Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease
Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease
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 may have a peripheral arterial tonometry (Endo-Pat) test to check the function
 of their blood vessels. For this, a thimble-shaped cup is placed on their finger and a blood
 pressure cuff is placed on their arm.

 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 will take folic acid once a day.

 Participants will have an end-of-study visit. They will discuss any side effects and repeat
 some of the screening tests. They may have an Endo-Pat test.

 About a month after the last study 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 blood tests.

 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, retinopathy and other end-organ damage. The current scientific literature
 currently recognizes the contribution of an acquired hypercoagulable state in SCD to vascular
 pathobiology, chronic organ dysfunction, and mortality.

 Similar to cancer, sickle cell disease is associated with an acquired hypercoagulable state
 and exhibits a high prevalence of incident and recurrent venous thromboembolism (VTE).
 Elevated levels of the procoagulant protein tissue factor and its activator, protein
 disulfide isomerase in humans with SCD suggest a causal role for thrombogenesis. In cancer
 patients, pharmacological inhibition of plasma PDI with Isoquercetin (IQ) led to a reduction
 in VTE biomarkers and VTE recurrence. These findings provide support to test the hypothesis
 that Isoquercetin in sickle cell disease would diminish thrombo-inflammatory VTE biomarkers
 and attenuate the associated hypercoagulable state.
-  INCLUSION CRITERIA:

 For enrollment onto the active phase of the study (IQ supplement vs placebo), subjects must
 meet all of the following criteria during the screening period (visit #1) which can last
 from 0-28 days prior to start of study intervention:

 -  Unequivocal diagnosis of sickle cell anemia (Hemoglobin SS or Hemoglobin SC or Beta
 Thalassemia Major or Beta Thalassemia Minor) confirmed by hemoglobin electrophoresis
 performed on patients at least 90 days after a blood transfusion if previously
 transfused, or DNA genotyping.

 -  Age 18-70 years old

 -  Steady state SCD (no acute vaso-occlusive crisis within 60 days of D0 of the study)
 and if on HU therapy, on a stable dose for at least 90 days.

 -  Steady state SCD patient with a previous history of VTE, and/or those receiving
 anticoagulant/antiplatelet therapy are eligible, so long as the VTE occurred >90 days
 prior to D0 of the study.

 -  Be willing to comply with all study procedures for the duration of the study.

 -  Have provided signed written informed consent prior to performing any study procedure,
 including screening procedures.

 EXCLUSION CRITERIA:

 Subjects who meet any of the following criteria during screening will not receive the study
 intervention and will be counted toward study accrual. Screen failures will not be included
 in the analysis for statistical purposes:

 -  Severe SCD defined as frequent (>6/year) or severe (requiring hospitalization >14
 days) vaso-occlusive crisis.

 -  SCD with a recent VOC (<60 days from D0 of study).

 -  SCD with history of recent blood transfusion (<60 days from D0 of study) or exchange
 transfusion (<90 days from D0 of study).

 -  SCD with a recent VTE (within 90 days of diagnosis of either DVT, PE or both).

 -  Any patient receiving crizanlizumab therapy for SCD or that has received crizanlizumab
 within the past 30 days of D0 of study.

 -  Have a significant medical condition that confers an unacceptable risk to
 participating in the study, and/or that could confound the interpretation of the study
 data. Such significant medical conditions include, but are not limited to the
 following:

 1. History of recent (within 3 months prior to signing informed consent) congestive
 heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic,
 embolic, or thrombotic stroke.

 2. Active infection requiring the use of parenteral antimicrobial agents or Grade
 greater than or equal to 3 in severity (per National Cancer Institute Common
 Terminology Criteria for Adverse Events v5.0) within 2 months prior to the first
 dose of study drug.

 3. Active viral infection as evidenced by testing positive for hepatitis B surface
 antigen or hepatitis C virus (HCV) antibody (Ab) with signs of active hepatitis B
 or C virus infection. If the subject is positive for HCV Ab, a reverse
 transcriptase-polymerase chain reaction test will be conducted. Subjects with
 hepatitis C may be rescreened after receiving appropriate hepatitis C treatment.

 4. Testing positive for human immunodeficiency virus (HIV) 1 or 2 Ab with evidence
 for ongoing active infection (i.e., CD4 count <400/microL and viral load >100,000
 copies/mL) on antiretroviral therapy.

 5. Active acute inflammatory disorders rheumatoid arthritis or systemic lupus
 erythematosus on disease modifying therapy.

 6. Diabetes mellitus judged to be under poor control by the Investigator evidenced
 by a single fasting sugar value >250 gm/dl or requiring >3 antidiabetic agents,
 including insulin (all insulins are considered 1 agent); use of insulin per se is
 not exclusionary.

 7. History of any primary malignancy, with the exception of curatively treated
 nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in
 situ; or other primary tumor treated with curative intent, no known active
 disease present, and no treatment administered during the last 3 years.

 8. Any injury or medical condition that, in the judgement of the Investigator would
 prevent the subject from participating

 in the study.

 -  Have a prior bone marrow or stem cell transplant.

 INCLUSION OF VULNNERABLE PARTICIPANTS:

 Vulnerable subjects will not be included in this study.