Background: Sickle cell disease (SCD) is an inherited hemoglobin disorder. People with SCD have an increased chance for getting blood clots. Researchers want to see if a dietary supplement called isoquercetin can decrease levels of inflammation and blood clotting in people with SCD. Objective: To see how isoquercetin works in people with SCD. Eligibility: Adults age 18-70 years old who have SCD and are in a steady-state (have not experienced a pain crisis in the last 60 days and, if taking hydroxyurea, have not had a dose change in the past 90 days). Design: Participants will be screened with a physical exam, medical history, medicine review, and blood tests. Participants will be put in 1 of 2 treatment groups. They will take 4 capsules of isoquercetin or placebo all at once, by mouth, every day for 4 weeks. They will get a pill dispenser and keep a medicine diary. Participants may have an optional near infrared spectroscopy (NIRS) test to measure how treatment affects blood flow. In this test, probes will be placed on the skin to measure tissue oxygen level and blood flow. A blood pressure cuff placed on the arm will be filled with air briefly to restrict the blood flow in the arm (for up to 5 minutes) and then released. Participants may also be asked to breathe at a certain rate or hold their breath for as long as they can during measurements. Participants will take folic acid once a day. Participants will have an end-of-study drug visit. They will discuss any side effects and repeat some of the screening tests. They may have an additional optional NIRS test. About a month after the end of study drug visit, participants will be contacted by phone to see if they have any side effects. Those who do may have a follow-up visit. At this visit, they may have additional blood tests performed. Participation will last from 8 to 12 weeks.
Sickle Cell Disease (SCD) is an inherited monogenic hemoglobin disorder caused by a mutation in the gene encoding the beta globin subunit of adult hemoglobin (HbA) resulting in a substitution of valine for glutamic acid at position 6 and thus producing hemoglobin S (HbS). When deoxygenated, HbS polymerizes, rendering the red cell rigid, viscous, and abnormally adherent to the capillary endothelium. This impedes blood flow in the microcirculation, causing ischemia and microinfarcts that lead to painful crises, cerebrovascular stroke, renal impairment, venous blood clots, retinopathy and other end-organ damage. The current scientific literature recognizes the contribution of an acquired hypercoagulable state in SCD to vascular pathobiology, chronic organ dysfunction, and mortality. Like cancer, SCD is associated with a hypercoagulable state and patients have a high risk of new onset and recurrent venous thromboembolism (VTE). Elevated blood levels of the procoagulant protein tissue factor and its activator, protein disulfide isomerase (PDI) in patients with SCD suggest a causal role for these proteins in the development of venous blood clots. In cancer patients, inhibiting plasma PDI activity with isoquercetin (IQ) led to a significant reduction in VTE biomarkers (soluble P-selectin and D-dimer) and venous thrombosis over the short term. These findings provide support to test the hypothesis that isoquercetin treatment in sickle cell disease would diminish thrombo-inflammatory biomarkers and attenuate the hypercoagulable state.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
46
Isoquercetin (quercetin-3-O-beta-D-glucoside, also referred to as isoquercitrin) is a naturally occurring monoglucoside of the most studied and widely consumed bioflavonoid, quercetin. Isoquercetin given at 1000 mg, once daily by mouth for 28 days.
Silicified microcrystalline cellulose NF, Ascorbic acid, Nicotinic acid, Mg stearate, Silica and Colloidal Anhydrous Ph. Eur./Colloidal Silicon dioxide USP/NF. Placebo give at 1000 mg, once daily by mouth for 28 days.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Mean Change in the Plasma Soluble P-selectin Level
Mean change in plasma soluble P-selectin level comparing the baseline versus IQ or placebo.
Time frame: Baseline and Day 28
Mean Change in Plasma Protein Disulfide Isomerase Activity
Mean Change in Plasma Protein Disulfide Isomerase Activity comparing baseline and end of study
Time frame: Baseline and 28 days
Median Change of Tissue Factor Vesicle Number
Median change of Tissue Factor Vesicle Number comparing baseline and end of study
Time frame: Baseline and Day 28
Mean Change in Tissue Factor Vesicle Procoagulant Activity
Mean change in tissue factor vesicle procoagulant activity comparing baseline and end of study
Time frame: Baseline and Day 28
Mean Change in D-Dimer
Mean Change in D-Dimer comparing baseline and end of study
Time frame: Baseline and Day 28
Mean Change in Vascular Cell Adhesion Molecule
Mean Change in Vascular Cell Adhesion Molecule (inflammation marker) comparing baseline to Day 28
Time frame: Baseline and Day 28
Median Relative Blood Flow Index (rBFI) Determined by Near-infrared Spectroscopy (NIRS)
Median Relative Blood Flow Index (rBFI) determined by Near-infrared spectroscopy (NIRS). Near-infrared spectroscopy (NIRS) is a noninvasive technology that measures blood flow by directing near-infrared light into tissue, collects scattered light due to red blood cell movements using photodiodes, and calculates the blood flow index (BFI) using the correlation diffusion equation (CDE). Briefly, participants were seated upright and NIRS probe and a blood pressure cuff was placed on the right arm and resting baseline data was collected for three minutes followed by occlusion of the blood flow for three minutes and reperfusion recorded for three minutes. The post-occlusion hyperemic reperfusion response represented as the relative Blood Flow Index (rBFI) is determined by normalizing the maximal change in light absorption following occlusion (dBFI) by the corresponding time interval (dt); (rBFI = dBFI/dt; unit (cm\^2/s)/s)\].
Time frame: Day 28
Mean Percent Adherence to Study Drug
Mean percent adherence to study drug. Adherence was defined as number of study drug pills participant took divided by number of study drug pills dispensed multiplied by 100.
Time frame: Baseline and Day 28
Number of Adverse Events Grade 2 and Above
Number of adverse events Grade 2 and above using Common Terminology Criteria for Adverse Events (CTCAE) 5.0
Time frame: Up to Day 56
Number of Participants That Tolerated Study Drug
Number of participants that tolerated study drug for full duration of study
Time frame: Up to day 28
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