STUDY TITLE: Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)
CLINICAL TRIALS.GOV IDENTIFIER: NCT04084080
PARTICIPATING CENTERS: 22 sites across the United States and France
ACCRUAL GOAL: Approximately 150 participants
STUDY DESIGN: SCD-CARRE is a multicenter, prospective, randomized phase III clinical trial comparing standard-of-care treatment for sickle cell disease (SCD) with automated red blood cell (RBC) exchange transfusion in patients at high risk for mortality. Eligibility criteria include a diagnosis of SCD (HbSS, HbSC, HbSβ-thalassemia, HbSO, or HbSD genotypes), stable doses of SCD therapy for at least two months prior to randomization, age of at least 18 years, no participation in a chronic exchange transfusion program in the two months prior to enrollment, and “steady state” readings indicating at least one of the following abnormalities in vasculopathy biomarkers in the 24 months prior to randomization: elevated tricuspid regurgitation velocity (TRV), elevated mean pulmonary artery pressure (PAP), chronic kidney disease (CKD). CKD is defined based on evidence of macroalbuminuria, proteinuria, or an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2. Patients with elevated NT-proBNP accompanied by modest elevation of mean PAP or TRV will also be considered eligible. Exclusion criteria include recent stroke, inability to receive transfusions (history of alloimmunization, religious objection, history of hyper-hemolysis syndrome), or frequent episodes of pain necessitating hospitalization.
Participants will be randomized to receive either standard-of-care treatment according to expert SCD guidelines or standard-of-care treatment plus RBC exchange transfusions every three to six weeks, with target pre- and post-transfusion hemoglobin S levels of <30% and <20%, respectively. The primary endpoint, examined over a 13-month period, will compare episodes characterized by “clinical worsening” of SCD requiring acute health care encounters (visits to infusion centers/emergency departments/hospitals) or resulting in death between the two arms. Numerous secondary endpoints, including functional measures such as six-minute walk distance and exercise capacity; biomarkers such as TRV, eGFR, NT-proBNP, and nocturnal desaturation; and SCD-specific, patient-reported outcomes such as pain and quality-of-life will be compared at four, eight, and 12 months. The study began on February 26, 2020, and has an anticipated completion date of December 31, 2025.
RATIONALE: Although the majority of individuals living with SCD in high-income countries now survive to the fifth decade of life and beyond, the cumulative toll of chronic vaso-occlusive episodes, anemia, and hemolysis is considerable, often resulting in progressive end-organ damage and failure.1,2 There is a pressing need for evidence-based approaches to caring for these individuals at high risk for morbidity and mortality. Manifestations in these high-risk cases often involve cardiovascular complications including pulmonary hypertension, left ventricular dysfunction, restrictive lung disease, and renal disease.2 Studies conducted over the past two decades have established that elevated TRV (≥2.5 m/s),3–5 elevated NT-proBNP (>160 pg/mL),4,6,7 and declining renal function8,9 are potent risk factors for morbidity and mortality in adults living with SCD. However, evidence supporting optimal management strategies for SCD and end-organ-directed therapy for individuals at the highest risk for mortality remains limited.
RBC transfusions are used for acute management of SCD complications, including acute chest syndrome, stroke, splenic sequestration, and multi-organ failure.10 Transfusions also represent an established treatment for the secondary prevention of acute chest syndrome, preoperative management, pregnancy, and stroke.10 Apart from those focused on secondary stroke prevention, no randomized trials have directly investigated the utility of transfusion therapy for SCD among individuals at the highest risk for morbidity and mortality. SCD-CARRE represents the first such trial to compare standard-of-care treatment (primarily hydroxyurea and supportive care) with additional chronic exchange transfusion therapy.
COMMENT: Due to the paucity of high-quality evidence, practice patterns for high-risk SCD are highly variable. In my practice, exchange transfusion is regarded as the best option for individuals carrying the highest risk of mortality, despite the risks of iron overload, alloimmunization, infection, and a potentially negative impact on quality-of-life. Evidence supporting the effectiveness of transfusions in addressing chronic SCD complications such as pain remains mixed, despite studies supporting their effectiveness in secondary stroke prevention. While transfusions have been shown to reduce healthcare utilization,10,11 they do not appear to reduce opioid use or mitigate the impact of pain.11,12 This clinical equipoise underscores the need for the ambitious SCD-CARRE trial, which will enhance our understanding of the utility and risks of chronic transfusions and provide much needed evidence related to the optimal management of SCD in individuals with the highest risk for mortality.
The University of North Carolina is a participating institution of SCD-CARRE under site investigator Dr. Jane Little. Dr. Wilson is not affiliated with the trial and indicated no relevant conflicts of interest.