle cell disease, hemoglobin-SC, Sβ-thalassemia, hemoglobin-SO or hemoglobin-SD.
• Patients not on a chronic exchange transfusion program for at least 60 days.
• If patients are on a SCD drug (e.g. hydroxyurea, glutamine, or P-selectin inhibitors), the doses must be stable for at least 60 days prior to randomization. At the time of randomization, participants must be off Oxbryta for at least 30 days.
• Any one of the following vasculopathy biomarker clinical results (a, b, c, d or e) measured in the last 24 months before randomization that indicates a high-risk patient:

1. Both a TRV 2.5- <3.0 m/sec and NT-proBNP plasma level ≥ 160 pg/mL,

2. TRV ≥ 3.0 m/sec,

3. Both a mean pulmonary artery pressure (PAP) by right heart catheterization 20-24 mmHg and NT-proBNP plasma level ≥ 160 pg/mL,

4. Mean PAP by right heart catheterization ≥ 25 mmHg,

5. Chronic kidney disease (CKD) due to SCD with abnormal measures on 2 separate occasions as defined by: macroalbuminuria (albumin to creatinine ratio (ACR) >300 mg/g) or proteinuria (protein to creatinine ratio >30 mg/mmol), or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. (It is recommended that local laboratories use Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation without ethnic factors when estimating and reporting GFR).

Clinical results of these biomarkers measured locally at sites within 24 months prior to randomization are acceptable to determine eligibility. TRV, PAP, NT-proBNP, albumin to creatinine ratio, protein to creatinine ratio, or eGFR values must be measured in a steady state (defined as measured ≥ 14 days since an acute care pain event) on different days.

vi. Written informed consent obtained from patient to participate in the trial.

Exclusion Criteria

• RBC alloimmunization resulting in inability of blood bank to obtain compatible components for chronic exchange transfusions
• Previous history of hyper-hemolysis syndrome
• Previous history of severe transfusion reaction resulting in renal failure or due to serious complications such as hypotension or respiratory distress
• More than 10 vaso-occlusive episodes in the past 12 months requiring admission to a hospital to receive treatment.
• Religious objection to receiving blood transfusion
• Diagnosis of ischemic stroke within the past 6 months
• Clinical evidence of liver failure or advanced cirrhosis or any co-existing medical condition that in the Investigator's judgement will substantially increase the risk associated with the patient's participation in the trial
• Women of childbearing potential who have a positive pregnancy test at baseline

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Pittsburgh

OTHER

Sponsor Role: lead

Responsible Party

Mark Gladwin

Vice President for Medical Affairs, University of Maryland and Dean, University of Maryland School of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mark Gladwin, MD

Role: STUDY_CHAIR

University of Maryland

Darrell Triulzi, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Maria Brooks, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

University of Alabama

Tuscaloosa, Alabama, United States

UCSF Benioff Children's Hospital Oakland

Oakland, California, United States

Howard University Center for Sickle Cell Disease

Washington D.C., District of Columbia, United States

Emory University

Atlanta, Georgia, United States

University of Illinois at Chicago

Chicago, Illinois, United States

University of Maryland

Baltimore, Maryland, United States

Johns Hopkins University

Baltimore, Maryland, United States

Boston Medical Center

Boston, Massachusetts, United States

Washington University-St. Louis

St Louis, Missouri, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Montefiore Medical Center

New York, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Atrium Health

Charlotte, North Carolina, United States

Duke University

Durham, North Carolina, United States

East Carolina University

Greenville, North Carolina, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

University of Texas Health Science Center at Houston

Houston, Texas, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Hemorio

Rio de Janeiro, , Brazil

Kremlin-Bicêtre

Créteil, , France

Henri Mondor Hopital

Paris, , France

Countries

United States; Brazil; France

References

Abbasi M, Srivastava A, Saraf SL. Management of Kidney Disease with Sickle Cell Disease. J Am Soc Nephrol. 2025 Oct 1;36(10):2041-2054. doi: 10.1681/ASN.0000000804. Epub 2025 Jun 26.

Reference Type: DERIVED

PMID: 40569673 (View on PubMed)

Other Identifiers

UG3HL143192

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY20110362

Identifier Type: -

Identifier Source: org_study_id